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

Phase 3

Completed

Conditions: Pneumonia, Viral

Interventions: Other: Placebo
Drug: Reparixin

Registration Number: NCT04878055

Lead Sponsor: Dompé Farmaceutici S.p.A

Brief Summary: The study objective is to assess Efficacy and safety of Reparixin treatment as compared to placebo (both on top of standard treatment) in adult patients with severe COVID-19 pneumonia.

Detailed Description: This is a phase 3 clinical trial designed as a randomized, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of Reparixin in hospitalized adult patients with severe COVID-19 pneumonia.

Patients will be screened for the participation in the study and eventually randomized based on an unbalanced randomization scheme (2:1) to Reparixin oral tablets (2 x 600 mg TID) for up to 21 days or to placebo.

An unequal randomization is justified by the need to gain experience and more safety data with the investigated treatment and by an expected better acceptability of the trial by patients.

The placebo control arm is justified by the unavailability of a well-defined standard of care for subjects with COVID-19 pneumonia who are candidates for this study.

All patient will receive the standard supportive care based on the patient's clinical need. Follow-up information on the patient's clinical condition will be collected until day 90.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 287

Inclusion Criteria

Age 18 to 90, male and female subject of any race
Reverse transcriptase Polymerase Chain Reaction (rt-PCR)-confirmed COVID-19 infection based on a nasal / oropharyngeal swab within 10 days before randomization
At least one of the following: 1) Respiratory distress with tachypnea (RR ≥ 24 breaths/min without oxygen); 2) Partial arterial oxygen pressure (PaO2) / Fraction of inspiration O2 (FiO2), P/F >100 and <300 mmHg (1mmHg = 0.133kPa), 3) SpO2 ≤ 94% while breathing ambient air.

Calculation through validated Sat/FiO2 scales is allowed. P/F value of reference if the last available before the signature of consent.
Need of supplemental oxygen (i.e. new use of supplemental oxygen, or increased oxygen requirement if on chronic oxygen) requiring low- or high-flow oxygen or non-invasive mechanical ventilation (7-point WHO-OS category 4 or 5).
Radiological chest imaging (X-rays, CT scan) confirms lung involvement and inflammation.

Exclusion Criteria

Cannot obtain informed consent.
Hepatic dysfunction with Child Pugh score B or C, or ALT or AST> 5 times the upper limit.
Renal dysfunction with estimated glomerular filtration rate (MDRD) < 50 mL/min/1.73 m2 or patient receiving continuous renal replacement therapy, hemodialysis, or peritoneal dialysis.
Bacterial sepsis (besides COVID-19 sepsis).
Known congenital or acquired immune deficiency.
Positive or missing pregnancy test before first drug intake or day 1; pregnant or lactating women; women of childbearing potential and fertile men who do not agree to use at least one primary form of contraception for the duration of the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care.
Reparixin	Reparixin	Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care

Primary Outcome Measures

Name	Time	Method
Proportion of Patients Alive and Free of Respiratory Failure at Day 28	At day 28	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.

