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Clinical Trial Results:
A phase 3, double-blind, randomized, placebo-controlled, multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with severe COVID-19 pneumonia.

Summary
EudraCT number	2020-005919-51
Trial protocol	IT
Global end of trial date	21 Sep 2021

Results information
Results version number	v1(current)
This version publication date	31 Dec 2022
First version publication date	31 Dec 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

REP0220

ISRCTN number

US NCT number

NCT04878055

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, Clinical Trial Transparency Manager, +39 02583831, clinops@pec.dompe.com

Scientific contact

Clinical Trial Transparency Manager, Clinical Trial Transparency Manager, +39 02583831, clinops@pec.dompe.com

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

20 Jan 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

21 Sep 2021

Global end of trial reached?

Yes

Global end of trial date

21 Sep 2021

Was the trial ended prematurely?

Main objective of the trial

The objective of this study was to assess the efficacy and safety of Reparixin treatment as compared to placebo (both on top of standard treatment) in adult patients with severe Coronavirus disease 2019 (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

All patients received the standard supportive care, based on the patient’s clinical need. It could eventually include anticoagulants, corticosteroids, antibiotics, among others, as per local standard therapy and in line with international guidelines. Optimal oxygenation could be considered a SpO2 between 92% and 96%; however, no specific oxygen target was required by the protocol.

Evidence for comparator

Please note that 287 patients were enrolled in the study, but 270 are the subjects in the FAS (8 enrolled and not randomized, 9 randomized but not treated). Results are reported for the FAS population, except where otherwise specified.

Actual start date of recruitment

14 Feb 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 270

Worldwide total number of subjects

270

EEA total number of subjects

270

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)

170

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

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

Screening details

Patients were included in the study after a variable period at home with initial symptoms of the COVID-19 infection. In case of worsening of general and pulmonary condition, the patient started the screening phase for the confirmation of the selection criteria.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Blinding implementation details

The realization of the double-blind design was made possible by the production of placebo tablets that were identical in appearance to the active formulation.

Are arms mutually exclusive

Yes

Reparixin (randomised and treated)

Arm description

Reparixin oral tablets, 1200 mg TID (2 tablets 600 mg each, TID) for up to 21 days or until the decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.

Arm type

Experimental

Investigational medicinal product name

Reparixin

Investigational medicinal product code

Other name

REP

Pharmaceutical forms

Buccal tablet

Routes of administration

Buccal use, Oral use

Dosage and administration details

Reparixin oral tablets, 1200 mg TID (2 tablets 600 mg each) for a total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing.

Placebo (randomised and treated)

Arm description

Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Buccal tablet

Routes of administration

Buccal use

Dosage and administration details

2 tablets TID (2 tablets 600 mg each, TID) for a total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing.

Number of subjects in period 1	Reparixin (randomised and treated)	Placebo (randomised and treated)
Started	182	88
Completed	147	70
Not completed	35	18
Adverse event, serious fatal	11	7
Consent withdrawn by subject	7	3
Physician decision	1	1
unknown	5	-
Patient transferred in another department	-	2
Adverse event, non-fatal	1	-
Lost to follow-up	10	1
Day 60 visit not performed by mistake	-	4

Baseline characteristics

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Reporting group title

Reparixin (randomised and treated)

Reporting group description

Reporting group title

Placebo (randomised and treated)

Reporting group description

Reporting group values	Reparixin (randomised and treated)	Placebo (randomised and treated)	Total
Number of subjects	182	88	270
Age categorical
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)	112	58	170
From 65-84 years	67	28	95
85 years and over	3	2	5
Age continuous
Units: years
arithmetic mean (standard deviation)	61.3 ( 11.8 )	60.0 ( 12.0 )	-
Gender categorical
Units: Subjects
Female	50	25	75
Male	132	63	195

Subject analysis set title

Reparixin FAS

Subject analysis set type

Full analysis

Subject analysis set description

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

Subject analysis set title

Placebo FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis sets values	Reparixin FAS	Placebo FAS
Number of subjects	182	88
Age categorical
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)	112	58
From 65-84 years	66	28
85 years and over	4	2
Age continuous
Units: years
arithmetic mean (standard deviation)	61.3 ( 11.8 )	60.0 ( 12.0 )
Gender categorical
Units: Subjects
Female	50	25
Male	132	63

End points

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Reporting group title

Reparixin (randomised and treated)

Reporting group description

Reporting group title

Placebo (randomised and treated)

Reporting group description

Subject analysis set title

Reparixin FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Placebo FAS

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Proportion of patients alive and free of respiratory failure at Day 28

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End point title

Proportion of patients alive and free of respiratory failure at Day 28

End point description

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

End point type

Primary

End point timeframe

At day 28 (+/-2)

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182	88
Units: Patients	152	71

Reparixin FAS vs Placebo FAS

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.216

Method

Two-sided regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.626

Confidence interval

level

95%

sides

2-sided

lower limit

0.752

upper limit

3.514

Notes
[1] - Analysis is based on logistic regression model with Multiple Imputation under missing not at random using retrieve dropouts with proportion of patients alive and free of respiratory failure at Day 28 as dependent variable, treatment, age group, gender and presence of concomitant disease at baseline as qualitative independent variables. Site is considered as random effects that vary randomly among patients.

Secondary: Proportion of patients alive and free of respiratory failure at Day 60

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End point title

Proportion of patients alive and free of respiratory failure at Day 60

End point description

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

End point type

Secondary

End point timeframe

At day 60

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	159	78
Units: Patients	141	66

Reparixin FAS vs placebo FAS

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

237

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.377 ^[2]

Method

Chi-squared

Confidence interval

Notes
[2] - Comparison between treatment arms is performed by means of a Chi-squared test

Secondary: Mortality rates up to Day 28

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End point title

Mortality rates up to Day 28

End point description

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

End point type

Secondary

End point timeframe

Up to day 28

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	168	81
Units: Patients	10	7

Reparixin FAS vs placebo FAS

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

249

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.17

Method

Two-sided regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.468

Confidence interval

level

95%

sides

2-sided

lower limit

0.158

upper limit

1.386

Notes
[3] - Analysis is based on logistic regression model with proportion of patients died up to Day 28 as dependent variable, treatment, age group, gender and presence of concomitant disease at baseline as qualitative independent variables. Site is considered as random effects that vary randomly among patients.

Secondary: Incidence of ICU admission until Day 28

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End point title

Incidence of ICU admission until Day 28

End point description

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

End point type

Secondary

End point timeframe

up to day 28

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	171	83
Units: Patients	27	18

Reparixin FAS vs placebo FAS

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.168

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.561

Confidence interval

level

95%

sides

2-sided

lower limit

0.247

upper limit

1.277

Secondary: Time to recovery until Day 28

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End point title

Time to recovery until Day 28

End point description

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

End point type

Secondary

End point timeframe

At day 28

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182	88
Units: Cumulative number of patients with event	141	63

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 28

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.167

Method

Gray's Test

Confidence interval

Notes
[4] - Estimates are calculated using a nonparametric method for cumulative incidence function with competing risks data. the cumulative incidence function was 81.6% (95% CI, 74.8 to 86.7%) in the REP group and 74.9% (95% CI, 64.0 to 83.0%) in the Placebo. Null hypothesis: the cumulative incidence functions are identical across treatment groups and estimates are calculated taking into account the following competing risks: Death, discontinuation for AEs and patient transferred to another institution.

