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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
223
administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)
administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)
Dignity Health
Gilbert, Arizona, United States
University of Southern California
Los Angeles, California, United States
Stanford University
Stanford, California, United States
Emory University
Atlanta, Georgia, United States
Lutheran Hospital
Fort Wayne, Indiana, United States
Ochsner Clinic
New Orleans, Louisiana, United States
Maine Medical Center
Portland, Maine, United States
University of Maryland
Baltimore, Maryland, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
...and 11 more locations
Number of all-cause mortality
Number of all-cause mortality within 30 days of randomization.
Time frame: 30 days
Number of days alive off mechanical ventilatory support
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.
Time frame: 60 days
Number of adverse events
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.
Time frame: 30 days
Number of participants alive at day 7
Time frame: 7 days
Number of participants alive at day 14
Time frame: 14 days
Number of participants alive at day 60
Time frame: 60 days
Number of participants alive at day 90
Time frame: 90 days
Number of participants alive at 12 Months
Time frame: 12 Months
Number of participants with resolution and/or improvement of ARDS
The number and percent of patients with resolution and/or improvement of ARDS at day 7
Time frame: 7 days
Number of participants with resolution and/or improvement of ARDS
The number and percent of patients with resolution and/or improvement of ARDS at day 14
Time frame: 14 days
Number of participants with resolution and/or improvement of ARDS
The number and percent of patients with resolution and/or improvement of ARDS at day 21
Time frame: 21 days
Number of participants with resolution and/or improvement of ARDS
The number and percent of patients with resolution and/or improvement of ARDS at day 30
Time frame: 30 days
Severity of ARDS
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.
Time frame: baseline and 7 days
Severity of ARDS
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.
Time frame: baseline and 14 days
Severity of ARDS
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.
Time frame: baseline and 21 days
Severity of ARDS
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.
Time frame: baseline and 30 days
Length of stay
Hospital length of stay
Time frame: 12 months
Readmissions
number of readmission
Time frame: 12 months
Length of Stay in Intensive Care Unit
Time frame: 12 months
Clinical Improvement Scale
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.
Time frame: 7 days
Clinical Improvement Scale
Change from baseline in Clinical Improvement Scale at day 14. Full scale from 1 to 7, with higher score indicating more clinical improvement.
Time frame: 14 days
Clinical Improvement Scale
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.
Time frame: 21 days
Clinical Improvement Scale
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.
Time frame: 30 days
Change in plasma hs-CRP concentration
Changes from baseline in plasma hs-CRP concentration at days 7
Time frame: baseline and 7 days
Change in plasma hs-CRP concentration
Changes from baseline in plasma hs-CRP concentration at days 14
Time frame: baseline and 14 days
Change in plasma hs-CRP concentration
Changes from baseline in plasma hs-CRP concentration at days 21
Time frame: baseline and 21 days
Change in serum hs-CRP concentration
Changes from baseline in serum hs-CRP concentration at days 30
Time frame: baseline and 30 days
Change in IL-6 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 7 days
Time frame: baseline and 7 days
Change in IL-6 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 14 days
Time frame: baseline and 14 days
Change in IL-6 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 21 days
Time frame: baseline and 21 days
Change in IL-6 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 30 days
Time frame: baseline and 30 days
Change in IL-8 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 7 days
Time frame: baseline and 7 days
Change in IL-8 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 21 days
Time frame: baseline and 21 days
Change in IL-8 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 14 days
Time frame: baseline and 14 days
Change in IL-8 inflammatory marker level
Changes from baseline in IL-6 inflammatory marker level at 30 days
Time frame: baseline and 30 days
Change in TNF-alpha inflammatory marker level
Changes from baseline in TNF-alpha inflammatory marker level at 7 days
Time frame: baseline and 7 days
Change in TNF-alpha inflammatory marker level
Changes from baseline in TNF-alpha inflammatory marker level at 14 days
Time frame: baseline and 14 days
Change in TNF-alpha inflammatory marker level
Changes from baseline in TNF-alpha inflammatory marker level at 21 days
Time frame: baseline and 21 days
Change in TNF-alpha inflammatory marker level
Changes from baseline in TNF-alpha inflammatory marker level at 30 days
Time frame: baseline and 30 days
Pulmonary symptoms
including the presence of emphysema, COPD, asthma, pulmonary fibrosis, other pulmonary disease, and the need for respiratory support will be reported by randomization
Time frame: 6 months
Pulmonary symptoms
including the presence of emphysema, COPD, asthma, pulmonary fibrosis, other pulmonary disease, and the need for respiratory support will be reported by randomization
Time frame: 12 months
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