Secondary Outcome Measures

Name	Time	Method
Incidence of ICU Admission Until Day 28	Until day 28	This is a key secondary efficacy endpoint. Admissions to Intensive Care Unit (ICU) had to be considered only in presence of significant worsening of respiratory status. This condition was objectively identified by means of a decrease of PaO2/FiO2 ratio of at least 40% from the baseline value or by a worsening of Investigator's Interpretation.
Percentage of Participants With Clinical Improvement 2 up to Day 28	At Day 28	Clinical improvement 2 up to Day 28 is defined as cumulative incidence function (CIF, in %). CIF allows for estimation of the occurrence of an event while taking into account the following competing risks: death, reasons for discontinuation for Adverse events and patient transferred to another institution. Estimates are calculated using a nonparametric method. The null hypothesis is that the cumulative incidence functions are identical across treatment groups.
Proportion of Patients Alive and Free of Respiratory Failure at Fixed Timepoints	At Days 3, 7(±1),14(±2), 21(±2) and 90(±2) after randomization (randomization = day 1)	The event variable is defined as the proportion of patients alive and free of respiratory failure at fixed timepoints. This means no need of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) or admission to intensive care unit (ICU) linked to worsening of respiratory parameters compared to baseline. Admissions to ICU had to be considered only in presence of significant worsening of respiratory status. This condition was objectively identified by means of a decrease of PaO2/FiO2 ratio of at least 40% from the baseline value or by a worsening of Investigator's Interpretation.
Mortality Rates up to Day 28	Up to Day 28	This key secondary efficacy endpoint describes number and proportion along with the 95% CI (Clopper-Pearson's formula) of patients who died up to Day 28.
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS)	Day 1 (baseline), Days 3, 7, 14, 21, 28.	Clinical improvement 1 is defined as the decline of 1 category in the 7-point WHO-OS up to Date 28. The clinical improvement 1 up to Day 28 was analyzed as described for time to recovery: an event was considered as such, if patient declined of at least 1 category in the 7-point WHO-OS respect to the baseline, otherwise it was be considered free of event.
Proportion of Patients Alive and Free of Respiratory Failure at Day 60	At day 60	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.
Duration of Supplemental Oxygen Treatment up to Day 28	From baseline up to day 28	This endpoint is expressed as: * The number and proportion along with the 95% CI (Clopper-Pearson's formula) of patients using supplemental oxygen treatment by treatment group; * The Cumulative duration of supplemental oxygen treatment in days analyzed by means of descriptive statistics by treatment. This latter is reported in the system.
Number of Patients Requiring Invasive Mechanical Ventilation Use, or ECMO up to Day 28 and up to Day 60	day 28 and Day 60	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.
Duration of ICU Admission up to Day 60	Up to day 60	Admission to intensive care unit or ICU is linked to worsening of respiratory parameters compared to baseline.
Time to Recovery (Category 1 - 2 - 3 of the 7-point WHO Ordinal Scale of Clinical Improvement (WHO-OS)) Until Day 28	Until Day 28	This is a key secondary efficacy endpoint. The event "recovery" was considered as such, if the patient has scored category 1, 2 or 3 from the 7-point WHO Ordinal Scale of clinical improvement (WHO-OS), otherwise it will be considered free of event. Category 1: not hospitalized, with resumption of normal activities; 2: not hospitalized, but unable to resume normal activities; 3: hospitalized, not requiring supplemental oxygen; \[4: hospitalized, requiring supplemental oxygen; 5: hospitalized, requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6: hospitalized, requiring ECMO, invasive mechanical ventilation, or both; 7: death\]. The lower the category, the better the outcome.
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	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.
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	Clinical status is analyzed based on the 7-point WHO-OS. The 7-point WHO Ordinal Scale of clinical improvement (WHO-OS), comprises the following categories: 1: not hospitalized, with resumption of normal activities; 2: not hospitalized, but unable to resume normal activities; 3: hospitalized, not requiring supplemental oxygen; 4: hospitalized, requiring supplemental oxygen; 5: hospitalized, requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6: hospitalized, requiring ECMO, invasive mechanical ventilation, or both; 7: death. The higher the score, the worse the outcome.
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2).	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	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.
Duration of Non-invasive Mechanical Ventilation up to Day 60	From baseline up to day 60	Non-invasive ventilation (NIV) is the delivery of oxygen (ventilation support) via a face mask and therefore eliminating the need of an endotracheal airway. NIV achieves comparative physiological benefits to conventional mechanical ventilation by reducing the work of breathing and improving gas exchange.
Mortality Rates up to Days 60 and 90	up to Days 60 and 90	Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. The death event variable is defined as the proportion of patients died up to Day 90.
Percentage of Participants With Clinical Improvement 1 up to Day 28	At day 28	Clinical improvement 1 up to Date 28 for this outcome is expressed as cumulative incidence function (CIF in %). CIF allows for estimation of the occurrence of an event while taking into account the following competing risks: death, reasons for discontinuation for Adverse events and patient transferred to another institution. Estimates are calculated using a nonparametric method. The null hypothesis is that the cumulative incidence functions are identical across treatment groups.
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	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.
Duration of Invasive Mechanical Ventilation, or ECMO up to Day 60	Up to day 60	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.
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.	Throughout the study, till Day 90 (= end of the follow-up period).	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.
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS)	Day 1 (baseline), Days 3, 7, 14, 21, 28	Clinical improvement 2 is defined as the decline of 2 categories in the 7-point WHO-OS) up to Date 28. Clinical improvement 2 up to Date 28 was analyzed as described for time to recovery. An event was considered as such, if patient declined of at least 2 categories in the 7-point WHO-OS respect to the baseline, otherwise it was considered free of event.
Time to Discharge From Hospital up to Day 28	Day 1 (baseline), Days 3, 7, 14, 21, 28	Time to discharge from hospital up to Day 28 is analyzed as described for time to recovery.
Freedom From (Time to) Death or Respiratory Failure up to Day 90	at baseline, day 3, day 7, day 14, day 21, day 28, day 60, day 90	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.
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	The number of patients with Dyspnea severity Likert scale by score and treatment group is calculated for each time point. Likert scale: grading the current experience of breathing discomfort compared to baseline (randomization) status (from -3 to 3) where: "-1 = minimally worse; -2 = moderately worse; -3 = markedly worse; 0 = no change; 1 = minimally better; 2 = moderately better; 3 = markedly better" More negative the score, the worse the outcome.
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2)	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	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.
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio.	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	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.
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP)	At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)	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).

Trial Locations

Locations (17): Franciscan Alliance, 421 N Emerson Ave,
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Greenwood, Indiana, United States
Policlinico S. Orsola Malpighi UO di Pneumologia e Terapia Int. Respiratoria
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Bologna, Italy
Ospedale Policlinico San Martino Malattie infettive e tropicali
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Genova, Italy
Ospedale regionale San Salvatore U.O.C. Anestesia e Rianimazione
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L'Aquila, Italy
IRCCS Istituto Clinico Humanitas U.O. Medicina D'Urgenza
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Milano, Italy
IRCCS Ospedale San Raffaele Centro di Ricerca Anestesia e Rianimazione
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MIlan, Italy
ASST SANTI PAOLO E CARLO Ospedale San Paolo Struttura Complessa Malattie Infettive
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Milan, Italy
ASST-Monza Ospedale San Gerardo Malattie Infettive
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Monza, Italy
A.O.U. Federico II Malattie Infettive del Policlinico Federico II
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Napoli, Italy
Università della Campania "Luigi Vanvitelli" Dipartimento di Malattie Infettive
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Napoli, Italy
Policlinico Universitario Campus Bio-Medico UOC Anestesia e Rianimazione
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Roma, Italy
Azienda Ospedaliero-Universitaria Policlinico Umberto I, UOC Malattie Infettive
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Roma, Italy
Università Cattolica del Sacro Cuore - Policlinico Universitario "Agostino Gemelli" - Istituto di Clinica delle Malattie Infettive
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Roma, Italy
ASST dei Sette Laghi Ospedale di Circolo e Fondazione Macchi Struttura Complessa Malattie infettive e tropicali
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Varese, Italy
A.O.U. Integrata di Verona U.O. Medicina Respiratoria, sezione di Medicina Interna
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Verona, Italy
The George Washington University Medical Faculty Associates, 2150 Pennsylvania Avenue NW
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Washington, District of Columbia, United States
ASST Grande Ospedale Metropolitano Niguarda Dipartimento Malattie Infettive
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Milano, Italy