MSCs in COVID-19 ARDS

NCT ID: NCT04371393

Last Updated: 2022-04-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 223 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-30
• Study Completion Date: 2022-01-02

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.

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.

Conditions

Mesenchymal Stromal Cells; Remestemcel-L; Acute Respiratory Distress Syndrome; COVID

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Remestemcel-L Plus Standard of Care

Intravenous infusion of remestemcel-L 2x10\^6 MSC/kg of body weight plus standard of care

Group Type: EXPERIMENTAL

Remestemcel-L

Intervention Type: BIOLOGICAL

administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)

Placebo Plus Standard of Care

Placebo (Plasma-Lyte) plus standard of care

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)

Interventions

Remestemcel-L

administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)

Intervention Type: BIOLOGICAL

Placebo

administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mesoblast, Inc.

INDUSTRY

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Icahn School of Medicine at Mount Sinai

OTHER

Sponsor Role: lead

Responsible Party

Annetine Gelijns

Chair, Department of Population Health Science & Policy

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Annetine C Gelijns, PhD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Michael Mack, MD

Role: STUDY_DIRECTOR

Baylor Research Institute

Peter Smith, MD

Role: STUDY_DIRECTOR

Duke University

Locations

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

Countries

United States

Other Identifiers

GCO 08-1078-0014

Identifier Type: -

Identifier Source: org_study_id