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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
287
The George Washington University Medical Faculty Associates, 2150 Pennsylvania Avenue NW
Washington D.C., District of Columbia, United States
Proportion of Patients Alive and Free of Respiratory Failure 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.
Time frame: At day 28
Proportion of Patients Alive and Free of Respiratory Failure 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.
Time frame: At day 60
Mortality Rates 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.
Time frame: Up to Day 28
Incidence of ICU Admission 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.
Time frame: Until day 28
Time to Recovery (Category 1 - 2 - 3 of the 7-point WHO Ordinal Scale of Clinical Improvement (WHO-OS)) 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.
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Franciscan Alliance, 421 N Emerson Ave,
Greenwood, Indiana, United States
Policlinico S. Orsola Malpighi UO di Pneumologia e Terapia Int. Respiratoria
Bologna, Italy
Ospedale Policlinico San Martino Malattie infettive e tropicali
Genova, Italy
Ospedale regionale San Salvatore U.O.C. Anestesia e Rianimazione
L’Aquila, Italy
IRCCS Ospedale San Raffaele Centro di Ricerca Anestesia e Rianimazione
Milan, Italy
ASST SANTI PAOLO E CARLO Ospedale San Paolo Struttura Complessa Malattie Infettive
Milan, Italy
IRCCS Istituto Clinico Humanitas U.O. Medicina D'Urgenza
Milan, Italy
ASST Grande Ospedale Metropolitano Niguarda Dipartimento Malattie Infettive
Milan, Italy
ASST-Monza Ospedale San Gerardo Malattie Infettive
Monza, Italy
...and 7 more locations
Time frame: Until Day 28
Proportion of Patients Alive and Free of Respiratory Failure at Fixed Timepoints
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.
Time frame: At Days 3, 7(±1),14(±2), 21(±2) and 90(±2) after randomization (randomization = day 1)
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints
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.
Time frame: 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)
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS)
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.
Time frame: Day 1 (baseline), Days 3, 7, 14, 21, 28.
Percentage of Participants With Clinical Improvement 1 up to 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.
Time frame: At day 28
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS)
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 frame: Day 1 (baseline), Days 3, 7, 14, 21, 28
Percentage of Participants With Clinical Improvement 2 up to 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.
Time frame: At Day 28
Time to Discharge From Hospital up to Day 28
Time to discharge from hospital up to Day 28 is analyzed as described for time to recovery.
Time frame: Day 1 (baseline), Days 3, 7, 14, 21, 28
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points
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.
Time frame: 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 Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints
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.
Time frame: 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)
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2).
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.
Time frame: 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)
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints
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.
Time frame: 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)
Duration of Supplemental Oxygen Treatment 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.
Time frame: From baseline up to day 28
Number of Patients Requiring Invasive Mechanical Ventilation Use, or ECMO up to Day 28 and 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.
Time frame: day 28 and Day 60
Duration of Non-invasive Mechanical Ventilation 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.
Time frame: From baseline up to day 60
Duration of Invasive Mechanical Ventilation, or ECMO 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.
Time frame: Up to day 60
Duration of ICU Admission up to Day 60
Admission to intensive care unit or ICU is linked to worsening of respiratory parameters compared to baseline.
Time frame: Up to day 60
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2)
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.
Time frame: 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)
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio.
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.
Time frame: 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)
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP)
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).
Time frame: 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)
Mortality Rates 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.
Time frame: up to Days 60 and 90
Freedom From (Time to) Death or Respiratory Failure up to 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.
Time frame: at baseline, day 3, day 7, day 14, day 21, day 28, day 60, day 90
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.
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.
Time frame: Throughout the study, till Day 90 (= end of the follow-up period).