Extracellular Vesicles From Mesenchymal Cells in the Treatment of Acute Respiratory Failure

Study Overview
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Brief Summary
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This is a phase I/II, randomized, double-blind, placebo-controlled clinical trial that will evaluate the safety and potential efficacy of therapy with extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs), patients with moderate to severe acute respiratory distress syndrome due to COVID-19 or other etiology. Participants will be allocated to receive EVs obtained from MSCs or placebo (equal volume of Plasma-Lyte A). Blinding will cover the participants, the multidisciplinary intensive care team and the investigators.

Detailed Description
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The studied population will consist of 15 patients diagnosed with acute respiratory failure syndrome admitted to the intensive care unit of Hospital São Rafael. This research aims to assess the safety and potential effectiveness of intravenous therapy using extracellular vesicles derived from mesenchymal cells in patients with moderate to severe acute respiratory distress syndrome. The treatment group will receive intravenous administration of extracellular vesicles obtained from mesenchymal cells, while the control group will receive a placebo. EV group: will consist of 10 participants who will receive two infusions of 25 mL of the investigational product (Plasma-Lyte A solution containing EVs obtained from MSCs), intravenously, at intervals of 48 h. Placebo group: will consist of 5 participants who will receive an equal volume of Plasma-Lyte A, intravenously, following the same schedule as the IV group: two infusions with an interval of 48 hours.

Official Title
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Extracellular Vesicles From Mesenchymal Cells in the Treatment of Acute Respiratory Failure Associated With SARS-CoV-2 and Other Etiologies: a Clinical Trial, Randomized, Double-blind.

Conditions
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Severe Acute Respiratory Syndrome (SARS), Acute Respiratory Distress Syndrome (ARDS), Pneumonia

Intervention / Treatment
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* Biological: intravenous treatment with EVs
* Biological: intravenous treatment with placebo solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years old; Chest CT radiological image with ground-glass opacities or chest X-ray with - bilateral infiltrates characteristic of pulmonary edema; In invasive mechanical ventilation with PEEP 5 cm H2O and PaO2/FiO2<250mmHg; Respiratory failure not explained by cardiac causes or fluid overload. Exclusion Criteria: Unable to provide informed consent; Pregnancy or breastfeeding; Patients with active malignancy who have received chemotherapy in the last 2 years; Life expectancy of less than 6 months or in exclusive palliative care; Severe liver failure, with a Child-Pugh score > 12; Previous renal failure: patients already undergoing dialysis or patients with GFR < 30ml/min/1.73 m2 Clinical or radiological suspicion of tuberculosis; Chronic respiratory failure; Use of ECMO; Moribund (high probability of death within the next 48 hours).

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EV group<br>will consist of 10 participants who will receive two infusions of 25 mL of the investigational product (Plasma-Lyte A solution containing EVs obtained from MSCs), intravenously, at intervals of 48 h. | Biological: intravenous treatment with EVs<br>* intravenous treatment with extracellular vesicles<br>|
| Placebo Comparator: Placebo group<br>will consist of 5 participants who will receive an equal volume of Plasma-Lyte A, intravenously, following the same schedule as the IV group: two infusions with an interval of 48 hours. | Biological: intravenous treatment with placebo solution<br>* intravenous treatment with placebo solution (without extracellular vesicles)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure administration of extracellular vesicles (EVs) up to 28 days | Measure as reported adverse events up to 28 days after treatment or placebo administration to evaluate safety of treatment | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | at days 14 and 28 after randomization; | Day 14 and day 28 | 
| Variation in the Ratio PaO2/FiO2 | PaO2 (arterial partial pressure of oxygen)/FiO2 (fraction of inspired oxygen) on the day of randomization and at 24 hours, 48 hours and 7 days after the first infusion; | Baseline, day 01, day 02 and day 07 | 
| Variation in the SOFA index | Variation in the SOFA index (Assessment of Sequential Organ Failure) at the time of randomization and during follow-up until discharge from the intensive care unit; | day 01, day 02, day 07, day 09, day 14 and day 29 | 
| Exploratory laboratory analysis | variation in total and differential laboratory analysis. | 30 days | 
| Duration of the period of hospitalization | from hospital time in the intensive care unit (ICU) | 30 days | 
| Duration of the period of ICU ventilation | If applicable,will be measured the time of mechanical ventilation. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, intravenous therapy, extracellular vesicles, ARDS, mesenchymal cells