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.
Biological: Remestemcel-L
administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)
Drug: Placebo
administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)
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
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
Dartmouth-Hitchcock
Lebanon, New Hampshire, United States
New York University Langone Health
New York, New York, United States
Mount Sinai Health
New York, New York, United States
Northwell Health
New York, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
WakeMed
Raleigh, North Carolina, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
University of Pennsylvania Health System
Philadelphia, Pennsylvania, United States
Houston Methodist Hospital
Houston, Texas, United States
Baylor, Smith & White
Plano, Texas, United States
University of Virginia
Charlottesville, Virginia, United States