Secondary: Proportion of patients alive and free of respiratory failure at fixed timepoints

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End point title

Proportion of patients alive and free of respiratory failure at fixed timepoints

End point description

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

End point type

Secondary

End point timeframe

At days 3, 7 (± 1), 14 (± 2), 21 (± 2), 28 (± 2), 60 (±2) and 90 (±2) after randomization (randomization = day 1);

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[5]	88 ^[6]
Units: Patients
Day 3	179	87
Day 7 (+/-1)	171	79
Day 14 (+/-2)	160	73
Day 21 (+/-2)	155	71
Day 28 (+/-2)	152	71
Day 60 (+/-2)	141	66
Day 90	15	5

Notes
[5] - Day 3: n=180 Day 7: n=179 Day 14: n=173 Day 21: n=172 Day 28: n=170 Day 60: n=159 D90: n=33
[6] - Day 7: n=87 Day 14: n=83 Day 21: n=83 Day 28: n=83 Day 60: n=78 Day 90: n=17

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 3 - please note that the number of subjects is 268 (180+88) and not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.55 ^[7]

Method

Fisher exact

Confidence interval

Notes
[7] - Comparison between treatment arms is performed by means of a Fisher’s Exact test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 7 - Please note that the total of subjects in this analysis is not 270 but 266 (n=179 in the Reparixin group and n=87 in the placebo group).

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.128 ^[8]

Method

Chi-squared

Confidence interval

Notes
[8] - Comparison between treatment arms is performed by means of a Chi-squared mean.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 14 - Please note that the total of subjects in this analysis is not 270 but 256 (n=173 in the Reparixin group and n=83 in the placebo group).

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.235 ^[9]

Method

Chi-squared

Confidence interval

Notes
[9] - Comparison between treatment arms is performed by means of a Chi-squared test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 21 - Please note that the total of subjects in this analysis is not 270 but 255 (n=172 in the Reparixin group and n=83 in the placebo group).

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.281 ^[10]

Method

Chi-squared

Confidence interval

Notes
[10] - Comparison between treatment arms is performed by means of a Chi-squared test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 28 - Please note that the total of subjects in this analysis is not 270 but 253 (n=170 in the Reparixin group and n=83 in the placebo group).

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.371 ^[11]

Method

Chi-squared

Confidence interval

Notes
[11] - Comparison between treatment arms is performed by means of a Chi-squared test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 60 - Please note that the total of subjects in this analysis is not 270 but 237 (n=159 in the Reparixin group and n=78 in the placebo group.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.377 ^[12]

Method

Chi-squared

Confidence interval

Notes
[12] - Comparison between treatment arms is performed by means of a Chi-squared test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 90 - Please note that the total of subjects in this analysis is not 270 but 50 (n=33 in the Reparixin group and n=17 in the placebo group).

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.273 ^[13]

Method

Chi-squared

Confidence interval

Notes
[13] - Comparison between treatment arms is performed by means of a Chi-squared test.

Secondary: Mean changes from baseline in clinical severity score based on the 7-point WHO-OS at fixed timepoints

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End point title

Mean changes from baseline in clinical severity score based on the 7-point WHO-OS at fixed timepoints

End point description

Changes from baseline in clinical severity score are analyzed based on the 7-point WHO-OS. The 7-point WHO Ordinal Scale of clinical improvement (WHO-OS), comprises the following categories: 1: not hospitalized, with resumption of normal activities; 2: not hospitalized, but unable to resume normal activities; 3: hospitalized, not requiring supplemental oxygen; 4: hospitalized, requiring supplemental oxygen; 5: hospitalized, requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6: hospitalized, requiring ECMO, invasive mechanical ventilation, or both; 7: death.

End point type

Secondary

End point timeframe

At days 3, 7, 14, 21, 28 and EoT; days 60 and 90; at hospital discharge (HD), and at the EoS.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[14]	88 ^[15]
Units: score on a scale
arithmetic mean (standard deviation)
Day 3	-0.1 ( 0.4 )	0.0 ( 0.5 )
Day 7	-0.4 ( 1.0 )	-0.3 ( 0.9 )
Day 14	-1.7 ( 1.5 )	-1.5 ( 1.6 )
Day 21	-2.4 ( 1.5 )	-2.3 ( 1.6 )
Day 28	-2.8 ( 1.4 )	-2.6 ( 1.5 )
EoT	-0.9 ( 1.0 )	-0.7 ( 1.1 )
Day 60	-3.4 ( 0.6 )	-3.2 ( 0.9 )
Day 90	-3.4 ( 0.6 )	-3.5 ( 0.6 )
Hospital discharge	-1.6 ( 0.9 )	-1.6 ( 0.8 )
EoS	-3.0 ( 1.5 )	-2.6 ( 1.8 )

Notes
[14] - D3:n=171 D7:n=166 D14:n=142 D21:n=121 EoT:n=164 D28:n=131 HD: n=134 D60:136 D90:14 EoS:154
[15] - D3:n=84 D7:n=80 D14:n=67 D21:n=55 EoT:n=77 D28:n=59 HD=n=61 D60:n=65 D90:n=4 EOS:n=75

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 3 - Please note that the number of subjects in this analysis is not 270 but 255

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047 ^[16]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[16] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 7 - Please note that the number of subjects in this analysis is not 270 but 246

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.262 ^[17]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[17] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 14 - Please note that the number of subjects in this analysis is not 270 but 209

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.367 ^[18]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[18] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 21 - Please note that the number of subjects in this analysis is not 270 but 176

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.882 ^[19]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[19] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 28 - Please note that the number of subjects in this analysis is not 270 but 190

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.19 ^[20]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[20] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 60 - Please note that the number of subjects in this analysis is not 270 but 201

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.161 ^[21]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[21] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 90 - Please note that the number of subjects in this analysis is not 270 but 18

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.853 ^[22]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[22] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At EOS - Please note that the number of subjects in this analysis is not 270 but 229

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.068 ^[23]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[23] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At hospital discharge (HD) - Please note that the number of subjects in this analysis is not 270 but 195

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.672 ^[24]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[24] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Reparixin FAS vs placebo FAS

Statistical analysis description

At end of treatment (EoT) - Please note that the number of subjects in this analysis is not 270 but 241

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.153 ^[25]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[25] - Comparison between treatment arms is performed by means of two-sample Mann-Whitney U test.

