MSCs in COVID-19 ARDS

• ClinicalTrials.gov Identifier: NCT04371393
• Recruitment Status: Terminated
• First Posted: May 1, 2020
• Last Update Posted: April 25, 2022
• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: Mesoblast, Inc.; National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Annetine Gelijns, Icahn School of Medicine at Mount Sinai

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Mesenchymal Stromal Cells; Remestemcel-L; Acute Respiratory Distress Syndrome; COVID	Biological: Remestemcel-L; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 223 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This will be a randomized (1:1 ratio), double blind, parallel design, placebo controlled trial.
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: This is a randomized clinical trial, in which the patients and investigators are masked to treatment assignment.
• Primary Purpose: Treatment
• Official Title: Mesenchymal Stromal Cells for the Treatment of Moderate to Severe COVID-19 Acute Respiratory Distress Syndrome
• Actual Study Start Date: April 30, 2020
• Actual Primary Completion Date: January 14, 2021
• Actual Study Completion Date: January 2, 2022

Arms and Interventions

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	Biological: Remestemcel-L; 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	Drug: Placebo; administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)

Outcome Measures

Primary Outcome Measures :

1. Number of all-cause mortality [ Time Frame: 30 days ]
   Number of all-cause mortality within 30 days of randomization.

Secondary Outcome Measures :

1. 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.
2. 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.
3. Number of participants alive at day 7 [ Time Frame: 7 days ]
4. Number of participants alive at day 14 [ Time Frame: 14 days ]
5. Number of participants alive at day 60 [ Time Frame: 60 days ]
6. Number of participants alive at day 90 [ Time Frame: 90 days ]
7. Number of participants alive at 12 Months [ Time Frame: 12 Months ]
8. 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
9. 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
10. 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
11. 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
12. 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.
13. 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.
14. 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.
15. 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.
16. Length of stay [ Time Frame: 12 months ]
    Hospital length of stay
17. Readmissions [ Time Frame: 12 months ]
    number of readmission
18. Length of Stay in Intensive Care Unit [ Time Frame: 12 months ]
19. 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.
20. 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.
21. 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.
22. 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.
23. Change in plasma hs-CRP concentration [ Time Frame: baseline and 7 days ]
    Changes from baseline in plasma hs-CRP concentration at days 7
24. Change in plasma hs-CRP concentration [ Time Frame: baseline and 14 days ]
    Changes from baseline in plasma hs-CRP concentration at days 14
25. Change in plasma hs-CRP concentration [ Time Frame: baseline and 21 days ]
    Changes from baseline in plasma hs-CRP concentration at days 21
26. Change in serum hs-CRP concentration [ Time Frame: baseline and 30 days ]
    Changes from baseline in serum hs-CRP concentration at days 30
27. 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
28. 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
29. 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
30. 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
31. 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
32. 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
33. 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
34. 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
35. 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
36. 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
37. 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
38. 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
39. 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
40. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Dignity Health

Gilbert, Arizona, United States, 85297

United States, California

University of Southern California

Los Angeles, California, United States, 90033

Stanford University

Stanford, California, United States, 94305

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30308

United States, Indiana

Lutheran Hospital

Fort Wayne, Indiana, United States, 46825

United States, Louisiana

Ochsner Clinic

New Orleans, Louisiana, United States, 70121

United States, Maine

Maine Medical Center

Portland, Maine, United States, 04102

United States, Maryland

University of Maryland

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, New Hampshire

Dartmouth-Hitchcock

Lebanon, New Hampshire, United States, 03766

United States, New York

New York University Langone Health

New York, New York, United States, 10016

Mount Sinai Health

New York, New York, United States, 10029

Northwell Health

New York, New York, United States, 10075

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

WakeMed

Raleigh, North Carolina, United States, 27610

United States, Ohio

Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Houston Methodist Hospital

Houston, Texas, United States, 77030

Baylor, Smith & White

Plano, Texas, United States, 75093

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

Sponsors and Collaborators

Icahn School of Medicine at Mount Sinai

Mesoblast, Inc.

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Annetine C Gelijns, PhD; Icahn School of Medicine at Mount Sinai
• Study Director: Michael Mack, MD; Baylor Research Institute
• Study Director: Peter Smith, MD; Duke University

More Information

• Responsible Party: Annetine Gelijns, Chair, Department of Population Health Science & Policy, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT04371393
• Other Study ID Numbers: GCO 08-1078-0014
• First Posted: May 1, 2020
• Last Update Posted: April 25, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All of the individual participant data collected during the trial, after deidentification.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• 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.
• Access Criteria: Anyone who wishes to access the data.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Annetine Gelijns, Icahn School of Medicine at Mount Sinai:

mesenchymal stem cells; SARS-CoV-2; cytokine storm

Additional relevant MeSH terms:

Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome; Disease; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Remestemcel-l; Anti-Inflammatory Agents; Antiviral Agents; Anti-Infective Agents