MSCs in COVID-19 ARDS

Acute Respiratory Distress Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04371393
• Other study ID #: GCO 08-1078-0014
• Status: Terminated
• Phase: Phase 3
• Start date: April 30, 2020
• Est. completion date: January 2, 2022

Study information

• Verified date: April 2022
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 223
• Est. completion date: January 2, 2022
• Est. primary completion date: January 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• COVID
• Mesenchymal Stromal Cells
• Remestemcel-L
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

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)

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Maryland	Baltimore	Maryland
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	University of Virginia	Charlottesville	Virginia
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Lutheran Hospital	Fort Wayne	Indiana
United States	Dignity Health	Gilbert	Arizona
United States	Houston Methodist Hospital	Houston	Texas
United States	Dartmouth-Hitchcock	Lebanon	New Hampshire
United States	University of Southern California	Los Angeles	California
United States	Ochsner Clinic	New Orleans	Louisiana
United States	Mount Sinai Health	New York	New York
United States	New York University Langone Health	New York	New York
United States	Northwell Health	New York	New York
United States	University of Pennsylvania Health System	Philadelphia	Pennsylvania
United States	Baylor, Smith & White	Plano	Texas
United States	Maine Medical Center	Portland	Maine
United States	WakeMed	Raleigh	North Carolina
United States	Stanford University	Stanford	California

Sponsors (3)

Lead Sponsor	Collaborator
Icahn School of Medicine at Mount Sinai	Mesoblast, Inc., National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of all-cause mortality	Number of all-cause mortality within 30 days of randomization.	30 days
Secondary	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.	60 days
Secondary	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.	30 days
Secondary	Number of participants alive at day 7		7 days
Secondary	Number of participants alive at day 14		14 days
Secondary	Number of participants alive at day 60		60 days
Secondary	Number of participants alive at day 90		90 days
Secondary	Number of participants alive at 12 Months		12 Months
Secondary	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	7 days
Secondary	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	14 days
Secondary	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	21 days
Secondary	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	30 days
Secondary	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.	baseline and 7 days
Secondary	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.	baseline and 14 days
Secondary	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.	baseline and 21 days
Secondary	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.	baseline and 30 days
Secondary	Length of stay	Hospital length of stay	12 months
Secondary	Readmissions	number of readmission	12 months
Secondary	Length of Stay in Intensive Care Unit		12 months
Secondary	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.	7 days
Secondary	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.	14 days
Secondary	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.	21 days
Secondary	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.	30 days
Secondary	Change in plasma hs-CRP concentration	Changes from baseline in plasma hs-CRP concentration at days 7	baseline and 7 days
Secondary	Change in plasma hs-CRP concentration	Changes from baseline in plasma hs-CRP concentration at days 14	baseline and 14 days
Secondary	Change in plasma hs-CRP concentration	Changes from baseline in plasma hs-CRP concentration at days 21	baseline and 21 days
Secondary	Change in serum hs-CRP concentration	Changes from baseline in serum hs-CRP concentration at days 30	baseline and 30 days
Secondary	Change in IL-6 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 7 days	baseline and 7 days
Secondary	Change in IL-6 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 14 days	baseline and 14 days
Secondary	Change in IL-6 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 21 days	baseline and 21 days
Secondary	Change in IL-6 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 30 days	baseline and 30 days
Secondary	Change in IL-8 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 7 days	baseline and 7 days
Secondary	Change in IL-8 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 21 days	baseline and 21 days
Secondary	Change in IL-8 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 14 days	baseline and 14 days
Secondary	Change in IL-8 inflammatory marker level	Changes from baseline in IL-6 inflammatory marker level at 30 days	baseline and 30 days
Secondary	Change in TNF-alpha inflammatory marker level	Changes from baseline in TNF-alpha inflammatory marker level at 7 days	baseline and 7 days
Secondary	Change in TNF-alpha inflammatory marker level	Changes from baseline in TNF-alpha inflammatory marker level at 14 days	baseline and 14 days
Secondary	Change in TNF-alpha inflammatory marker level	Changes from baseline in TNF-alpha inflammatory marker level at 21 days	baseline and 21 days
Secondary	Change in TNF-alpha inflammatory marker level	Changes from baseline in TNF-alpha inflammatory marker level at 30 days	baseline and 30 days
Secondary	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	6 months
Secondary	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	12 months