Secondary: Time to clinical improvement 1 up to Day 28

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End point title

Time to clinical improvement 1 up to Day 28

End point description

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

End point type

Secondary

End point timeframe

Day 1 (baseline), Days 3, 7, 14, 21, EoT, 28, HD.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182	88
Units: number of patients with event
Day 1	0	0
Day3	19	6
Day 7	56	22
Day 14	123	50
Day 21	146	66
Day 28	152	68

Reparixin FAS vs placebo FAS

Statistical analysis description

At day 28

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.07

Method

Gray's Test

Confidence interval

Notes
[26] - Estimates are calculated using a nonparametric method for cumulative incidence function with competing risks data. The null hypothesis is that the cumulative incidence functions are identical across treatment groups and estimates are calculated taking into consideration the following competing risks: Death, reasons for discontinuation for Adverse events and patient transferred to another institution.

Secondary: Time to clinical improvement 2 up to Day 28

Top of page

End point title

Time to clinical improvement 2 up to Day 28

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182	88
Units: number of patients with event
Day 1	0	0
Day 3	0	0
Day 7	19	6
Day 14	78	35
Day 21	105	50
Day 28	120	56

Reparixin FAS vs placebo FAS

Statistical analysis description

At day 28

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.668

Method

Gray's Test

Confidence interval

Notes
[27] - Estimates are calculated using a nonparametric method for cumulative incidence function with competing risks data. The null hypothesis is that the cumulative incidence functions are identical across treatment groups and estimates are calculated taking into consideration the following competing risks: Reasons for discontinuation for Adverse events and patient transferred to another institution.

Secondary: Time to discharge from hospital up to Day 28

Top of page

End point title

Time to discharge from hospital up to Day 28

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182	88
Units: number of patients with event
Day 1	0	0
Day 3	2	0
Day 7	19	10
Day 14	100	40
Day 21	127	58
Day 28	143	64

Reparixin FAS vs placebo FAS

Statistical analysis description

At Day 28

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.23

Method

Gray's Test

Confidence interval

Notes
[28] - Estimates are calculated using a nonparametric method for cumulative incidence function with competing risks data. The null hypothesis is that the cumulative incidence functions are identical across treatment groups and estimates are calculated taking into consideration the following competing risks: Reasons for discontinuation for Adverse events and patient transferred to another institution.

Secondary: Clinical status at fixed time points either in hospital or at home (7-point WHO-OS)

Top of page

End point title

Clinical status at fixed time points either in hospital or at home (7-point WHO-OS)

End point description

Clinical status is analyzed based on the 7-point WHO-OS. The 7-point WHO Ordinal Scale of clinical improvement (WHO-OS), comprises the following categories: 1: not hospitalized, with resumption of normal activities; 2: not hospitalized, but unable to resume normal activities; 3: hospitalized, not requiring supplemental oxygen; 4: hospitalized, requiring supplemental oxygen; 5: hospitalized, requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6: hospitalized, requiring ECMO, invasive mechanical ventilation, or both; 7: death.

End point type

Secondary

End point timeframe

Days 3, 7(+/-1), 14(+/-2), 21(+/-2), 28(+/-2), 60 (+/-2), 90 (+/- 7), EOS. Hospital discharge and End of Treatment (EoT) data are attached.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[29]	88 ^[30]
Units: number of patients with event
day 3 score 1	0	0
day 3 score 2	0	0
day 3 score 3	5	1
day 3 score 4	85	40
day 3 score 5	81	42
day 3 score 6	0	0
day 3 score 7	0	1
day 7 score 1	7	2
day 7 score 2	1	0
day 7 score 3	31	16
day 7 score 4	66	27
day 7 score 5	54	30
day 7 score 6	6	5
day 7 score 7	1	0
day 14 score 1	52	24
day 14 score 2	10	3
day 14 score 3	28	12
day 14 score 4	29	13
day 14 score 5	17	10
day 14 score 6	4	4
day 14 score 7	2	1
day 21 score 1	74	36
day 21 score 2	8	2
day 21 score 3	13	5
day 21 score 4	14	5
day 21 score 5	6	5
day 21 score 6	5	0
day 21 score 7	1	2
day 28 score 1	100	40
day 28 score 2	8	8
day 28 score 3	7	1
day 28 score 4	8	5
day 28 score 5	2	2
day 28 score 6	4	2
day 28 score 7	2	1
Day 60 score 1	125	56
Day 60 score 2	9	6
Day 60 score 3	1	0
Day 60 score 4	0	1
Day 60 score 5	1	2
Day 60 score 6	0	0
Day 60 score 7	0	0
Day 90 score 1	14	4
Day 90 score 2	0	0
Day 90 score 3	0	0
Day 90 score 4	0	0
Day 90 score 5	0	0
Day 90 score 6	0	0
Day 90 score 7	0	0
EOS score 1	132	57
EOS score 2	7	6
EOS score 3	1	0
EOS score 4	2	1
EOS score 5	3	4
EOS score 6	1	2
EOS score 7	8	5

Attachments

Hospital discharge and EoT data

Notes
[29] - D3:n=171 D7: n=166 D14:n=142 D21:n=121 D28:131 EoT:164 HD:134 D60:136 D90:n=14 EOS:n=154
[30] - D3: n=84 D7: n=80 D14:n=67 D21:n=55 D28:n=59 HD:n=61 EoT:n=77 D60:n=65 D90:n=4 EoS:n=75

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 3 - please note that the number of subjects in this analysis is not 270 but 255

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.444

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 7 - please note that the number of subjects in this analysis is not 270 but 246

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.357

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 14 - please note that the number of subjects in this analysis is not 270 but 209

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.484

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 21 - please note that the number of subjects in this analysis is not 270 but 176

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.753

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 28 - please note that the number of subjects in this analysis is not 270 but 190

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.26

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 60 - please note that the number of subjects in this analysis is not 270 but 201

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.19

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 90 - please note that the number of subjects in this analysis is not 270 but 18

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

EOS - please note that the number of subjects in this analysis is not 270 but 229

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.074

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

EOT - please note that the number of subjects in this analysis is not 270 but 241

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.193

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

Hospital discharge - please note that the number of subjects in this analysis is not 270 but 195

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.131

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Dyspnea severity (Likert scale) at fixed timepoints

Top of page

End point title

Dyspnea severity (Likert scale) at fixed timepoints

End point description

The number of patients with Dyspnea severity Likert scale by score and treatment group is calculated for each time point. Likert scale: grading the current experience of breathing discomfort compared to baseline (randomization) status (from -3 to 3). -1 = minimally worse, -2 = moderately worse, -3 = markedly worse 0 = no change, 1 = minimally better, 2 = moderately better, 3 = markedly better, . Please note for the EoS timepoint, the statistical comparison IMP vs placebo was not reported because the p value is not available and the system doesn't permit to enter "NA" expression.

End point type

Secondary

End point timeframe

Days 3, 7(+/-1), 14(+/-2), 21(+/-2), 28(+/-2), EOS, 60(+/-2). EoT and hospital discharge data are attached.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[31]	88 ^[32]
Units: Number of patient with event
day 3 score -3	1	0
day 3 score -2	1	3
day 3 score -1	5	1
day 3 score 0	22	10
day 3 score 1	37	18
day 3 score 2	26	17
day 3 score 3	11	3
day 7 score -3	1	0
day 7 score -2	0	1
day 7 score -1	0	1
day 7 score 0	9	6
day 7 score 1	19	8
day 7 score 2	31	13
day 7 score 3	36	18
day 14 score -3	0	0
day 14 score -2	2	0
day 14 score -1	0	0
day 14 score 0	9	1
day 14 score 1	6	6
day 14 score 2	18	7
day 14 score 3	41	25
day 21 score -3	1	0
day 21 score -2	0	0
day 21 score -1	0	0
day 21 score 0	6	3
day 21 score 1	9	2
day 21 score 2	9	7
day 21 score 3	35	20
day 28 score -3	0	0
day 28 score -2	0	0
day 28 score -1	0	0
day 28 score 0	9	3
day 28 score 1	7	3
day 28 score 2	9	7
day 28 score 3	48	20
EOS score -3	0	0
EOS score -2	0	0
EOS score -1	0	0
EOS score 0	1	0
EOS score 1	1	0
EOS score 2	0	0
EOS score 3	0	0

Attachments

HD & EoT dyspnea severity (likert scale)

Notes
[31] - D3: n= 103 D7: n= 96 D14: n= 76 D21: n=60 28: n= 73 EoT: n=77 HD: n=38 EOS: n= 2
[32] - Day3: n=52 D7: n=47 D14: n=39 D21: n=32 D28: n=33 EoT: n=38 HD:n=27 EOS:N=0

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 3 - Please note that the number of subjects in this analysis is not 270 but 155.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.997

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 7 - Please note that the number of subjects in this analysis is not 270 but 143.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.712

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 14 - Please note that the number of subjects in this analysis is not 270 but 115.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.241

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 21 - Please note that the number of subjects in this analysis is not 270 but 92.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.528

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 28 - Please note that the number of subjects in this analysis is not 270 but 106.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.814

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at EOT - Please note that the number of subjects in this analysis is not 270 but 115.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.242

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at hospital discharge (HD) - Please note that the number of subjects in this analysis is not 270 but 65.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.722

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Change from baseline in dyspnea severity (VAS scale) at fixed timepoints

Top of page

End point title

Change from baseline in dyspnea severity (VAS scale) at fixed timepoints

End point description

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

End point type

Secondary

End point timeframe

Days 3, 7(+/-1), 14(+/-2), 21(+/-2), 28(+/-2). EoT and hospital discharge data are attached.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[33]	88 ^[34]
Units: score on a scale
arithmetic mean (standard deviation)
day 3	6.4 ( 25.3 )	2.2 ( 20.6 )
day 7 (+/-1)	8.3 ( 31.1 )	-0.2 ( 31.1 )
day 14(+/-2)	12.7 ( 38.5 )	6.6 ( 37.4 )
day 21 (+/-2)	16.0 ( 39.5 )	32.5 ( 14.3 )
day 28 (+/-2)	31.1 ( 20.3 )	40.7 ( 8.3 )

Attachments

HD & EoT dyspnea VAS scale

Notes
[33] - Day3: n=105 Day7: n=93 Day14:n=46 Day21:n=15 Day28:n=14 EOS:n=2 EoT: n=77 HD: n=38
[34] - Day3: n=52 Day7: n=46 Day14:n=27 Day21:n=8 Day28:n=3 EoT: n=36 HD: n=20

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 3 - Please note that the number of subjects in this analysis is not 270, but it is 157

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.399

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 7 - Please note that the number of subjects in this analysis is not 270, but it is 139

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.07

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 14 - Please note that the number of subjects in this analysis is not 270, but it is 73

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 21 - Please note that the number of subjects in this analysis is not 270, but it is 23

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.517

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 28 - Please note that the number of subjects in this analysis is not 270, but it is 17

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.445

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at EoT - Please note that the number of subjects in this analysis is not 270, but it is 113

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.324

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at Hospital discharge - Please note that the number of subjects in this analysis is not 270, but it is 67.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.752

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Duration of supplemental oxygen treatment up to Day 28

Top of page

End point title

Duration of supplemental oxygen treatment up to Day 28

End point description

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

End point type

Secondary

End point timeframe

From baseline up to day 28

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[35]	88 ^[36]
Units: day
arithmetic mean (standard deviation)	10.5 ( 7.3 )	10.8 ( 6.8 )

Notes
[35] - The n. of patients using supplemental oxygen was 174
[36] - The n. of patients using supplemental oxygen was 81

Reparixin FAS vs Placebo FAS

Statistical analysis description

Please note that the number of patients in this analysis is not 270 but 255, because patients who used supplement oxygen were 174 in the Reparixin group and 81 in the placebo group.

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.447

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Number of patients requiring invasive mechanical ventilation use, or ECMO up to Day 28 and up to day 60

Top of page

End point title

Number of patients requiring invasive mechanical ventilation use, or ECMO up to Day 28 and up to day 60

End point description

End point type

Secondary

End point timeframe

Up to day 28 and Day 60

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[37]	88 ^[38]
Units: Number of patient with event
Up to day 28	9	10
Up to day 60	9	10

Notes
[37] - at day 28 n=163 at day 60 n= 150
[38] - at day 28 n=82 at day 60 n= 77

Reparixin FAS vs Placebo FAS

Statistical analysis description

At day 28 - Please note that the number of patients in this analysis is not 270 but 245, because patients requiring IMV or ECMO were 163 in the Reparixin group and 82 in the placebo group.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.065 ^[39]

Method

Chi-squared

Confidence interval

Notes
[39] - Comparison between treatment arms is performed by means of a Chi-squared test

Reparixin FAS vs Placebo FAS

Statistical analysis description

At day 60 - Please note that the number of patients in this analysis is not 270 but 18, because patients who required IMV or ECMO were 9 in the Reparixin group and 9 in the placebo group.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.072 ^[40]

Method

Chi-squared

Confidence interval

Notes
[40] - Comparison between treatment arms is performed by means of a Chi-squared test

Secondary: Duration of non-invasive mechanical ventilation up to Day 60

Top of page

End point title

Duration of non-invasive mechanical ventilation up to Day 60

End point description

Non-invasive ventilation (NIV) is the delivery of oxygen (ventilation support) via a face mask and therefore eliminating the need of an endotracheal airway. NIV achieves comparative physiological benefits to conventional mechanical ventilation by reducing the work of breathing and improving gas exchange. This endpoint is expressed as: -Number of patients with ICU admission up to Day 60 (n=66 in Reparixin and n= 32 in the placebo group), or -Duration of ICU admission in days up to Day 60. This latter is reported in the system.

