Acute Respiratory Distress Syndrome, COVID, Mesenchymal Stromal Cells, Remestemcel-L
Conditions
Keywords
mesenchymal stem cells, SARS-CoV-2, cytokine storm
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.
Interventions
BIOLOGICALRemestemcel-L
administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)
DRUGPlacebo
administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)
Sponsors
Mesoblast, Inc.
National Heart, Lung, and Blood Institute (NHLBI)
Icahn School of Medicine at Mount Sinai
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
This is a randomized clinical trial, in which the patients and investigators are masked to treatment assignment.
Intervention model description
This will be a randomized (1:1 ratio), double blind, parallel design, placebo controlled trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of all-cause mortality | 30 days | Number of all-cause mortality within 30 days of randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of adverse events | 30 days | 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. |
| 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 | 7 days | The number and percent of patients with resolution and/or improvement of ARDS at day 7 |
| Severity of ARDS | baseline and 7 days | 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. |
| Length of stay | 12 months | Hospital length of stay |
| Number of days alive off mechanical ventilatory support | 60 days | 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. |
| Length of Stay in Intensive Care Unit | 12 months | — |
| Clinical Improvement Scale | 7 days | 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. |
| Change in plasma hs-CRP concentration | baseline and 7 days | Changes from baseline in plasma hs-CRP concentration at days 7 |
| Change in serum hs-CRP concentration | baseline and 30 days | Changes from baseline in serum hs-CRP concentration at days 30 |
| Change in IL-6 inflammatory marker level | baseline and 7 days | Changes from baseline in IL-6 inflammatory marker level at 7 days |
| Change in IL-8 inflammatory marker level | baseline and 7 days | Changes from baseline in IL-6 inflammatory marker level at 7 days |
| Change in TNF-alpha inflammatory marker level | baseline and 7 days | Changes from baseline in TNF-alpha inflammatory marker level at 7 days |
| Pulmonary symptoms | 6 months | including the presence of emphysema, COPD, asthma, pulmonary fibrosis, other pulmonary disease, and the need for respiratory support will be reported by randomization |
| Readmissions | 12 months | number of readmission |
Countries
United States
Outcome results
None listed