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

Covid19 Clinical Trial

— ARDOXSO  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04798716
• Other study ID #: 020582
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: September 2023
• Est. completion date: December 2024

Study information

• Verified date: March 2022
• Source: AVEM HealthCare
• Contact: Tammy C Luttrell, PhD
• Phone: 833-957-0079
• Email: tammy.luttrell[@]avemhealthcare.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 55
• Est. completion date: December 2024
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Coronavirus Infections
• COVID-19
• Covid19
• Novel Coronavirus Pneumonia
• Pneumonia
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Drug:
• 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
• 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
• MSC-exosomes delivered intravenously every other day (8:8:8)
Dosed 8 X 10^9, 8 X 10^9, 8 X 10^9 mL

Locations

Country	Name	City	State
United States	Mission Community Hospital	Panorama City	California

Sponsors (1)

Lead Sponsor	Collaborator
AVEM HealthCare

Country where clinical trial is conducted

United States, 

References & Publications (18)

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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. — View Citation

Chiappelli F, Khakshooy A, Greenberg G. CoViD-19 Immunopathology and Immunotherapy. Bioinformation. 2020 Mar 31;16(3):219-222. doi: 10.6026/97320630016219. eCollection 2020. — View Citation

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. — View Citation

Gao Y, Sun J, Dong C, Zhao M, Hu Y, Jin F. Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Alleviate PM2.5-Induced Lung Injury and Pulmonary Fibrosis. Med Sci Monit. 2020 Apr 18;26:e922782. doi: 10.12659/MSM.922782. — View Citation

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. Review. — View Citation

Liang X, Zhang L, Wang S, Han Q, Zhao RC. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci. 2016 Jun 1;129(11):2182-9. doi: 10.1242/jcs.170373. — View Citation

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. Review. — View Citation

Munford RS, Pugin J. Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med. 2001 Feb;163(2):316-21. Review. — View Citation

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. Review. — View Citation

Ruan L, Wen M, Zeng Q, Chen C, Huang S, Yang S, Yang J, Wang J, Hu Y, Ding S, Zhang Y, Zhang H, Feng Y, Jin K, Zhuge Q. New Measures for the Coronavirus Disease 2019 Response: A Lesson From the Wenzhou Experience. Clin Infect Dis. 2020 Jul 28;71(15):866-869. doi: 10.1093/cid/ciaa386. — View Citation

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. Erratum in: Intensive Care Med. 2020 Apr 6;:. — View Citation

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. — View Citation

Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, Lin YT, Lai WY, Yang DM, Chou SJ, Yang YP, Wang ML, Chiou SH. A Review of SARS-CoV-2 and the Ongoing Clinical Trials. Int J Mol Sci. 2020 Apr 10;21(7). pii: E2657. doi: 10.3390/ijms21072657. Review. — View Citation

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;6:42. — View Citation

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. — View Citation

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. Review. Erratum in: J Autoimmun. 2020 Jul;111:102487. — View Citation

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. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	90 Days
Primary	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.	90 Days
Secondary	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.	90 Days from last dose
Secondary	Record and analyze respiratory measures (Berlin Score/PEEP) following treatment regime.	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™.	90 Days from last dose