Reparixin in COVID-19 Pneumonia - Efficacy and Safety

Composite event is defined as the onset of at least one of the following events: * supplemental oxygen requirement based on a worsening of PaO2/FiO2 ratio, * invasive mechanical ventilation use, * admission to Intensive Care Unit (ICU), * use of a rescue medication for any reason. Please note that in the measure type number actually is a rate of patients. Rate is referred to a binomial response rate while the 95% CIs are estimated by using the Clopper-Pearson's method

Time frame: Up to Day 1

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

Variations in the mean body temperature from baseline to any post-baseline timepoint were assessed. n is the number of subjects for which the evaluation of the body temperature at each time point is available.

Time frame: Baseline, Day 1, Day 2, Week 1, EOT and EOS

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

The severity of dyspnea is measured also through the VAS scale. The VAS scale is used as follows: the patient draws a horizontal line on an axial graph (from 0 to 100) to show the degree of how he feels about breathing. The number 0 equals the worst breathing the patient has ever felt and the number 100 equals the best he has ever felt. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

Population: The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP.~Please note that N (36 for Reparixin and 19 for SoC) is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n - hereunder reported (28 for Reparixin and 19 for SoC) - is the number of subjects improved at each time point in comparison with the randomization.

SpO2 measures the amount of oxygen-carrying hemoglobin in the blood relative to the amount of hemoglobin not carrying oxygen. Acceptable normal ranges for patients without pulmonary pathology are from 95 to 99 percent.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

PaO2 measures the pressure of oxygen dissolved in the blood and how well oxygen is able to move from the airspace of the lungs into the blood. Normally, PaO2 is between 75 and 100 mmHg (at sea level). Lower levels indicate an unsufficient amount of oxygen flowing from the alveoli to the blood. Please note that a significant proportion of patients in both groups did not have post-baseline assessments of PaO2.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Population: The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP. Please note that N, hereunder reported, is the number of subjects for which the evaluation of the PaO2 at each time point is available (very low at Day 1 and EOS time points in the Reparixin Arm and at the Day 1, 2, and Week 1 time points in the Standard of Care Arm).

For a standard CRP test, a normal reading is less than 10 milligram per liter (mg/L). Levels between 10 mg/L and 100 mg/L are moderately elevated and are usually due to more significant inflammation from an infectious or non-infectious cause. Inflammatory status is documented by C-reactive protein (CRP) ≥ 100mg/L.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

Cumulative duration of mechanical ventilation (in hours) = Sum of duration of mechanical ventilation (hours) in mechanical ventilation form, from randomization to time point of interest. Duration of mechanical ventilation (hours) = End date/time - Start date/time / 60. n is the number of subjects for which the evaluation of the use of mechanical ventilation is available

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

Cumulative ICU stay was assessed at different timepoints and measured in days

Time frame: Day 1, Day 2, Week 1, EOT, EOS

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

Lung damage extensions is assessed by Chest CT or Rx. This damage can be as follows: none, trace, mild, moderate, or severe. N is the number of subjects for which the evaluation of the lung damage extension at each time point is available.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Population: The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP. Please note that N, hereunder reported, is the number of subjects for which the evaluation of the lung damage extension or lung damage exudation degree at each time point is available (very low at Day 1 and EOS time points in the Reparixin Arm and at the Day 1, 2, and Week 1 time points in the Standard of Care Arm).

Lung exudation is assessed by Chest CT or Rx. This can be as follows: none, trace, mild, moderate, or severe. N is the number of subjects for which the evaluation of the lung damage extension at each time point is available.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

This outcome assesses the oxygen cumulative duration during the study. N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio or Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point in comparison with the randomization.

Time frame: Week 1, EOT, EOS

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

In this endpoint is assessed the oxygen cumulative quantity needed at each single timepoint. N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio or Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point in comparison with the randomization.

Time frame: Week 1, EOT and EOS

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

PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage) also known as the Horowitz index, the Carrico index, and (most conveniently) the P/F ratio at sea level, the normal PaO2/FiO2 ratio is \ 400-500 mmHg (\ 55-65 kPa).

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

The severity of dyspnea can be measured through the Liker scale. The Liker scale is used as follows: the patient grades his current breathing compared to when he first started the drug (from -3 to 3). 0 = no change, 1 =minimally better, 2 =moderately better, 3 =markedly better, -1 =minimally worse, -2 =moderately worse, -3 =markedly worse. The higher the score, the better the outcome. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

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

Changes in clinical severity score are defined as the time to clinical improvement of two points from the time of randomization on a seven-category ordinal scale or live discharge from the hospital, whichever came first. The seven-category ordinal scale consisted of the following: 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 Extracorporeal Membrane Oxygenation (ECMO), invasive mechanical ventilation, or both; and 7) death. The higher the score, the worse the outcome. A subject is considered improved with a clinical severity score improvement of at least two points compared to randomization or live discharge from the hospital. n are the subjects improved at each time point vs baseline.

Time frame: At day 1, day 2, week 1, day 21(end of treatment, EOT), EOS (end of study, i.e. 7±3 days after EOT)

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

Percentage along with the 95% confidence interval (Clopper-Pearson's formula) of subjects requiring mechanical ventilation are calculated and compared. N is the number of subjects for which the evaluation of the use of mechanical ventilation is available. n is the number, expressed in percentage, of subjects requiring mechanical ventilation, overall.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

Percentage, along with the 95% confidence interval (Clopper-Pearson's formula), of subjects requiring ICU admission are calculated and compared.N is the number of subjects for which the evaluation of the ICU admission need is available.

Time frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

Duration of oxygen administration (hours) = Administration end date/time - Administration start date/time / 60. N is the number of subjects for which the evaluation of the Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point, expressed in percentage, in comparison with the randomization. According to Oxygen Delivery System, the classification is 'invasive' if there is Invasive Medicinal Ventilation or ECMO, else 'high flow' if there is High Flow Nasal Cannula or BIPAP or CPAP, else 'low flow' if there is Nasal Cannula or Mask then Class=Low Flow Classification. A patient is considered 'Worsened' after baseline if there is an increase in the level of severity within the oxygen delivery system classification (Invasive \> High Flow \> Low Flow).

Time frame: day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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

Cumulative quantity of oxygen treatment (L) = Sum of all Quantity (L) in CONCOMITANT OXYGEN TREATMENT form, from randomization to time point of interest. According to PaO2/FiO2, the classification is 'mild' if 200 \<= PaO2/FiO2 \< 300 mmHg, 'moderate' if 100 \<= PaO2/FiO2 \< 200 mmHg, 'severe' if PaO2/FiO2 \< 100 mmHg. A patient with ARDS (PaO2/FiO2\<300 mmHg) is considered 'worsened' in case of a decrease of PaO2/FiO2 of at least one third (-33,3%) from the baseline PaO2/FiO2 value. NOTE that: N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio at each time point is available. While n is the number of subjects worsened at each time point in comparison with the randomization, expressed in percentage.

Time frame: At day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

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