Reparixin add-on Therapy to Standard Care to Limit Progression in Pts With COVID19 & Other Community Acquired Pneumonia

Key secondary endpoint. All-cause mortality is a measurement of the total number of deaths from any cause within a specific population over a defined period. It is a broad metric used in medical research and public health to assess overall population health, identify risk factors for premature death, and evaluate the effectiveness of interventions. The number of participants (in the form of unadjusted proportion) who met the endpoint is reported.

Key secondary endpoint. The number of participants alive or discharged, expressed in the form of unadjusted proportion, who met the endpoint at the final analysis at day 28 is provided.

Key secondary endpoint. Number of days from Day 0 to Day 28 when the patient was alive and free of invasive ventilation is reported. In case of multiple periods of IMV during the first 28 days, the total duration of ventilation considered all periods of ventilation during the index admission. Patients who died within 28 days or who still were on invasive ventilation after 28 days were scored 0 VFDs.

Key secondary endpoint.The number of participants, expressed in the form of unadjusted proportion, who met the endpoint at the final analysis is reported.

Key secondary endpoint. The duration of primary hospital stay, expressed in days, are reported. This parameter is included in the set of final evaluation, which comprises: no. of days of hospitalization, etiologic agents (if identified), ICU admission and total days in ICU, occurrence, and duration of IMV and/or ECMO, if any.

Clinical failure was defined as the occurrence of IMV/ECMO or vasopressor, or death.

IMV= invasive mechanical ventilation. ECMO=extracorporeal membrane oxygenation.

ICU-free days = days of hospitalization out of the Intensive Care Unit. Death within Day 28 was handled as an unfavorable event and ICU-free days were set at 0.

These parameters are expressed as number of days with NIAID-OS score not equal to 7 or 8, where NIAID-OS is the National Institute of Allergy and Infectious Disease Ordinal Scale; a scale ranging from 1 to 8, where the lower the score, the better the outcome.

The IMV/ECMO-free days at Day 28 were analyzed according to MI approach and ANOVA model. Death due to progression of the respiratory disease within Day 28 was handled as an unfavorable event and IMV/ECMO-free days at Day 28 was set at 0.

A descriptive summary of duration of antibiotic therapy (days) at day 28 for the FAS is reported.

Results for hospital-free days at day 28 in the FAS are presented through an unadjusted descriptive summary.

Results for the proportion of participants recovered at fixed timepoints in the FAS are presented. Recovering was defined as a downward shift from screening of ≤2 points on the NIAID-OS or live discharge from hospital. Unadjusted proportion is reported.

Results for the proportion of participants worsening at fixed timepoints in the FAS are presented.

Worsening was expressed as upward shift from screening of at least >1 point of the NIAID-OS or if patient died before X Visit Day. An unadjusted proportion is reported.

Descriptive statistics for the change from baseline in arterial partial pressure of oxygen (PaO2) at fixed timepoints are reported.

Descriptive statistics for the change from baseline in pulse oximetry, measured as peripheral arterial oxygen saturation (SpO2), at fixed timepoints are reported.

FiO2 is a parameter of lung function representing the fraction of oxygen in the inspired air, ranging from 0.21 (room air) to 1.00 (100% oxygen). The endpoint assesses the change from baseline in FiO2 levels at predefined timepoints during the study.

The PaO2/FiO2 ratio is a parameter of lung function that reflects the efficiency of oxygen transfer from the lungs to the blood. It is calculated as the ratio between the arterial partial pressure of oxygen (PaO2, measured in mmHg) and the fraction of inspired oxygen (FiO2, expressed as a fraction ranging from 0.21 to 1.00). This endpoint assesses the change from baseline in the PaO2/FiO2 ratio at predefined timepoints during the study.

The SpO2/FiO2 ratio is a noninvasive indicator of lung function and oxygenation efficiency, calculated as the ratio between peripheral oxygen saturation (SpO2, expressed as a percentage) and the fraction of inspired oxygen (FiO2, expressed as a fraction ranging from 0.21 to 1.00). This endpoint assesses the change from baseline in the SpO2/FiO2 ratio at predefined timepoints during the study.

Results for all-cause mortality rates in the FAS are reported, at day 28, day 60, and day 90. Analysis was based on logistic regression model with Multiple Imputation using retrieve dropouts with proportion of patients died up to Day 28 as dependent variable, treatment, disease severity at baseline (NIAID-OS <=5 vs. NIAID-OS 6), age class (<65, >= 65 years), sex and presence of concomitant disease at baseline as qualitative independent variables.

Hospital Re-admission by Day 90 and 180 in the FAS is presented. The number of participants is expressed as unadjusted proportion.

The median time to discharge or to a NEWS (National Early Warning Score) of ≤ 2 (for 24 hours), whichever occurs first, was expressed using a "time to event" approach, and measured in days.

NIAID-OS, National Early Warning Score (NEWS) was evaluated daily until day 28 (or hospital discharge). In a scored system standardizing the assessment of acute-illness severity in the NHS, NEWS includes Blood Pressure (BP), Heart Rate (HR), Respiratory Rate (RR), body temperature, level of consciousness (A, V, P, U), peripheral arterial oxygen saturation (SpO2) and supplemental oxygen.

Time to discharge or to a NEWS of <= 2 (for 24 hours) = Min(Date of discharge, Date of NEWS of <= 2 (for 24 hours)) - Day 1 date + 1.

Date of NEWS of <= 2 (for 24 hours): Given two consecutive days with NEWS of <= 2, the date of the first assessment has been considered.

The EQ-5D-5L asks patients to indicate whether they have no, slight, moderate, severe, extreme problems on each of 5 dimensions of health: mobility; self-care; usual activities; pain/discomfort; anxiety/depression.The count of patients of each level (1 - no problems, 2 - slight problems, 3 - moderate problems, 4 - severe problems, 5 - extreme problems) for each of the 5 dimensions were reported. The higher the score for each dimension (range 1-5), the worse the outcome.

The summary of IMV/ECMO duration by day 90 and day 180 for the FAS is presented. The duration of IMV/ECMO use by day 90 was calculated as the total number of days between day 1 and the last available assessment day (≥ day 83) during which the participant was either receiving IMV/ECMO or had a NIAID-OS score of 7. Participants with less than 83 days of follow-up were considered non-evaluable for this endpoint.

Similarly, the duration of IMV/ECMO by day 180 was calculated using the same methodology.

Unadjusted proportion of ICU admission is reported as number and percentage of participants requiring ICU admission by day 90 and day 180.

Results for the Intensive Care Unit length of stay (days) by day 90 and day 180 in the FAS are reported.

Results for hospital length of stay (days) by day 90 and 180 in the FAS are reported.

Occurrence of infections was expressed as the unadjusted proportion of participants with at least one infection by days 90 and 180 in the FAS.

A TEAE is defined as any adverse event reported in the study having a possible, probable, or highly probable relationship to investigational product. A serious AE is defined as any untoward medical occurrence that at any dose:

• results in death.
• is life-threatening (i.e. 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),
• requires inpatient hospitalization or prolongation of existing hospitalization,
• results in persistent or significant disability/incapacity,
• is a congenital anomaly/birth defect
• is a medically significant or important medical condition, i.e. an important medical event that based upon appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed above.