Safety and Efficacy of Exosomes Overexpressing CD24 in Two Doses for Patients With Moderate or Severe COVID-19

Study Overview
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Brief Summary
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This is a phase II randomized, single-blind dose study to evaluate the safety and efficacy of exosomes overexpressing CD24 of two doses, Dose 1 - 10^9 exosome particles (per dose) versus Dose 2 - 10^10 exosome particles (per dose), to prevent clinical deterioration in patients with Moderate or Severe COVID-19 infection.

Detailed Description
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The study population will include patients with moderate or severe COVID-19 and laboratory markers predictive of the cytokine storm, who have provided an informed consent. 90 patients will be randomized in a 1:1 ratio to receive either 109 exosome particles (45 patients) or 1010 exosome particles (45 patients). The exosomes will be diluted in normal saline for inhalation via mouthpiece nebulization, administered once daily (QD) for 5 days. Study treatments will be given as an add-on to the standard of care. Following the 5 days of treatment, patients will remain in follow-up for 23 additional days. In case of hospital discharge before the full follow-up planned, the patient will be required to return to the site for completion of all study assessments.

Official Title
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A Phase II Randomized, Single-blind Dose Study to Evaluate the Safety and Efficacy of Exosomes Overexpressing CD24 in 10^9 Dose Versus 10^10 Dose, for the Prevention of Clinical Deterioration in Patients With Moderate or Severe COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Drug: CovenD24


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A COVID-19 diagnosis confirmed with a SARS-CoV-2 infection positive polymerase chain reaction (PCR) within 30 days of screening. Age 18-80 years. 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 > 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 Willing and able to sign an informed consent. Exclusion Criteria: Any concomitant illness that, based on the judgment of the Investigator might affect the interpretation or the results of the study (i.e., immunodeficiency). Mechanically-ventilated patient or patient who will probably require ICU admission or mechanical ventilation within 24 hours from enrolment, according to the Investigator's judgment. Previous complete or partial vaccination for SARS-CoV-2. Pregnancy [positive urine pregnancy test (women of childbearing potential only)] or breastfeeding. Participation in any other Interventional study in the last 30 days Active cancer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a two arms study; one arm will receive 10^9 dose and the second arm will receive 10^10 dose of exosomes overexpressing CD24
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10^9 dose of exosomes overexpressing CD24<br>The patients will receive the dose of 10^9 exosomes overexpressing CD24 | Drug: CovenD24<br>* The drug will be administrated once daily for 5 days<br>* Other names: Exo-CD24;|
| Experimental: 10^10 dose of exosomes overexpressing CD24<br>The patients will receive the dose of 10^10 exosomes overexpressing CD24 | Drug: CovenD24<br>* The drug will be administrated once daily for 5 days<br>* Other names: Exo-CD24;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Collection of serious adverse events | Incidence of treatment (dose)-related serious adverse events. Incidence of all adverse events related or unrelated to the study treatment. | Through study completion, an average of 4 months | 
| Proportion of patients related with Respiratory rate and SpO2 saturation | Proportion of patients with respiratory rate < 23/min for at least 24 hours, on Day 7. Proportion of patients with SpO2 saturation >94%, on room air for at least 24 hours, on Day 7. Proportion of patients with a decrease by 50% in either CRP/LDH/Fibrinogen/Ferritin/D-dimers from baseline to Day 7. | Through study completion, an average of 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of COVID19 status from severe to moderate | • Rate of categorical and absolute score improvement of COVID-19 status on Day 7 improving from Severe to at least Moderate or from Moderate to Moderate-Mild | Through study completion, an average of 4 months | 
| Time to recovery | • Time to recovery, measured from enrolment (Day 1) to recovery or last follow-up (Day 28). | Through study completion, an average of 4 months | 
| Death rate | • Death rate at end of study (Day 28) | Through study completion, an average of 4 months | 
| No need for mechanical ventilation | • Proportion of patients with no mechanical ventilation (ECMO, NIV, high flow) on Day 7. | Through study completion, an average of 4 months | 
| Patients status regarding haemodynamic instability | • Proportion of patients with haemodynamic instability or requiring vasopressors on Day 7. | Through study completion, an average of 4 months | 
| Oxygen saturation | • Change in the SpO2/FiO2 ratio on Day 7. | Through study completion, an average of 4 months | 
| Time to death or respiratory failure | • Time to death or respiratory failure (defined as an arterial oxygen pressure (PaO2) of <60 mmHg and/or an arterial carbon dioxide pressure (PaCO2) of >45 mmHg, or the need for mechanical ventilation, ECMO, non-invasive ventilation, or high-flow oxygen devices) within 28 days of the study period (Day 1 to Day 28). | Through study completion, an average of 4 months | 
| Hospital discharge time | • Hospital discharge time within 28 days of the study period, calculated from the day of randomization (Day 1) to discharge or last follow-up (Day 28), whichever comes first. | Through study completion, an average of 4 months | 
| No of patients that will need Intensive Care Unit | • Proportion of patients requiring admission to an Intensive-Care Unit (ICU) on Day 7. | Through study completion, an average of 4 months | 
| No of patients with respiratory rate < 23/min | • Proportion of patients with respiratory rate < 23/min for 24 hours at every visit until Day 28, inclusive. | Through study completion, an average of 4 months | 
| No of patients with change in respiratory change | • Proportion of patients with change [decrease/no change (±2 breaths/min)/improvement] in respiratory rate from baseline to Day 7. | Through study completion, an average of 4 months | 
| No of patients with SpO2 >94% | • Proportion of patients with SpO2 >94% on room air, for at least 24 hours at every visit until Day 28, inclusive. | Through study completion, an average of 4 months | 
| No of patients with change in oxygen saturation | • Proportion of patients with change [decrease/no change (±2 %)/improvement] in SpO2 saturation from baseline to Day 7. | Through study completion, an average of 4 months | 
| No of patients with change in lymphocyte count | • Proportion of patients with an increase of 25% in the absolute lymphocyte count, sustained for ≥24 hours on Day 7. | Through study completion, an average of 4 months | 
| Changes in absolute lymphocyte count | • Change in absolute lymphocyte count from baseline to Day 7. | Through study completion, an average of 4 months | 
| No of patients with changes in the neutrophil-to-lymphocyte ratio | • Proportion of patients with a decrease of 20% in the neutrophil-to-lymphocyte ratio (NLR), sustained for ≥24 hours on Day 7. | Through study completion, an average of 4 months | 
| Changes in the neutrophil-to-lymphocyte ratio | • Change in NLR from baseline to Day 7. | Through study completion, an average of 4 months | 
| No of patients with changes in disease severity | • Percentage of patients within each severity rating on the ordinal scale within 28 days of the study period (Day 1 to Day 28). | Through study completion, an average of 4 months | 
| Time of disease improvement | • Time to improvement in the categorical and ordinal scale, measured from randomization (Day 1) to last study follow-up (Day 28). | Through study completion, an average of 4 months | 
| Changes in COVID-19 clinical severity | • Change in the COVID-19 clinical severity from baseline [before-treatment assessment (Screening/Day 1)] up to Day 28. | Through study completion, an average of 4 months | 
| Changes in common COVID-19 related symptoms | • Change from baseline of 14 Common COVID-19-Related Symptoms, as assessed through an Investigator interview. | Through study completion, an average of 4 months | 
| Changes in supplemental oxygen over time | • Change in the flow rate of supplemental oxygen administration over time. | Through study completion, an average of 4 months | 
| Duration of oxygen administration | • The duration of supplemental (non-invasive) oxygen administration. | Through study completion, an average of 4 months |