A Phase IIb Randomized, Quadruple-blinded Multicenter, Multinational, Placebo-controlled Study to Evaluate the safety and efficacy of exosomes overexpressing CD24 to prevent clinical deterioration in Patients with Moderate or Severe COVID-19

INTERVENTION: Product Name: CovenD24 Product Code: CovenD24 Pharmaceutical Form: Inhalation solution INN or Proposed INN: Exo‐CD24 Other descriptive name: Exosomes expressing CD24 Concentration unit: Other Concentration type: equal Concentration number: 10000000000‐ Pharmaceutical form of the placebo: Inhalation solution Route of administration of the placebo: Inhalation use CONDITION: COVID‐19 disease ; MedDRA version: 23.1 Level: PT Classification code 10084460 Term: COVID‐19 treatment System Organ Class: 10042613 ‐ Surgical and medical procedures Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] PRIMARY OUTCOME: Primary end point(s): Primary Safety Endpoint:; • Incidence of all adverse events by severity, related or unrelated to the study drug.; Primary Efficacy Endpoint:; • Rate of improvement of COVID‐19 status on Day 7 (2 days post last therapy), transitioning from “Severe” to at least “Moderate” or from “Moderate” to “Moderate‐Mild” using the 10‐point COVID‐19 clinical severity ordinal scale ; Secondary Objective: •To evaluate the rate of respiratory failure ; •To evaluate the ratio of patients with the ability to be discharged from the hospital. ; •To evaluate the time to improvement ; •To evaluate the time to recovery (COVID‐19 clinical severity score of 3 or lower).; •To evaluate the rate of ICU admissions ; •To evaluate the time from hospitalization to hospital discharge.; •To evaluate the clinical outcome throughout the study period using the WHO Ordinal Scale (OS); •To assess the COVID‐19‐related symptoms using patient‐reported outcome (PRO) measure score; • To evaluate the death rate.; ; Exploratory Objectives:; • To evaluate the effect of EXO‐CD24 on the respiratory rate.; • To evaluate the effect of EXO‐CD24 on the blood oxygen saturation (SpO2).; • To evaluate the effect of EXO‐CD24 on the level of inflammatory markers; • Blood samples for inflammatory and other biomarkers will be stored for future analyses. Main Objective: • To evaluate the safety of EXO‐CD24 in the treatment of patients with moderate or severe COVID‐19 throughout the 28‐day follow‐up period.; Primary Efficacy Objective:; • To assess the efficacy of EXO‐CD24 in the clinical improvement of COVID‐19. Timepoint(s) of evaluation of this end point: After follow up period SECONDARY OUTCOME: Timepoint(s) of evaluation of this end point: After follow up period Secondary end point(s): Secondary efficacy endpoints: ; • Rate of respiratory failure (defined as a PaO2<60 mmHg and/or a PaCO2>45 mmHg, or the need for mechanical ventilation, ECMO, NIV, or high‐flow oxygen devices] within 28 days of the study period (Day 28). ; • The percentage of patients with the ability to be discharged from the hospital. ; • Time to improvement (transitioning from “Severe” to at least “Moderate” or from “Moderate” to “Moderate‐Mild” using the 10‐point COVID‐19 clinical severity ordinal scale, measured from randomization (Day 1) to last study follow‐up (Day 28). ; • Time to recovery, measured from randomization (Day 1) to recovery or last follow‐up (Day 28), whichever comes first. Recovery is defined as achieving a COVID‐19 clinical severity score of 3 or lower. ; • Percent of patients admitted to the intensive care unit (ICU) within 28 days of the study period. ; • Hospital discharge time within 28 days of the study period, calculated from the day of randomization (Day 1) to discharge or the last follow‐up (Day 28), whichever comes first. ; • Percentage of patients reporting each severity rating on the OS within 28 days of the study period (Day 1 to Day 28). ; • Change from baseline in the COVID‐19 clinical severity OS [before‐treatment assessment (Screening/Day 1)] up to Day 28. ; • Death rate at end of study (Day 28). ; • Change from baseline in the PRO score of the COVID‐19‐Related symptoms in outpatient adult and adolescent subjects in clinical trials of drugs and biological products for COVID‐19 prevention or treatment questionnaire (2). ; Exploratory Endpoints: ; • Proportion of patients with respiratory rate < 23/min at every visit until Day 28, inclusive. ; • Change [decrease/no change (±2 breaths/min)/improvement] in the respiratory rate from baseline to Day 7 visit. ; • Proportion of patients with SpO2 saturation >94%, on room air, at every visit until Day 28, inclusive. ; • Change [decrease/no change (±2 %)/improvement] in the SpO2 saturation from baseline to Day 7 visit. ; • Proportion of patients with an increase from baseline of 25% in the absolute lymphocyte count, hours on Day 7. ; • Change in the absolute lymphocyte count from baseline to Day 7. ; • Proportion of patients with a decrease from baseline of 20% in the neutrophil‐to‐lymphocyte ratio (NLR) on Day 7. ; • Change from baseline to Day 7 in NLR. ; • Change from baseline in CRP/LDH/Fibrinogen/Ferritin/ from baseline on Day 7. ; • Blood samples for inflammatory and other biomarkers will be stored for future analyses. INCLUSION CRITERIA: 1. A COVID‐19 diagnosis confirmed with a SARS‐CoV‐2 viral infection positive polymerase chain reaction (PCR) test within 15 days from screening 2. Age =18 years 3. Severity of disease according to the following criteria (at least one clinical parameter and one laboratory parameter are required): a. Clinical and Imaging‐based evaluation i. Respiratory rate > 23/min and < 30/min ii. SpO2 at room air = 94% and =90% iii. Bilateral pulmonary infiltrates > 25% within 24‐48 hours or a severe deterioration compared to imaging at admission b. Evidence of an exacerbated inflammatory process i. LDH score > 300 U/L or what is the upper limit for normal per age ii. CRP >25 mg/L iii. Ferritin >500 ng/ml iv. Lymphocytes <800 cells/mm3 v. D‐dimers >500ng/ml 4. Willing and able to sign an informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.