MSCs in COVID-19 ARDS

April 18, 2022 updated by: Annetine Gelijns, Icahn School of Medicine at Mount Sinai

Mesenchymal Stromal Cells for the Treatment of Moderate to Severe COVID-19 Acute Respiratory Distress Syndrome

The mortality rate in SARS-CoV-2-related severe ARDS is high despite treatment with antivirals, glucocorticoids, immunoglobulins, and ventilation. Preclinical and clinical evidence indicate that MSCs migrate to the lung and respond to the pro-inflammatory lung environment by releasing anti-inflammatory factors reducing the proliferation of pro-inflammatory cytokines while modulating regulatory T cells and macrophages to promote resolution of inflammation. Therefore, MSCs may have the potential to increase survival in management of COVID-19 induced ARDS.

The primary objective of this phase 3 trial is to evaluate the efficacy and safety of the addition of the mesenchymal stromal cell (MSC) remestemcel-L plus standard of care compared to placebo plus standard of care in patients with acute respiratory distress syndrome (ARDS) due to SARS-CoV-2. The secondary objective is to assess the impact of MSCs on inflammatory biomarkers.

Study Overview

Detailed Description

This will be a randomized (1:1 ratio), double blind, parallel design, placebo controlled trial. Randomization will be stratified by clinical center and by moderate versus severe ARDS. The study is designed to have three interim analyses for stopping accrual early for efficacy and futility when 30%, 45% and 60% of the 300 patients have reached the primary endpoint using Bayesian predictive probabilities.

Patients will be randomized in a 1:1 allocation to intravenous infusion of MSCs (remestemcel-L) plus standard of care versus placebo plus standard of care for the treatment of COVID-19 related ARDS:

  • Group 1: 2x10^6 MSC/kg of body weight plus standard of care, administered twice during the first week, with the second infusion at 4 days following the first infusion (± 1 day)
  • Group 2: Placebo (Plasma-Lyte) plus standard of care, administered twice during the first week, with the second infusion at 4 days following the first infusion (± 1 day) (control)

MSCs and placebo will initially be administered intravenously in the dose defined above at randomization. The rate of infusion may be tailored to the patient's respiratory status and fluid status, but the duration of infusion should not exceed 60 minutes.

Patients will be followed for 90 days post randomization, with assessment of pulmonary symptoms at 6 and 12 months.

Study Type

Interventional

Enrollment (Actual)

223

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Arizona
      • Gilbert, Arizona, United States, 85297
        • Dignity Health
    • California
      • Los Angeles, California, United States, 90033
        • University of Southern California
      • Stanford, California, United States, 94305
        • Stanford University
    • Georgia
      • Atlanta, Georgia, United States, 30308
        • Emory University
    • Indiana
      • Fort Wayne, Indiana, United States, 46825
        • Lutheran Hospital
    • Louisiana
      • New Orleans, Louisiana, United States, 70121
        • Ochsner Clinic
    • Maine
      • Portland, Maine, United States, 04102
        • Maine Medical Center
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Brigham and Women's Hospital
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan
    • New Hampshire
      • Lebanon, New Hampshire, United States, 03766
        • Dartmouth-Hitchcock
    • New York
      • New York, New York, United States, 10075
        • Northwell Health
      • New York, New York, United States, 10016
        • New York University Langone Health
      • New York, New York, United States, 10029
        • Mount Sinai Health
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center
      • Raleigh, North Carolina, United States, 27610
        • WakeMed
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Foundation
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania Health System
    • Texas
      • Houston, Texas, United States, 77030
        • Houston Methodist Hospital
      • Plano, Texas, United States, 75093
        • Baylor, Smith & White
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • University of Virginia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria

  • 18 years or older
  • Patient has SARS-CoV-2 (COVID-19) confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR) assay or other diagnostic test
  • Patient requiring mechanical ventilatory support with moderate to severe ARDS as determined by the following criteria (adapted from the Berlin criteria)

    • Bilateral opacities must be present on a chest radiograph or computerized tomographic (CT) scan. These opacities are not fully explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules.
    • Respiratory failure not fully explained by cardiac failure or fluid overload.
    • Moderate to severe impairment of oxygenation must be present, as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2). The severity of the hypoxemia defines the severity of the ARDS:
  • Moderate ARDS: PaO2/FiO2 >100 mmHg and ≤200 mmHg, on ventilator settings that include PEEP ≥5 cm H2O OR
  • Severe ARDS: PaO2/FiO2 ≤100 mmHg on ventilator settings that include PEEP ≥5 cm H2O
  • High sensitivity C-Reactive Protein (hs-CRP) or CRP serum level >4.0 mg/dL
  • Acute Physiologic and Chronic Health Evaluation (APACHE IV) score >5
  • Creatinine clearance of ≥ 30 mL/minute OR a creatinine clearance of 20-29 mL/minute with urine output of ≥0.3 mLs/kg/hour over the last 8 hours or ≥500 mLs over the last 24 hours
  • The patient or his/her legally authorized representative (LAR) is able to provide informed consent