End point type

Secondary

End point timeframe

Up to day 60

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	66	32
Units: day
arithmetic mean (standard deviation)	9.0 ( 7.9 )	10.1 ( 11.0 )

Reparixin FAS vs Placebo FAS

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.485

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Duration of invasive mechanical ventilation, or ECMO up to Day 60

Top of page

End point title

Duration of invasive mechanical ventilation, or ECMO up to Day 60

End point description

Invasive mechanical ventilation is defined as the delivery of positive pressure to the lungs via an endotracheal or tracheostomy tube. During mechanical ventilation, a predetermined mixture of air (ie, oxygen and other gases) is forced into the central airways and then flows into the alveoli. This endpoint is expressed as: -Number of patients with ICU admission up to Day 60 (n=9 in both arms), or -Duration of ICU admission in days up to Day 60. This latter is reported in the system.

End point type

Secondary

End point timeframe

Up to day 60

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	8	9
Units: days
arithmetic mean (standard deviation)	24.8 ( 16.8 )	15.9 ( 13.9 )

Reparixin FAS vs Placebo FAS

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.267

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Duration of ICU admission up to Day 60

Top of page

End point title

Duration of ICU admission up to Day 60

End point description

Admission to intensive care unit or ICU is linked to worsening of respiratory parameters compared to baseline. This endpoint is expressed as: -Number of patients with ICU admission up to Day 60 (n=12 in both arms), or -Duration of ICU admission in days up to Day 60. This latter is reported in he system.

End point type

Secondary

End point timeframe

Up to day 60

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	11	8
Units: day
arithmetic mean (standard deviation)	17.9 ( 10.1 )	11.4 ( 6.7 )

Reparixin FAS vs Placebo FAS

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.137

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Change from baseline to fixed timepoints of partial pressure of oxygen (PaO2)

Top of page

End point title

Change from baseline to fixed timepoints of partial pressure of oxygen (PaO2)

End point description

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

End point type

Secondary

End point timeframe

at days 3, 7, 14, 21, 28, 60, HD, EoT, and EOS. Data on timepoints hospital discharge (HD) and end of treatment (EoT) are attached.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[41]	88 ^[42]
Units: mmHg
arithmetic mean (standard deviation)
day 3	13.377 ( 36.568 )	-5.274 ( 41.103 )
day 7	3.147 ( 33.541 )	12.777 ( 81.367 )
day 14	4.002 ( 54.235 )	-7.257 ( 50.645 )
day 21	3.388 ( 43.520 )	-14.014 ( 54.603 )
day 28	-6.700 ( 31.896 )	-52.171 ( 76.278 )
EOS	1.825 ( 20.570 )	51.950 ( 215.446 )
day 60	1 ( 73.000 )	0 ( 0 )

Attachments

Pao2 HD and EoT

Notes
[41] - D3:n=111 D7:n=99 D14:n=48 D21:n=24 EoT:n=87 D28:n=16 HD:n=48 D60:n=1 EoS:n=4
[42] - D3:n=57 D7:n=47 D14:n=28 D21:n=14 EoT:n=44 D28:n=7 HD:n=26 D60:n=0 EoS:n=4

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 3 - Please note that the number of subjects in this analysis is 168

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 7 - Please note that the number of subjects in this analysis is not 168, but it is 146

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.943

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 14 - Please note that the number of subjects in this analysis is not 168, but it is 76

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.88

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 21 - Please note that the number of subjects in this analysis is not 168, but it is 38

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.458

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 28 - Please note that the number of subjects in this analysis is not 168, but it is 23.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.285

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at EOS - Please note that the number of subjects in this analysis is not 168, but it is 8

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.885

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at HD - Please note that the number of subjects in this analysis is not 270, but it is 74

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.583

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at End of treatment - Please note that the number of subjects in this analysis is not 270, but it is 131.

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Change from baseline to fixed timepoints in Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2)

Top of page

End point title

Change from baseline to fixed timepoints in Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2)

End point description

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

End point type

Secondary

End point timeframe

At days 3(± 1), 7 (± 1), 14 (± 2), 21 (± 2), 28 (± 2), 60(± 2), EoT, HD, EOS. Data on HD and EoT are attached.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[43]	88 ^[44]
Units: Percentage
arithmetic mean (standard deviation)
day 3	0.79 ( 2.88 )	0.36 ( 2.78 )
day 7	0.76 ( 2.89 )	0.49 ( 3.38 )
day 14	0.46 ( 2.93 )	-0.83 ( 3.99 )
day 21	-0.85 ( 4.92 )	-5.35 ( 11.82 )
day 28	-0.99 ( 6.15 )	-1.56 ( 6.78 )
EOS	-7.57 ( 11.12 )	-11.01 ( 18.49 )
day 60	-2.70 ( 000 )	-2.00 ( 0.00 )

Attachments

Untitled (Filename: SpO2.pdf)

Notes
[43] - Day 3: n=166 Day 7: n=151 Day 14: n=75 Day 21: n=35 Day 28: n=22 EOS: n=7 Day 60: n=1
[44] - Day 3: n=80 Day 7: n=74 Day 14: n=43 Day 21: n=19 Day 28: n=10 EOS: n=7 Day 60: n=2

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 3 - Please note that the number of subjects in this analysis is not 270, but it is 246.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.053

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 7 - Please note that the number of subjects in this analysis is not 270, but it is 225.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.245

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 14 - Please note that the number of subjects in this analysis is not 270, but it is 118.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.067

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 21 - Please note that the number of subjects in this analysis is not 270, but it is 54.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.051

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at day 28 - Please note that the number of subjects in this analysis is not 270, but it is 32.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.684

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at EOS - Please note that the number of subjects in this analysis is not 246, but it is 14.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

at Day 60 - Please note that the number of subjects in this analysis is not 246, but it is 3.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.48

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Change from baseline to fixed timepoints in PaO2/FiO2 ratio

Top of page

End point title

Change from baseline to fixed timepoints in PaO2/FiO2 ratio

End point description

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

End point type

Secondary

End point timeframe

At days 3(± 1), 7 (± 1), 14 (± 2), 21 (± 2), 28 (± 2), 60(± 2), EOS. Data on HD and EoT are attached.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[45]	88 ^[46]
Units: mmHg
arithmetic mean (standard deviation)
day 3	30.329 ( 81.291 )	0.398 ( 87.607 )
day 7	77.528 ( 106.383 )	65.291 ( 138.832 )
day 14	127.111 ( 135.063 )	111.220 ( 171.013 )
day 21	122.746 ( 114.603 )	62.520 ( 163.712 )
day 28	145.043 ( 146.515 )	-22.125 ( 123.435 )
EOS	-5.333 ( 89.844 )	-30.714 ( 191.669 )
day 60	200.000 ( 000 )	334.000 ( 53.740 )

Attachments

Untitled (Filename: PaO2:FiO2.pdf)

Notes
[45] - Day3:n=163 Day7:n=148 Day14:n=74 Day21:n=31 Day28:n=21 Day60:n=1 HD:n=96 EoT:n=140 EOS:n=6
[46] - Day 3:n=82 D7:n=73 D14:n=43 D21:n=20 D28:n=8 HD:n=48 EoT:n=66 EOS:n=7 D60:n=2

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 3 - Please note that the number of subjects in this analysis is 245

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 7 - Please note that the number of subjects in this analysis is not 270, but it is 221

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.283

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 14 - Please note that the number of subjects in this analysis is not 245, but it is 117

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.512

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 21 - Please note that the number of subjects in this analysis is not 245, but it is 51

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.174

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 28 - Please note that the number of subjects in this analysis is not 245, but it is 206

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

EOS - Please note that the number of subjects in this analysis is not 245, but it is 13

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.224

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 60 - Please note that the number of subjects in this analysis is not 270, but it is 3.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.54

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Change from baseline to fixed endpoints in High-Sensitivity C Reactive Protein (hs-CRP)

Top of page

End point title

Change from baseline to fixed endpoints in High-Sensitivity C Reactive Protein (hs-CRP)

End point description

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

End point type

Secondary

End point timeframe

At days 3(± 1), 7 (± 1), 14 (± 2), 21 (± 2), 28 (± 2), HD, EoT and EoS. Data on HD and EoT are attached.

