MSCs in COVID-19 ARDS

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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COVID, Mesenchymal Stromal Cells, Remestemcel-L, Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Biological: Remestemcel-L
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a randomized (1:1 ratio), double blind, parallel design, placebo controlled trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remestemcel-L Plus Standard of Care<br>Intravenous infusion of remestemcel-L 2x10^6 MSC/kg of body weight plus standard of care | Biological: Remestemcel-L<br>* administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)<br>|
| Placebo Comparator: Placebo Plus Standard of Care<br>Placebo (Plasma-Lyte) plus standard of care | Drug: Placebo<br>* administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of all-cause mortality | Number of all-cause mortality within 30 days of randomization. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Number of participants alive at day 7 |  | 7 days | 
| Number of participants alive at day 14 |  | 14 days | 
| Number of participants alive at day 60 |  | 60 days | 
| Number of participants alive at day 90 |  | 90 days | 
| Number of participants alive at 12 Months |  | 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 | 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 | 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 | 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 | 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. | 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. | 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. | 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. | baseline and 30 days | 
| Length of stay | Hospital length of stay | 12 months | 
| Readmissions | number of readmission | 12 months | 
| Length of Stay in Intensive Care Unit |  | 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. | 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. | 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. | 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. | 30 days | 
| Change in plasma hs-CRP concentration | Changes from baseline in plasma hs-CRP concentration at days 7 | baseline and 7 days | 
| Change in plasma hs-CRP concentration | Changes from baseline in plasma hs-CRP concentration at days 14 | baseline and 14 days | 
| Change in plasma hs-CRP concentration | Changes from baseline in plasma hs-CRP concentration at days 21 | baseline and 21 days | 
| Change in serum hs-CRP concentration | Changes from baseline in serum hs-CRP concentration at days 30 | baseline and 30 days | 
| Change in IL-6 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 7 days | baseline and 7 days | 
| Change in IL-6 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 14 days | baseline and 14 days | 
| Change in IL-6 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 21 days | baseline and 21 days | 
| Change in IL-6 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 30 days | baseline and 30 days | 
| Change in IL-8 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 7 days | baseline and 7 days | 
| Change in IL-8 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 21 days | baseline and 21 days | 
| Change in IL-8 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 14 days | baseline and 14 days | 
| Change in IL-8 inflammatory marker level | Changes from baseline in IL-6 inflammatory marker level at 30 days | baseline and 30 days | 
| Change in TNF-alpha inflammatory marker level | Changes from baseline in TNF-alpha inflammatory marker level at 7 days | baseline and 7 days | 
| Change in TNF-alpha inflammatory marker level | Changes from baseline in TNF-alpha inflammatory marker level at 14 days | baseline and 14 days | 
| Change in TNF-alpha inflammatory marker level | Changes from baseline in TNF-alpha inflammatory marker level at 21 days | baseline and 21 days | 
| Change in TNF-alpha inflammatory marker level | Changes from baseline in TNF-alpha inflammatory marker level at 30 days | 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 | 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 | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mesenchymal stem cells, SARS-CoV-2, cytokine storm