Extracellular Vesicle Infusion Treatment for COVID-19 Associated ARDS

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of intravenous administration of bone marrow derived extracellular vesicles, ExoFlo, versus placebo as treatment for moderate-to-severe Acute Respiratory Distress Syndrome (ARDS) in patients with severe COVID-19.

Detailed Description
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This is a Phase II, double-blinded, placebo-controlled, randomized controlled trial that enrolled 102 subjects that were admitted with COVID-19 associated moderate-to-severe ARDS across 6 sites in the United States.

Official Title
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Phase II Clinical Trial

Conditions
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COVID-19, ARDS

Intervention / Treatment
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* Biological: ExoFlo
* Other: Intravenous normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form (either by the individual or by the individual's healthcare proxy). Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged 18-85. COVID-19 positive as defined by positive Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) SARS-CoV-2. Moderate to severe ARDS as defined by modified Berlin definition, * which includes timing within 1 week of known clinical insult or new or worsening respiratory symptoms; bilateral opacities not fully explained by effusions, or lung collapse; respiratory failure not fully explained by cardiac failure or fluid overload; PaO2/FiO2 ≤ 200 mm Hg. *Modified Berlin definition used in this study is the full Berlin definition, albeit without the PEEP specification, which implies mechanical ventilation. Hypoxia requiring noninvasive oxygen support such as Nasal Cannula (NC), Nonrebreather (NRB), Bilevel Positive Airway Pressure (BIPAP), Continuous Positive Airway Pressure (CPAP), high flow nasal cannula oxygen (HFNC O2) or mechanical ventilation (MV) despite initiating standard of care. If the candidate is either a male or female of reproductive potential, he or she must agree to use of double barrier method of highly effective birth control contraception such as condoms with oral contraceptive pill or choose to remain abstinent if already practicing abstinence during the screening period. The required duration of usage of double barrier method OR maintenance of abstinence must include the time from the beginning of the screening period until 90 days following the last dose of the study treatment. Exclusion Criteria: Vulnerable populations such as pregnant patients, children, individuals with severe physical or mental disabilities who cannot provide meaningful consent. Active malignancy requiring treatment within the last five years. Major physical trauma in the last 5 days, including motor vehicle accidents, assaults, mechanical falls with sequelae of significant bleeding or craniofacial bruising, and surgeries. Active tuberculosis or cystic fibrosis. Severe chronic respiratory disease including chronic obstructive pulmonary disease or pulmonary fibrosis requiring home oxygen > 5L/min. Use of extracorporeal membrane oxygenation (ECMO) during the current hospitalization. Pre-existing pulmonary hypertension. Severe pre-existing hepatic impairment (presence of cirrhosis, liver function tests (LFTs) ≥ 6x baseline, INR ≥ 2.0). Pre-existing Chronic Kidney Disease (CKD) stage IIIb or End Stage Renal Disease (ESRD) prior to onset of COVID-19 (stage I, II, and IIIa are acceptable) Irreversible coagulopathy (e.g., frequently occluded vascular access despite anticoagulation, precipitous platelet drops concurrent with end-organ damage suggesting consumptive process) or irreversible bleeding disorder (e.g., frequent bleeding from vascular access, endotracheal tubes, and foley). Pneumonia clearly attributable to a non-COVID-19 related process, including aspiration pneumonia or pneumonia that is exclusively bacterial, or originating from a diagnosed alternative virus (e.g., influenza). Patients who are not full code. Endotracheal intubation duration ≤ 24 hours. Moribund-expected survival < 24 hours. Severe metabolic disturbances on presentation (e.g., ketoacidosis, pH < 7.3)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Multi-center, double-blinded, placebo-controlled, randomized controlled trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Normal saline 100 mL | Other: Intravenous normal saline<br>* Placebo<br>|
| Experimental: Experimental Dose 1<br>Normal saline 90 mL and ExoFlo 10 mL | Biological: ExoFlo<br>* Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles<br>|
| Experimental: Experimental Dose 2<br>Normal saline 85 mL and ExoFlo 15 mL | Biological: ExoFlo<br>* Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of 60-day Mortality Rate | To evaluate the 60-day mortality rate for IP 15mL as a treatment for COVID-19 associated moderate to severe ARDS compared to placebo. Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect. | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rates | Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect. | Days 15, 30, 60 | 
| Proportion of Discharged Patients | Discharge is an unbiased measure of overall clinical improvement. | Days 7, 30, 60 | 
| Time to Discharge | Discharge is an unbiased measure of overall clinical improvement. | Number of days from the date of randomization until documented discharge from hospital, up to 60 days. | 
| Incidence of Treatment Emergent Serious Adverse Events | Safety comparison performed between IP 15 mL and placebo arms | 61 days | 
| Ventilation Free Days | Number of days for which patients are not on mechanical ventilation. | Within 60 days of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, ARDS, Extracellular Vesicles, Exosome