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

NCT ID: NCT04798716

Last Updated: 2022-03-11

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE1/PHASE2

Total Enrollment

55 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-09-30

Study Completion Date

2024-12-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Covid19 Novel Coronavirus Pneumonia Acute Respiratory Distress Syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SEQUENTIAL

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).
Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Caregivers
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.

Study Groups

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Escalating Dose First Cohort

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

Group Type EXPERIMENTAL

MSC-exosomes delivered intravenously every other day on an escalating dose: (2:4:8)

Intervention Type DRUG

Escalating dose 2 X 10\^9, 4 X 10\^9, 8 X 10\^9/mL

Escalating Dose Second Cohort

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.

Group Type EXPERIMENTAL

MSC-exosomes delivered intravenously every other day on an escalating dose (8:4:8)

Intervention Type DRUG

Escalating dose 8 X 10\^9, 4 X 10\^9, 8 X 10\^9 mL

Escalating Dose Third Cohort

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.

Group Type EXPERIMENTAL

MSC-exosomes delivered intravenously every other day (8:8:8)

Intervention Type DRUG

Dosed 8 X 10\^9, 8 X 10\^9, 8 X 10\^9 mL

Treatment Dose Fourth Cohort Randomized control ratio 1:3

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.

Group Type PLACEBO_COMPARATOR

MSC-exosomes delivered intravenously every other day (8:8:8)

Intervention Type DRUG

Dosed 8 X 10\^9, 8 X 10\^9, 8 X 10\^9 mL

Interventions

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MSC-exosomes delivered intravenously every other day on an escalating dose: (2:4:8)

Escalating dose 2 X 10\^9, 4 X 10\^9, 8 X 10\^9/mL

Intervention Type DRUG

MSC-exosomes delivered intravenously every other day on an escalating dose (8:4:8)

Escalating dose 8 X 10\^9, 4 X 10\^9, 8 X 10\^9 mL

Intervention Type DRUG

MSC-exosomes delivered intravenously every other day (8:8:8)

Dosed 8 X 10\^9, 8 X 10\^9, 8 X 10\^9 mL

Intervention Type DRUG

Other Intervention Names

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Ardoxso Ardoxso Ardoxso

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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AVEM HealthCare

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Mission Community Hospital

Panorama City, California, United States

Site Status

Countries

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United States

Central Contacts

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Tammy C Luttrell, PhD

Role: CONTACT

833-957-0079

Sant P Chawla, MD

Role: CONTACT

Facility Contacts

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Sant P Chawla, MD

Role: primary

References

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Leong DJ, Sun HB. Mesenchymal stem cells in tendon repair and regeneration: basic understanding and translational challenges. Ann N Y Acad Sci. 2016 Nov;1383(1):88-96. doi: 10.1111/nyas.13262. Epub 2016 Oct 5.

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Zhang B, Yin Y, Lai RC, Tan SS, Choo AB, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014 Jun 1;23(11):1233-44. doi: 10.1089/scd.2013.0479. Epub 2014 Feb 10.

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Yang Y, Peng F, Wang R, Yang M, Guan K, Jiang T, Xu G, Sun J, Chang C. Corrigendum to "The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China" [J. Autoimmun. 109C (2020) 102434]. J Autoimmun. 2020 Jul;111:102487. doi: 10.1016/j.jaut.2020.102487. Epub 2020 May 15. No abstract available.

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Yang Y, Peng F, Wang R, Yange M, Guan K, Jiang T, Xu G, Sun J, Chang C. The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun. 2020 May;109:102434. doi: 10.1016/j.jaut.2020.102434. Epub 2020 Mar 3.

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Chien JY, Hsueh PR, Cheng WC, Yu CJ, Yang PC. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology. 2006 Nov;11(6):715-22. doi: 10.1111/j.1440-1843.2006.00942.x.

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Wang CH, Liu CY, Wan YL, Chou CL, Huang KH, Lin HC, Lin SM, Lin TY, Chung KF, Kuo HP. Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir Res. 2005 May 11;6(1):42. doi: 10.1186/1465-9921-6-42.

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Atri D, Siddiqi HK, Lang JP, Nauffal V, Morrow DA, Bohula EA. COVID-19 for the Cardiologist: Basic Virology, Epidemiology, Cardiac Manifestations, and Potential Therapeutic Strategies. JACC Basic Transl Sci. 2020 Apr 10;5(5):518-536. doi: 10.1016/j.jacbts.2020.04.002. eCollection 2020 May.

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Reference Type BACKGROUND
PMID: 32246149 (View on PubMed)

Ruan Q, Yang K, Wang W, Jiang L, Song J. Correction to: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Jun;46(6):1294-1297. doi: 10.1007/s00134-020-06028-z.

Reference Type BACKGROUND
PMID: 32253449 (View on PubMed)

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-848. doi: 10.1007/s00134-020-05991-x. Epub 2020 Mar 3. No abstract available.

Reference Type BACKGROUND
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Liu A, Zhang X, He H, Zhou L, Naito Y, Sugita S, Lee JW. Therapeutic potential of mesenchymal stem/stromal cell-derived secretome and vesicles for lung injury and disease. Expert Opin Biol Ther. 2020 Feb;20(2):125-140. doi: 10.1080/14712598.2020.1689954. Epub 2019 Nov 18.

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Ringden O, Le Blanc K. Mesenchymal stem cells for treatment of acute and chronic graft-versus-host disease, tissue toxicity and hemorrhages. Best Pract Res Clin Haematol. 2011 Mar;24(1):65-72. doi: 10.1016/j.beha.2011.01.003. Epub 2011 Feb 25.

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Chang YS, Choi SJ, Ahn SY, Sung DK, Sung SI, Yoo HS, Oh WI, Park WS. Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury. PLoS One. 2013;8(1):e52419. doi: 10.1371/journal.pone.0052419. Epub 2013 Jan 21.

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Reference Type BACKGROUND
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Other Identifiers

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020582

Identifier Type: -

Identifier Source: org_study_id

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