- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04371393
MSCs in COVID-19 ARDS
Mesenchymal Stromal Cells for the Treatment of Moderate to Severe COVID-19 Acute Respiratory Distress Syndrome
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.
Study Overview
Status
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Arizona
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Gilbert, Arizona, United States, 85297
- Dignity Health
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California
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Los Angeles, California, United States, 90033
- University of Southern California
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Stanford, California, United States, 94305
- Stanford University
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Georgia
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Atlanta, Georgia, United States, 30308
- Emory University
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Indiana
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Fort Wayne, Indiana, United States, 46825
- Lutheran Hospital
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Louisiana
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New Orleans, Louisiana, United States, 70121
- Ochsner Clinic
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Maine
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Portland, Maine, United States, 04102
- Maine Medical Center
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Maryland
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Baltimore, Maryland, United States, 21201
- University of Maryland
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Massachusetts
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Boston, Massachusetts, United States, 02115
- Brigham and Women's Hospital
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Michigan
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Ann Arbor, Michigan, United States, 48109
- University of Michigan
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New Hampshire
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Lebanon, New Hampshire, United States, 03766
- Dartmouth-Hitchcock
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New York
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New York, New York, United States, 10075
- Northwell Health
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New York, New York, United States, 10016
- New York University Langone Health
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New York, New York, United States, 10029
- Mount Sinai Health
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North Carolina
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Durham, North Carolina, United States, 27710
- Duke University Medical Center
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Raleigh, North Carolina, United States, 27610
- WakeMed
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Ohio
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Cleveland, Ohio, United States, 44195
- Cleveland Clinic Foundation
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- University of Pennsylvania Health System
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Texas
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Houston, Texas, United States, 77030
- Houston Methodist Hospital
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Plano, Texas, United States, 75093
- Baylor, Smith & White
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Virginia
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Charlottesville, Virginia, United States, 22908
- University of Virginia
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Remestemcel-L Plus Standard of Care
Intravenous infusion of remestemcel-L 2x10^6 MSC/kg of body weight plus standard of care
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administered twice during the first week, with the second infusion at 4 days following the first injection (± 1 day)
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Placebo Comparator: Placebo Plus Standard of Care
Placebo (Plasma-Lyte) plus standard of care
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administered twice during the first week, with second infusion at 4 days following the first injection (± 1 day)
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of all-cause mortality
Time Frame: 30 days
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Number of all-cause mortality within 30 days of randomization.
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30 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of days alive off mechanical ventilatory support
Time Frame: 60 days
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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
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Number of adverse events
Time Frame: 30 days
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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.
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30 days
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Number of participants alive at day 7
Time Frame: 7 days
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7 days
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Number of participants alive at day 14
Time Frame: 14 days
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14 days
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Number of participants alive at day 60
Time Frame: 60 days
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60 days
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Number of participants alive at day 90
Time Frame: 90 days
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90 days
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Number of participants alive at 12 Months
Time Frame: 12 Months
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12 Months
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Number of participants with resolution and/or improvement of ARDS
Time Frame: 7 days
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The number and percent of patients with resolution and/or improvement of ARDS at day 7
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7 days
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Number of participants with resolution and/or improvement of ARDS
Time Frame: 14 days
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The number and percent of patients with resolution and/or improvement of ARDS at day 14
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14 days
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Number of participants with resolution and/or improvement of ARDS
Time Frame: 21 days
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The number and percent of patients with resolution and/or improvement of ARDS at day 21
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21 days
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Number of participants with resolution and/or improvement of ARDS
Time Frame: 30 days
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The number and percent of patients with resolution and/or improvement of ARDS at day 30
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30 days
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Severity of ARDS
Time Frame: baseline and 7 days
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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
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Severity of ARDS
Time Frame: baseline and 14 days
|
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
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Severity of ARDS
Time Frame: baseline and 21 days
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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
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Severity of ARDS
Time Frame: baseline and 30 days
|
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.
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baseline and 30 days
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Length of stay
Time Frame: 12 months
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Hospital length of stay
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12 months
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Readmissions
Time Frame: 12 months
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number of readmission
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12 months
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Length of Stay in Intensive Care Unit
Time Frame: 12 months
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12 months
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Clinical Improvement Scale
Time Frame: 7 days
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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.