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[47]	88 ^[48]
Units: mg/L
arithmetic mean (standard deviation)
day 3	-30.07 ( 23.13 )	-21.67 ( 53.33 )
day 7	-25.90 ( 95.74 )	-29.62 ( 37.85 )
day 14	-25.21 ( 66.53 )	-45.24 ( 62.83 )
day 21	-27.50 ( 72.23 )	-47.05 ( 99.48 )
day 28	-42.60 ( 30.15 )	9.65 ( 26.94 )

Attachments

Untitled (Filename: protein CRP.pdf)

Notes
[47] - Day3:n=9 Day7:n=8 Day14:n=8 Day21:n=5 Day28:n=4 HD:n=5 EoT:n=7 EOS:n=0
[48] - Day3:n=6 Day7:n=5 Day14:n=5 Day21:n=4 Day28:n=2 HD:n=3 EoT:n=6 EOS:n=1

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 3 - Please note that the number of subjects in this analysis is 15, not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.68

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 7 - Please note that the number of subjects in this analysis is 13, not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.272

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 14 - Please note that the number of subjects in this analysis is 13, not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 21 - Please note that the number of subjects in this analysis is 9, not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.903

Method

two-sample Mann-Whitney U test

Confidence interval

Reparixin FAS vs Placebo FAS

Statistical analysis description

day 28 - Please note that the number of subjects in this analysis is 6, not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.105

Method

two-sample Mann-Whitney U test

Confidence interval

Secondary: Mortality rates up to Day 60 and Day 90

Top of page

End point title

Mortality rates up to Day 60 and Day 90

End point description

Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. The death event variable is defined as the proportion of patients died up to Day 60 and Day 90.

End point type

Secondary

End point timeframe

up to day 60 (+/-2), up to day 90

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182 ^[49]	88 ^[50]
Units: Patients died
up to day 60	11	7
up to day 90	11	7

Notes
[49] - Day 60: n=156 Day 90: n=27
[50] - Day 60: n=76 Day 90: n=12

Reparixin FAS vs Placebo FAS

Statistical analysis description

up to day 60 - Please note that the number of subjects in this analysis is 232, not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.232 ^[51]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.178

upper limit

1.522

Notes
[51] - Analysis is based on logistic regression model with proportion of patients died up to Day 60 as dependent variable, treatment, age group, gender and presence of concomitant disease at baseline as qualitative independent variables. Site is considered

Reparixin FAS vs Placebo FAS

Statistical analysis description

up to day 90 - Please note that the number of subjects in this analysis is 39, not 270.

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.158 ^[52]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.246

Confidence interval

level

95%

sides

2-sided

lower limit

0.034

upper limit

1.782

Notes
[52] - Analysis is based on logistic regression model with proportion of patients died up to Day 90 as dependent variable, treatment, age group, gender and presence of concomitant disease at baseline as qualitative independent variables. Site is considered

Secondary: Freedom from (time to) death or respiratory failure up to Day 90

Top of page

End point title

Freedom from (time to) death or respiratory failure up to Day 90

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	182	88
Units: number of patient with event
day 1	0	0
day 3	2	1
day 7	4	2
day 14	9	5
day 21	11	5
day 28	16	6
day 60	103	49
day 90	154	72

Reparixin FAS vs Placebo FAS

Statistical analysis description

Up to day 90 -

Comparison groups

Placebo FAS v Reparixin FAS

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

= 0.33607

Method

Logrank

Confidence interval

Notes
[53] - Freedom from (time to) death or respiratory failure (need of invasive mechanical ventilation or ECMO or admission to ICU linked to worsening of respiratory parameters compared to baseline) up to Day 90 was performed using the same Kaplan-Meier analysis and the one-sided log-rank test that were used to test for differences between groups

Secondary: Time to clinical improvement 1 up to Day 28 (cumulative incidence function)

Top of page

End point title

Time to clinical improvement 1 up to Day 28 (cumulative incidence function)

End point description

Estimates are calculated using a nonparametric method for cumulative incidence function with competing risks data.

End point type

Secondary

End point timeframe

At day 28

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	15	10
Units: percent
number (confidence interval 95%)	87.2 (81.2 to 91.4)	81.1 (70.6 to 88.2)

Reparixin vs placebo

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.07

Method

Gray's test

Confidence interval

Secondary: Time to clinical improvement 2 up to Day 28 (cumulative incidence function)

Top of page

End point title

Time to clinical improvement 2 up to Day 28 (cumulative incidence function)

End point description

Estimates are calculated using a nonparametric method for cumulative incidence function with competing risks data.

End point type

Secondary

End point timeframe

At Day 28

End point values	Reparixin FAS	Placebo FAS
Number of subjects analysed	39	20
Units: percent
number (confidence interval 95%)	69.9 (62.3 to 76.2)	67.7 (56.3 to 76.7)

Reparixin vs placebo

Comparison groups

Reparixin FAS v Placebo FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.668

Method

Gray's test

Confidence interval

Other pre-specified: Number of subjects who exhibited at least 1 TEAE, at least 1 severe TEAE, at least 1 serious TEAE, at least 1 non-serious TEAE, at least 1 ADR, at least 1 serious ADR, at least 1 TEAE leading to discontinuation of IMP, etc

Top of page

End point title

Number of subjects who exhibited at least 1 TEAE, at least 1 severe TEAE, at least 1 serious TEAE, at least 1 non-serious TEAE, at least 1 ADR, at least 1 serious ADR, at least 1 TEAE leading to discontinuation of IMP, etc

End point description

AE= An adverse event is any untoward or unfavorable medical occurrence in a human. subject, including any abnormal sign (for example, abnormal physical exam or. laboratory finding), symptom, or disease, temporally associated with the subject's. serious AE=a SAE iA serious adverse event (SAE) in human drug trials is defined as any untoward medical occurrence that at any dose results in death Is life-threatening Requires inpatient hospitalization or causes prolongation of existing hospitalization Results in persistent or significant disability/incapacity May have caused a congenital anomaly/birth defect Requires intervention to prevent permanent impairment or damage. The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. Do note that starting from this point the safety endpoint is analysed.