Exclusion Criteria

  • Currently receiving extracorporeal membrane oxygenation (ECMO) or high frequency oscillatory ventilation (HFOV)
  • Females who are pregnant or lactating
  • Patients with established positive bacterial blood cultures prior to enrollment or suspicion of superimposed bacterial pneumonia
  • Patients with BMI >55
  • Patients with untreated HIV infection
  • Patients with malignancy who are within 12 months of active treatment with any chemotherapy, radiation or immunotherapy.
  • Patients who have been intubated for more than 72 hours in total at the time of randomization
  • Creatinine clearance less than 20 mL/minute or receiving renal replacement therapy
  • LFTs (isolated ALT or AST) > 8x upper limit of normal or > 5x upper limit of normal in the setting of other liver function abnormalities (i.e., total bilirubin ≥ 2x upper limit of normal)
  • Known hypersensitivity to DMSO or to porcine or bovine proteins
  • History of prior respiratory disease with requirement for supplemental oxygen
  • Any end-stage organ disease which in the opinion of the investigator may possibly affect the safety of remestemcel-L treatment
  • Receiving an investigational cellular therapy agent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Remestemcel-L Plus Standard of Care
Intravenous infusion of remestemcel-L 2x10^6 MSC/kg of body weight plus standard of care
administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)
Placebo Comparator: Placebo Plus Standard of Care
Placebo (Plasma-Lyte) plus standard of care
administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of all-cause mortality
Time Frame: 30 days
Number of all-cause mortality within 30 days of randomization.
30 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of days alive off mechanical ventilatory support
Time Frame: 60 days
Number of days alive off mechanical ventilatory support calculated as the number of days, within the 60 days window, that patients were alive and free of mechanical ventilatory support.
60 days
Number of adverse events
Time Frame: 30 days
Safety analyses will be assessed by adverse event rates calculated as the ratio of the total number of events over 30 days divided by total patient-time at risk for the specific event from randomization.
30 days
Number of participants alive at day 7
Time Frame: 7 days
7 days
Number of participants alive at day 14
Time Frame: 14 days
14 days
Number of participants alive at day 60
Time Frame: 60 days
60 days
Number of participants alive at day 90
Time Frame: 90 days
90 days
Number of participants alive at 12 Months
Time Frame: 12 Months
12 Months
Number of participants with resolution and/or improvement of ARDS
Time Frame: 7 days
The number and percent of patients with resolution and/or improvement of ARDS at day 7
7 days
Number of participants with resolution and/or improvement of ARDS
Time Frame: 14 days
The number and percent of patients with resolution and/or improvement of ARDS at day 14
14 days
Number of participants with resolution and/or improvement of ARDS
Time Frame: 21 days
The number and percent of patients with resolution and/or improvement of ARDS at day 21
21 days
Number of participants with resolution and/or improvement of ARDS
Time Frame: 30 days
The number and percent of patients with resolution and/or improvement of ARDS at day 30
30 days
Severity of ARDS
Time Frame: baseline and 7 days
severity of ARDS according to Berlin Criteria at days 7 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
baseline and 7 days
Severity of ARDS
Time Frame: baseline and 14 days
severity of ARDS according to Berlin Criteria at days 14 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
baseline and 14 days
Severity of ARDS
Time Frame: baseline and 21 days
severity of ARDS according to Berlin Criteria at days 21 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
baseline and 21 days
Severity of ARDS
Time Frame: baseline and 30 days
severity of ARDS according to Berlin Criteria at days 30 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
baseline and 30 days
Length of stay
Time Frame: 12 months
Hospital length of stay
12 months
Readmissions
Time Frame: 12 months
number of readmission
12 months
Length of Stay in Intensive Care Unit
Time Frame: 12 months
12 months
Clinical Improvement Scale
Time Frame: 7 days
Change from baseline in Clinical Improvement Scale at day 7. Clinical Improvement Scale full scale from 1 to 7, with higher score indicating more clinical improvement.
7 days
Clinical Improvement Scale
Time Frame: 14 days
Change from baseline in Clinical Improvement Scale at day 14. Full scale from 1 to 7, with higher score indicating more clinical improvement.
14 days
Clinical Improvement Scale