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7 days
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Clinical Improvement Scale
Time Frame: 14 days
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Change from baseline in Clinical Improvement Scale at day 14.
Full scale from 1 to 7, with higher score indicating more clinical improvement.
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14 days
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Clinical Improvement Scale
Time Frame: 21 days
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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
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Clinical Improvement Scale
Time Frame: 30 days
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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.
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30 days
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Change in plasma hs-CRP concentration
Time Frame: baseline and 7 days
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Changes from baseline in plasma hs-CRP concentration at days 7
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baseline and 7 days
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Change in plasma hs-CRP concentration
Time Frame: baseline and 14 days
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Changes from baseline in plasma hs-CRP concentration at days 14
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baseline and 14 days
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Change in plasma hs-CRP concentration
Time Frame: baseline and 21 days
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Changes from baseline in plasma hs-CRP concentration at days 21
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baseline and 21 days
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Change in serum hs-CRP concentration
Time Frame: baseline and 30 days
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Changes from baseline in serum hs-CRP concentration at days 30
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baseline and 30 days
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Change in IL-6 inflammatory marker level
Time Frame: baseline and 7 days
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Changes from baseline in IL-6 inflammatory marker level at 7 days
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baseline and 7 days
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Change in IL-6 inflammatory marker level
Time Frame: baseline and 14 days
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Changes from baseline in IL-6 inflammatory marker level at 14 days
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baseline and 14 days
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Change in IL-6 inflammatory marker level
Time Frame: baseline and 21 days
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Changes from baseline in IL-6 inflammatory marker level at 21 days
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baseline and 21 days
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Change in IL-6 inflammatory marker level
Time Frame: baseline and 30 days
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Changes from baseline in IL-6 inflammatory marker level at 30 days
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baseline and 30 days
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Change in IL-8 inflammatory marker level
Time Frame: baseline and 7 days
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Changes from baseline in IL-6 inflammatory marker level at 7 days
|
baseline and 7 days
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Change in IL-8 inflammatory marker level
Time Frame: baseline and 21 days
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Changes from baseline in IL-6 inflammatory marker level at 21 days
|
baseline and 21 days
|
Change in IL-8 inflammatory marker level
Time Frame: baseline and 14 days
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Changes from baseline in IL-6 inflammatory marker level at 14 days
|
baseline and 14 days
|
Change in IL-8 inflammatory marker level
Time Frame: baseline and 30 days
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Changes from baseline in IL-6 inflammatory marker level at 30 days
|
baseline and 30 days
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Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 7 days
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Changes from baseline in TNF-alpha inflammatory marker level at 7 days
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baseline and 7 days
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Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 14 days
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Changes from baseline in TNF-alpha inflammatory marker level at 14 days
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baseline and 14 days
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Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 21 days
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Changes from baseline in TNF-alpha inflammatory marker level at 21 days
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baseline and 21 days
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Change in TNF-alpha inflammatory marker level
Time Frame: baseline and 30 days
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Changes from baseline in TNF-alpha inflammatory marker level at 30 days
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baseline and 30 days
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Pulmonary symptoms
Time Frame: 6 months
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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
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Pulmonary symptoms
Time Frame: 12 months
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including the presence of emphysema, COPD, asthma, pulmonary fibrosis, other pulmonary disease, and the need for respiratory support will be reported by randomization
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12 months
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Collaborators and Investigators
Investigators
- Study Director: Michael Mack, MD, Baylor Research Institute
- Study Director: Peter Smith, MD, Duke University
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Respiratory Tract Diseases
- Respiration Disorders
- Lung Diseases
- Disease
- Infant, Newborn, Diseases
- Lung Injury
- Infant, Premature, Diseases
- Syndrome
- Respiratory Distress Syndrome
- Respiratory Distress Syndrome, Newborn
- Acute Lung Injury
- Anti-Infective Agents
- Antiviral Agents
- Anti-Inflammatory Agents
- Remestemcel-l
Other Study ID Numbers
- GCO 08-1078-0014
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- Study Protocol
- Statistical Analysis Plan (SAP)
- Informed Consent Form (ICF)
- Clinical Study Report (CSR)
- Analytic Code
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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