End point type

Other pre-specified

End point timeframe

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

End point values	Reparixin (randomised and treated)	Placebo (randomised and treated)
Number of subjects analysed	182	88
Units: number of subjects
Number of Subjects with at least one TEAE	83	48
Number of Subjects with at least one serious TEAE	20	13
Number of Subjects with at least one severe TEAE	16	12
N. sub with at least 1TEAE leading to quit IMP	19	11
N. sub with at least 1TEAE leading to quit the stu	1	0
Number of Subjects with TEAEs leading to death	10	7

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From Baseline up to day 90 of the trial (=the end of the follow-up period).

Adverse event reporting additional description

In the system AEs are reported for the overall period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Reparixin SAF

Reporting group description

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

Reporting group title

Placebo SAF

Reporting group description

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

Serious adverse events	Reparixin SAF	Placebo SAF
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 182 (10.99%)	13 / 88 (14.77%)
number of deaths (all causes)	11	7
number of deaths resulting from adverse events	10	7
Vascular disorders
Circulatory collapse
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Thrombosis
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	11 / 182 (6.04%)	7 / 88 (7.95%)
occurrences causally related to treatment / all	0 / 11	0 / 7
deaths causally related to treatment / all	0 / 8	0 / 4
Acute respiratory failure
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary embolism
subjects affected / exposed	0 / 182 (0.00%)	2 / 88 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Psychotic disorder
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	2 / 182 (1.10%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Clostridium difficile infection
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0.5%

Non-serious adverse events	Reparixin SAF	Placebo SAF
Total subjects affected by non serious adverse events
subjects affected / exposed	75 / 182 (41.21%)	42 / 88 (47.73%)
Vascular disorders
Hypertension
subjects affected / exposed	2 / 182 (1.10%)	2 / 88 (2.27%)
occurrences all number	2	2
Hypotension
subjects affected / exposed	2 / 182 (1.10%)	1 / 88 (1.14%)
occurrences all number	2	1
Poor venous access
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Thrombophlebitis
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Surgical and medical procedures
Tracheostomy
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	1
General disorders and administration site conditions
Illness
subjects affected / exposed	3 / 182 (1.65%)	1 / 88 (1.14%)
occurrences all number	4	1
Oedema peripheral
subjects affected / exposed	0 / 182 (0.00%)	3 / 88 (3.41%)
occurrences all number	0	4
Pyrexia
subjects affected / exposed	3 / 182 (1.65%)	0 / 88 (0.00%)
occurrences all number	3	0
Asthenia
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Extravasation
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Pain
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Metrorrhagia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 182 (0.55%)	2 / 88 (2.27%)
occurrences all number	1	2
Pulmonary embolism
subjects affected / exposed	2 / 182 (1.10%)	1 / 88 (1.14%)
occurrences all number	2	1
Epistaxis
subjects affected / exposed	2 / 182 (1.10%)	2 / 88 (2.27%)
occurrences all number	3	2
Dyspnoea
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Productive cough
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Tachypnoea
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	6 / 182 (3.30%)	4 / 88 (4.55%)
occurrences all number	7	4
Anxiety
subjects affected / exposed	5 / 182 (2.75%)	4 / 88 (4.55%)
occurrences all number	5	4
Agitation
subjects affected / exposed	3 / 182 (1.65%)	1 / 88 (1.14%)
occurrences all number	3	1
Mood altered
subjects affected / exposed	3 / 182 (1.65%)	0 / 88 (0.00%)
occurrences all number	5	0
Delirium
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Confusional state
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Depression
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Hallucination
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Panic attack
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Persistent depressive disorder
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 182 (0.55%)	2 / 88 (2.27%)
occurrences all number	1	2
Transaminases increased
subjects affected / exposed	2 / 182 (1.10%)	1 / 88 (1.14%)
occurrences all number	2	1
Blood culture positive
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Platelet count increased
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Culture urine positive
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Vitamin D decreased
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	4 / 182 (2.20%)	3 / 88 (3.41%)
occurrences all number	5	3
Atrial fibrillation
subjects affected / exposed	4 / 182 (2.20%)	1 / 88 (1.14%)
occurrences all number	4	1
Bradycardia
subjects affected / exposed	3 / 182 (1.65%)	0 / 88 (0.00%)
occurrences all number	3	0
Left ventricular failure
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Sinus tachycardia
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Supraventricular tachycardia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 182 (0.55%)	2 / 88 (2.27%)
occurrences all number	5	2
Dizziness
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Paraesthesia
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Disturbance in attention
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Memory impairment
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Psychomotor hyperactivity
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Syncope
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	3	0
Thrombocytopenia
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Iron deficiency anaemia
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Leukopenia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	2	0
Neutrophilia
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Pancytopenia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Eye disorders
Visual impairment
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	13 / 182 (7.14%)	10 / 88 (11.36%)
occurrences all number	14	10
Abdominal pain upper
subjects affected / exposed	2 / 182 (1.10%)	1 / 88 (1.14%)
occurrences all number	2	1
Diarrhoea
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Dysphagia
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Vomiting
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Diverticulum intestinal haemorrhagic
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	3 / 182 (1.65%)	2 / 88 (2.27%)
occurrences all number	3	2
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Decubitus ulcer
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Hyperhidrosis
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Rash macular
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Skin lesion
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Oliguria
subjects affected / exposed	3 / 182 (1.65%)	2 / 88 (2.27%)
occurrences all number	3	2
Acute kidney injury
subjects affected / exposed	2 / 182 (1.10%)	1 / 88 (1.14%)
occurrences all number	2	1
Endocrine disorders
Hyperparathyroidism secondary
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Euthyroid sick syndrome
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Hypothyroidism
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Pain in extremity
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Myalgia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Neck pain
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	3 / 182 (1.65%)	6 / 88 (6.82%)
occurrences all number	3	6
Pneumonia bacterial
subjects affected / exposed	4 / 182 (2.20%)	2 / 88 (2.27%)
occurrences all number	4	2
Sepsis
subjects affected / exposed	1 / 182 (0.55%)	4 / 88 (4.55%)
occurrences all number	1	4
Clostridium difficile infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Oral candidiasis
subjects affected / exposed	1 / 182 (0.55%)	2 / 88 (2.27%)
occurrences all number	1	2
Bacterial sepsis
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Klebsiella infection
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Pneumonia
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Lower respiratory tract infection fungal
subjects affected / exposed	1 / 182 (0.55%)	1 / 88 (1.14%)
occurrences all number	1	1
Acquired immunodeficiency syndrome
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Anal infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Bacteraemia
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Bronchitis
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Candida infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Cytomegalovirus syndrome
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Escherichia infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Fungal infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Hepatitis B
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Lower respiratory tract infection bacterial
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Moraxella infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Oral fungal infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Phlebitis infective
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Staphylococcal infection
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	4 / 182 (2.20%)	1 / 88 (1.14%)
occurrences all number	4	1
Hyperkalaemia
subjects affected / exposed	2 / 182 (1.10%)	2 / 88 (2.27%)
occurrences all number	2	2
Hypokalaemia
subjects affected / exposed	3 / 182 (1.65%)	1 / 88 (1.14%)
occurrences all number	3	1
Vitamin D deficiency
subjects affected / exposed	1 / 182 (0.55%)	3 / 88 (3.41%)
occurrences all number	1	3
Hypocalcaemia
subjects affected / exposed	2 / 182 (1.10%)	1 / 88 (1.14%)
occurrences all number	2	1
Eating disorder
subjects affected / exposed	2 / 182 (1.10%)	0 / 88 (0.00%)
occurrences all number	2	0
Dehydration
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Folate deficiency
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1
Hyperglycaemia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Hypertriglyceridaemia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Hypoalbuminaemia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Hyponatraemia
subjects affected / exposed	1 / 182 (0.55%)	0 / 88 (0.00%)
occurrences all number	1	0
Steroid diabetes
subjects affected / exposed	0 / 182 (0.00%)	1 / 88 (1.14%)
occurrences all number	0	1

