Clinical trial NCT04371393: MSCs in COVID-19 ARDS
Official title: Mesenchymal Stromal Cells for the Treatment of Moderate to Severe COVID-19 Acute Respiratory Distress Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Mesenchymal Stromal Cells
Remestemcel-L
Acute Respiratory Distress Syndrome
COVID
Keywords: mesenchymal stem cells
SARS-CoV-2
cytokine storm
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Mesoblast, Inc.
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2020-05-01
Enrollment: 223
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a randomized (1:1 ratio), double blind, parallel design, placebo controlled trial.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of all-cause mortality
timeFrame: 30 days
Secondary outcomes:
measure: Number of days alive off mechanical ventilatory support
timeFrame: 60 days
measure: Number of adverse events
timeFrame: 30 days
measure: Number of participants alive at day 7
timeFrame: 7 days
measure: Number of participants alive at day 14
timeFrame: 14 days
measure: Number of participants alive at day 60
timeFrame: 60 days
measure: Number of participants alive at day 90
timeFrame: 90 days
measure: Number of participants alive at 12 Months
timeFrame: 12 Months
measure: Number of participants with resolution and/or improvement of ARDS
timeFrame: 7 days
measure: Number of participants with resolution and/or improvement of ARDS
timeFrame: 14 days
measure: Number of participants with resolution and/or improvement of ARDS
timeFrame: 21 days
measure: Number of participants with resolution and/or improvement of ARDS
timeFrame: 30 days
measure: Severity of ARDS
timeFrame: baseline and 7 days
measure: Severity of ARDS
timeFrame: baseline and 14 days
measure: Severity of ARDS
timeFrame: baseline and 21 days
measure: Severity of ARDS
timeFrame: baseline and 30 days
measure: Length of stay
timeFrame: 12 months
measure: Readmissions
timeFrame: 12 months
measure: Length of Stay in Intensive Care Unit
timeFrame: 12 months
measure: Clinical Improvement Scale
timeFrame: 7 days
measure: Clinical Improvement Scale
timeFrame: 14 days
measure: Clinical Improvement Scale
timeFrame: 21 days
measure: Clinical Improvement Scale
timeFrame: 30 days
measure: Change in plasma hs-CRP concentration
timeFrame: baseline and 7 days
measure: Change in plasma hs-CRP concentration
timeFrame: baseline and 14 days
measure: Change in plasma hs-CRP concentration
timeFrame: baseline and 21 days
measure: Change in serum hs-CRP concentration
timeFrame: baseline and 30 days
measure: Change in IL-6 inflammatory marker level
timeFrame: baseline and 7 days
measure: Change in IL-6 inflammatory marker level
timeFrame: baseline and 14 days
measure: Change in IL-6 inflammatory marker level
timeFrame: baseline and 21 days
measure: Change in IL-6 inflammatory marker level
timeFrame: baseline and 30 days
measure: Change in IL-8 inflammatory marker level
timeFrame: baseline and 7 days
measure: Change in IL-8 inflammatory marker level
timeFrame: baseline and 21 days
measure: Change in IL-8 inflammatory marker level
timeFrame: baseline and 14 days
measure: Change in IL-8 inflammatory marker level
timeFrame: baseline and 30 days
measure: Change in TNF-alpha inflammatory marker level
timeFrame: baseline and 7 days
measure: Change in TNF-alpha inflammatory marker level
timeFrame: baseline and 14 days
measure: Change in TNF-alpha inflammatory marker level
timeFrame: baseline and 21 days
measure: Change in TNF-alpha inflammatory marker level
timeFrame: baseline and 30 days
measure: Pulmonary symptoms
timeFrame: 6 months
measure: Pulmonary symptoms
timeFrame: 12 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Dignity Health
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Fort Wayne
country: United States
facility: Lutheran Hospital
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Clinic
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock
state: New Hampshire
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: New York
country: United States
facility: Mount Sinai Health
state: New York
city: New York
country: United States
facility: Northwell Health
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Raleigh
country: United States
facility: WakeMed
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Plano
country: United States
facility: Baylor, Smith & White
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Annetine C Gelijns, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor Research Institute
name: Michael Mack, MD
role: STUDY_DIRECTOR
affiliation: Duke University
name: Peter Smith, MD
role: STUDY_DIRECTOR
References: