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

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.

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.

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.

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.

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.

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 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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

Admission to intensive care unit or ICU is linked to worsening of respiratory parameters compared to baseline.

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.

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.

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).

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.

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.

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.