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Were there any global substantial amendments to the protocol? Yes

27 Jan 2021

Protocol amendment No. 1 - The number of participating sites was increased; - Minor typographic errors were amended

14 Apr 2021

Protocol amendment No. 2 - According to comments received from the US FDA, the recently issued guidelines and the current updated knowledge of COVID-19 pandemic, the primary endpoint, the key secondary endpoints and (in a lesser extent) the exploratory endpoints were modified. In particular, the primary endpoint was no more defined as ‘time to event’ but as "the proportion of patients alive and free of respiratory failure" at a predefined time-point. - The use of a rescue therapy has been removed from secondary endpoints. - Further time-points (e.g. Day 60 and/or Day 90) were added for secondary endpoints and a safety follow-up at day 90 was added. - The sample size was recalculated, methods of analysis of the primary endpoint were changed and timelines for the interim analysis were updated based on the change of the primary endpoint. - Further specifications on contraceptive measures were added. - A clarification on the possibility of a follow-up in case of IMP discontinuation was added. - The determination of Reparixin levels was limited to sites in the US (however not performed). - Role and functions of the DMC were updated.

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.

No limitations and caveats are applicable to this summary of results.

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Clinical trials

Clinical Trial Results: A phase 3, double-blind, randomized, placebo-controlled, multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with severe COVID-19 pneumonia.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Proportion of patients alive and free of respiratory failure at Day 28

Primary: Proportion of patients alive and free of respiratory failure at Day 28

Secondary: Proportion of patients alive and free of respiratory failure at Day 60

Secondary: Proportion of patients alive and free of respiratory failure at Day 60

Secondary: Mortality rates up to Day 28

Secondary: Mortality rates up to Day 28

Secondary: Incidence of ICU admission until Day 28

Secondary: Incidence of ICU admission until Day 28

Secondary: Time to recovery until Day 28

Secondary: Time to recovery until Day 28

Secondary: Proportion of patients alive and free of respiratory failure at fixed timepoints

Secondary: Proportion of patients alive and free of respiratory failure at fixed timepoints

Secondary: Mean changes from baseline in clinical severity score based on the 7-point WHO-OS at fixed timepoints

Secondary: Mean changes from baseline in clinical severity score based on the 7-point WHO-OS at fixed timepoints

Secondary: Time to clinical improvement 1 up to Day 28

Secondary: Time to clinical improvement 1 up to Day 28

Secondary: Time to clinical improvement 2 up to Day 28

Secondary: Time to clinical improvement 2 up to Day 28

Secondary: Time to discharge from hospital up to Day 28

Secondary: Time to discharge from hospital up to Day 28

Secondary: Clinical status at fixed time points either in hospital or at home (7-point WHO-OS)

Secondary: Clinical status at fixed time points either in hospital or at home (7-point WHO-OS)

Secondary: Dyspnea severity (Likert scale) at fixed timepoints

Secondary: Dyspnea severity (Likert scale) at fixed timepoints

Secondary: Change from baseline in dyspnea severity (VAS scale) at fixed timepoints

Secondary: Change from baseline in dyspnea severity (VAS scale) at fixed timepoints

Secondary: Duration of supplemental oxygen treatment up to Day 28

Secondary: Duration of supplemental oxygen treatment up to Day 28

Secondary: Number of patients requiring invasive mechanical ventilation use, or ECMO up to Day 28 and up to day 60

Secondary: Number of patients requiring invasive mechanical ventilation use, or ECMO up to Day 28 and up to day 60

Secondary: Duration of non-invasive mechanical ventilation up to Day 60

Secondary: Duration of non-invasive mechanical ventilation up to Day 60

Secondary: Duration of invasive mechanical ventilation, or ECMO up to Day 60

Secondary: Duration of invasive mechanical ventilation, or ECMO up to Day 60

Secondary: Duration of ICU admission up to Day 60

Secondary: Duration of ICU admission up to Day 60

Secondary: Change from baseline to fixed timepoints of partial pressure of oxygen (PaO2)

Secondary: Change from baseline to fixed timepoints of partial pressure of oxygen (PaO2)

Secondary: Change from baseline to fixed timepoints in Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2)

Secondary: Change from baseline to fixed timepoints in Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2)

Secondary: Change from baseline to fixed timepoints in PaO2/FiO2 ratio

Secondary: Change from baseline to fixed timepoints in PaO2/FiO2 ratio

Secondary: Change from baseline to fixed endpoints in High-Sensitivity C Reactive Protein (hs-CRP)

Secondary: Change from baseline to fixed endpoints in High-Sensitivity C Reactive Protein (hs-CRP)

Secondary: Mortality rates up to Day 60 and Day 90

Secondary: Mortality rates up to Day 60 and Day 90

Secondary: Freedom from (time to) death or respiratory failure up to Day 90

Secondary: Freedom from (time to) death or respiratory failure up to Day 90

Secondary: Time to clinical improvement 1 up to Day 28 (cumulative incidence function)

Secondary: Time to clinical improvement 1 up to Day 28 (cumulative incidence function)

Secondary: Time to clinical improvement 2 up to Day 28 (cumulative incidence function)

Secondary: Time to clinical improvement 2 up to Day 28 (cumulative incidence function)

Other pre-specified: Number of subjects who exhibited at least 1 TEAE, at least 1 severe TEAE, at least 1 serious TEAE, at least 1 non-serious TEAE, at least 1 ADR, at least 1 serious ADR, at least 1 TEAE leading to discontinuation of IMP, etc

Other pre-specified: Number of subjects who exhibited at least 1 TEAE, at least 1 severe TEAE, at least 1 serious TEAE, at least 1 non-serious TEAE, at least 1 ADR, at least 1 serious ADR, at least 1 TEAE leading to discontinuation of IMP, etc

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A phase 3, double-blind, randomized, placebo-controlled, multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with severe COVID-19 pneumonia.