The Use of Exosomes for the Treatment of Acute Respiratory Distress Syndrome or Novel Coronavirus Pneumonia Caused by COVID-19 (ARDOXSO)

The Use of Exosomes for the Treatment of Acute Respiratory Distress Syndrome or Novel Coronavirus Pneumonia Caused by COVID-19

Mesenchymal Stem Cell Exosomes for the Treatment of COVID-19 Positive Patients With Acute Respiratory Distress Syndrome and/or Novel Coronavirus Pneumonia

Novel coronavirus pneumonia (NCP) and acute respiratory distress syndrome (ARDS) are both associated with the prevailing upper respiratory tract infections caused by the RNA-containing SARS-CoV2 virus of the genius Betacoronavirus of the Coronaviridae family. As both the viral infiltration and infection progress, the host immune system response can be one of a rapidly developing fatal cytokine storm. In the ARDS or NCP ensuing progression, the patient often succumbs to the effects of the hyper pro-inflammatory response, hence contributing to the associated increased mortality as a result of the cytokine storm and associated pathogenesis.

In December of 2019, in Wuhan, China, a novel coronavirus outbreak began. Globally this disease referred to as COVID-19, is the result of a novel SARS-CoV2 virus which predominantly targets Type II lung alveolar cells (AT2). The hyper response of the host immune system can rapidly evolve into a life-threatening cytokine-release syndrome or cytokine storm. The cytokine storm can predispose the patient to ARDS and/or NCP., or both. Left unchecked, the ARDS pathogenesis rapidly culminates in disruption of cell cytotoxicity mechanisms, excessive activation of cytotoxic lymphocytes, and a predominance of type I (M1) macrophage; resulting in the massive release of a host of proinflammatory cytokines (FNO-α, IL-1, IL-2, IL-6, IL-8, IL-10), granulocytic colony-stimulating factor, monocytic chemoattractive protein 1. The result systemically is a rise in surrogate inflammatory markers (C Reactive Protein, serum ferritin), with a corresponding infiltration of internal organs and tissues by activated macrophage, T-lymphocytes and a predominance of cellular apoptosis. The resulting hyperinflammatory pathogenic reaction may result in severe aveolar lesions leading to death, scarring, or severe lung damage, persisting well after discharge. Experimental studies have demonstrated that mesenchymal stem cells (MSCs) and MSC-culutre media (MSC-CM) may significantly reduce the pro-inflammatory bias and associated pathologic impairment resulting. The MSC-CM, known to contain exosomes, has been shown to have an anti-inflammatory effect. Further exosomes associated with the amniotic membrane, long used in the treatment of burn and wounds, have been show to have a regenerative effect. The purpose of this protocol is to explore the safety and efficacy of an intravenous injection of MSC derived exosomes in the treatment of severe patients (moderate to severe Berlin score) with ARDS or NCP.

Nested Cohort with Escalating Dose. The trial has three cohorts of 5 patients each. The subsequent cohort will receive an escalating dose of exosomes via intravenous infusion. The final group of 40 participants will be randomized 1:3 (placebo:intervention).

Open-label for the first 15 patients treated in dose escalation. The final 40 participants are included in RCT. Double; participant and physician are masked.

First Cohort: Five patients will receive an escalating dose every other day for a period of 5 days, with a minimum of 24 hours between doses recorded. Dose escalation will begin at 2 x 10^9 exosomes

Second Cohort: Five patients will receive an escalating dose every other day for a period of 5 days, with a minimum of 24 hours between doses recorded. Dose escalation will begin at 4 x 10^9 exosomes.

Five patients will receive a treatment dose of 8 X 10^9 exosomes every other day for a period of 5 days, with a minimum of 24 hours between doses recorded.

Fourth Cohort: Randomized Cohort Up to 40 patients may be enrolled in this phase of the trial. For those receiving the placebo (~25%), 3 doses will be given over the 5 day period, dispensed from identical vials with physician and patient blinded. The full dose of 8 X 10^9 exosomes will be given to 75% of the patients in 3 doses over the course of 5 days, with one dose occurring every other day.

Measure and report the number of participants with treatment-related-adverse events as assessed by CTCAE v4.0; for patients receiving ARDOXSO™, perinatal MSC-derived exosome therapy.

Quantify safety of ARDOXSO™, an interventional exosome therapy in COVID-19 in participants confirmed with SARS-CoV-2 infection who receive ARDOXSO™ as an intervention.

Tabulate and report the number of IMV days for patients receiving ARDOXSO™ perinatal MSC-derived exosome therapy.

Quantify efficacy of ARDOXSO™, an interventional exosome therapy in COVID-19 in participants confirmed with SARS-CoV-2 infection who receive ARDOXSO™ as an intervention.

Analyze and report organ failure, associated with ICU mortality in participants confirmed with SARS-CoV2 infection, receiving ARDOXSO™ as an interventional exosome therapy.

Correlate and analyze the Sequential Organ Failure Assessment (SOFA) score in participants confirmed with SARS-CoV2 infection, receiving ARDOXSO™, an interventional exosome therapy in COVID-19 patients. An increased SOFA score is predictive of increased mortality.

Berlin Score is a validated measure of Acute Respiratory Distress Syndrome diagnosis, which is common in COVID-19 patients, before and after receiving the interventional exosome therapy, ARDOXSO™.

Inclusion Criteria: Informed Consent given Male and female patients age 18 years or older Patients with coronavirus (SARS-CoV-2) infection confirmed prior to enrollment by any test with local regulatory approval Patients who require intensive care as determined by the following objective criteria: Respiratory rate>25/minute Oxygen saturation <93% on room air; or the Use of high flow oxygen by nasal cannula at a rate ≥ 4L/minute. Patients with lung imaging demonstrating bilateral or diffuse pulmonary infiltrates on chest X-ray or CT scan. Patients with moderate to severe ARDS as defined by Berlin Criteria Patients who require invasive mechanical ventilation (IMV) Exclusion Criteria: Patients will be excluded from the study if ONE of the following applies: History of hypersensitivity to any drugs of similar classes to exosomes Suspected active uncontrolled bacterial, fungal, or viral (besides SARS-CoV-2) infection Currently receiving ECMO, nitric oxide therapy, or high-frequency oscillatory ventilation In the option of the investigator, the patient is unlikely to survive for more than 24 hours post-enrollment Patients who are on long-term use of select oral or injectable anti-rejection or immunomodulatory drugs Pregnant or nursing (lacking) women

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