Time Frame: 21 days
Change from baseline in Clinical Improvement Scale at day 21. Clinical Improvement Scale full scale from 1 to 7, with higher score indicating more clinical improvement.
21 days
Clinical Improvement Scale
Time Frame: 30 days
Change from baseline in Clinical Improvement Scale at day 30. Clinical Improvement Scale full scale from 1 to 7, with higher score indicating more clinical improvement.
30 days
Change in plasma hs-CRP concentration
Time Frame: baseline and 7 days
Changes from baseline in plasma hs-CRP concentration at days 7
baseline and 7 days
Change in plasma hs-CRP concentration
Time Frame: baseline and 14 days
Changes from baseline in plasma hs-CRP concentration at days 14
baseline and 14 days
Change in plasma hs-CRP concentration
Time Frame: baseline and 21 days
Changes from baseline in plasma hs-CRP concentration at days 21
baseline and 21 days
Change in serum hs-CRP concentration
Time Frame: baseline and 30 days
Changes from baseline in serum hs-CRP concentration at days 30
baseline and 30 days
Change in IL-6 inflammatory marker level
Time Frame: baseline and 7 days
Changes from baseline in IL-6 inflammatory marker level at 7 days
baseline and 7 days
Change in IL-6 inflammatory marker level
Time Frame: baseline and 14 days
Changes from baseline in IL-6 inflammatory marker level at 14 days
baseline and 14 days
Change in IL-6 inflammatory marker level
Time Frame: baseline and 21 days
Changes from baseline in IL-6 inflammatory marker level at 21 days
baseline and 21 days
Change in IL-6 inflammatory marker level
Time Frame: baseline and 30 days
Changes from baseline in IL-6 inflammatory marker level at 30 days
baseline and 30 days
Change in IL-8 inflammatory marker level
Time Frame: baseline and 7 days
Changes from baseline in IL-6 inflammatory marker level at 7 days
baseline and 7 days
Change in IL-8 inflammatory marker level
Time Frame: baseline and 21 days
Changes from baseline in IL-6 inflammatory marker level at 21 days
baseline and 21 days
Change in IL-8 inflammatory marker level
Time Frame: baseline and 14 days
Changes from baseline in IL-6 inflammatory marker level at 14 days
baseline and 14 days
Change in IL-8 inflammatory marker level
Time Frame: baseline and 30 days
Changes from baseline in IL-6 inflammatory marker level at 30 days
baseline and 30 days
Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 7 days
Changes from baseline in TNF-alpha inflammatory marker level at 7 days
baseline and 7 days
Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 14 days
Changes from baseline in TNF-alpha inflammatory marker level at 14 days
baseline and 14 days
Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 21 days
Changes from baseline in TNF-alpha inflammatory marker level at 21 days
baseline and 21 days
Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 30 days
Changes from baseline in TNF-alpha inflammatory marker level at 30 days
baseline and 30 days
Pulmonary symptoms
Time Frame: 6 months
including the presence of emphysema, COPD, asthma, pulmonary fibrosis, other pulmonary disease, and the need for respiratory support will be reported by randomization
6 months
Pulmonary symptoms
Time Frame: 12 months
including the presence of emphysema, COPD, asthma, pulmonary fibrosis, other pulmonary disease, and the need for respiratory support will be reported by randomization
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Director: Michael Mack, MD, Baylor Research Institute
  • Study Director: Peter Smith, MD, Duke University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 30, 2020

Primary Completion (Actual)

January 14, 2021

Study Completion (Actual)

January 2, 2022

Study Registration Dates

First Submitted

April 28, 2020

First Submitted That Met QC Criteria

April 28, 2020

First Posted (Actual)

May 1, 2020

Study Record Updates

Last Update Posted (Actual)

April 25, 2022

Last Update Submitted That Met QC Criteria

April 18, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

All of the individual participant data collected during the trial, after deidentification.

IPD Sharing Time Frame

De-identified study data sets must be submitted to the designated NHLBI Program Official no later than 3 years after the end of the clinical activity (final patient follow-up, etc.) or 2 years after the main paper of the trial has been published, whichever comes first. Data are prepared by the study coordinating center and sent to the designated PO for review prior to release.

IPD Sharing Access Criteria

Anyone who wishes to access the data.

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)
  • Analytic Code

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on COVID

Clinical Trials on Remestemcel-L

3
Subscribe