Extracellular Vesicle Infusion Treatment for COVID-19 Associated ARDS (EXIT-COVID19)

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; ARDS
• Intervention / Treatment: Other: Intravenous normal saline; Biological: ExoFlo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Sheffield, Alabama, United States, 35660
      • Direct Biologics Investigational Site
  • California
    • Anaheim, California, United States, 92805
      • Direct Biologics Investigational Site
  • Pennsylvania
    • Sayre, Pennsylvania, United States, 18840
      • Direct Biologics Investigational Site
  • Texas
    • Houston, Texas, United States, 77024
      • Direct Biologics Investigational Site
    • Lubbock, Texas, United States, 79410
      • Direct Biologics Investigational Site
    • Mesquite, Texas, United States, 75149
      • Direct Biologics Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of signed and dated informed consent form (either by the individual or by the individual's healthcare proxy).
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged 18-85.
4. COVID-19 positive as defined by positive Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) SARS-CoV-2.

5. 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.

6. 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.
7. 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:

1. Vulnerable populations such as pregnant patients, children, individuals with severe physical or mental disabilities who cannot provide meaningful consent.
2. Active malignancy requiring treatment within the last five years.
3. 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.
4. Active tuberculosis or cystic fibrosis.
5. Severe chronic respiratory disease including chronic obstructive pulmonary disease or pulmonary fibrosis requiring home oxygen > 5L/min.
6. Use of extracorporeal membrane oxygenation (ECMO) during the current hospitalization.
7. Pre-existing pulmonary hypertension.
8. Severe pre-existing hepatic impairment (presence of cirrhosis, liver function tests (LFTs) ≥ 6x baseline, INR ≥ 2.0).
9. 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)
10. 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).
11. 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).
12. Patients who are not full code.
13. Endotracheal intubation duration ≤ 24 hours.
14. Moribund-expected survival < 24 hours.
15. Severe metabolic disturbances on presentation (e.g., ketoacidosis, pH < 7.3)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Ribonucleic Acid (RNA) Level	Viremia	Days = 1, 4, 7, 10, 15, 29 *Labs are not drawn after hospitalization.
CRP, D-dimer, Ferritin, IL-6, TNF-α	Acute Phase Reactants	Days = 1, 4, 7, 10, 15, 29 *Labs are not drawn after hospitalization
Absolute Neutrophil Count (ANC), CD3+, CD4+, and CD8+ T Cells, NK Cells	Immune Cell Counts	Days = 1, 4, 7, 10, 15, 29 *Labs are not drawn after hospitalization.
Sequential Organ Failure Assessment (SOFA)	Mortality Prediction Score Ranging from 0 to 24 with Higher SOFA Score Correlating with Higher Mortality	Days = 1, 15, 29 *Labs are only drawn if patient is still hospitalized.
EQ-5D-5L Description Part Only, Which Includes 5 Dimensions of Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety Depression)	Standardized Quality of Life Metric Where Each Dimension Is Assessed via 5 Levels; 5 Levels for Each Digit is Combined into a 5 Digit Descriptor.	Days = 15, 29, and 61 *Only Assessed for Outpatients

Collaborators and Investigators

• Sponsor: Direct Biologics, LLC
• Investigators: Study Director: Bill Arana, Direct Biologics, LLC

Publications and helpful links

General Publications

• Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev. 2020 Jun 15;29(12):747-754. doi: 10.1089/scd.2020.0080. Epub 2020 May 12.

Helpful Links

• Direct Biologics, LLC

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2020
• Primary Completion (Actual): May 1, 2021
• Study Completion (Actual): May 22, 2021

Study Registration Dates

• First Submitted: July 29, 2020
• First Submitted That Met QC Criteria: July 29, 2020
• First Posted (Actual): July 30, 2020

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19; ARDS; Exosome; Extracellular Vesicles
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: DB-EF-PHASEII-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No