Human Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (START)

Study Overview
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Brief Summary
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This was a Phase 2a, randomized, double-blind, placebo-controlled, multi-center trial to assess the safety and efficacy of a single dose of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) infusion in patients with Acute Respiratory Distress Syndrome (ARDS).

Detailed Description
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We carried out a randomized, double-blind placebo-controlled trial of allogeneic bone marrow derived human mesenchymal stromal cells for treatment of moderate to severe ARDS in 60 patients, 40 MSC and 20 placebo, in a 2:1 randomization. This trial is the extension of the Phase 1 pilot trial (NCT01775774). Patients were followed daily for adverse events through day 28, death or hospital discharge, whichever occurs first. Vital status was collected at 6 and 12 months after study enrollment.

Official Title
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Prospective, Randomized, Multi-center Phase 2 Clinical Trial of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) for the Treatment of Acute Respiratory Distress Syndrome (ARDS)

Conditions
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Respiratory Distress Syndrome, Adult

Intervention / Treatment
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* Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells
* Biological: Plasma-Lyte A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will be eligible for inclusion if they meet all of the below criteria. Criteria 1-3 must all be present within a 24-hour time period and at the time of enrollment: Acute onset (defined below) of: A need for positive pressure ventilation by an endotracheal or tracheal tube with a PaO2/FiO2 ratio < 200 with at least 8 cm H2O positive end-expiratory airway pressure (PEEP) Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph No clinical evidence of left atrial hypertension for bilateral pulmonary infiltrates. Exclusion Criteria: Age less than 18 years Greater than 96 hours since first meeting ARDS criteria per the Berlin definition of ARDS Pregnant or breast-feeding Prisoner Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last 2 years Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50% Moderate to severe liver failure (Childs-Pugh Score > 12) Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or the use of home oxygen Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest) Major trauma in the prior 5 days Lung transplant patient No consent/inability to obtain consent Moribund patient not expected to survive 24 hours World Health Organization (WHO) Class III or IV pulmonary hypertension Documented deep venous thrombosis or pulmonary embolism within past 3 months No arterial line/no intent to place an arterial line No intent/unwillingness to follow lung protective ventilation strategy or fluid management protocol Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV)

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human Mesenchymal Stromal Cells (hMSCs)<br>A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells was administered intravenously over approximately 60-80 minutes. | Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells<br>* Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells was administered intravenously over approximately 60-80 minutes.<br>|
| Placebo Comparator: Plasma-Lyte A (placebo)<br>A single dose of Plasma-Lyte A was administered intravenously over approximately 60-80 minutes. | Biological: Plasma-Lyte A<br>* Plasma-Lyte A placebo was administered intravenously over approximately 60-80 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numbers of Patients Occurred Pre-specified Infusion Associated Events Occurring Within 6 Hours of Study Infusion | Within 6 h of study product infusion: Increase in vasopressor dose to the following values or higher: Norepinephrine 10 μg/min Phenylephrine 100 μg/min Dopamine 10 μg/kg per min Epinephrine 0.1 μg/kg per min or addition of a third vasopressor New ventricular tachycardia, ventricular fibrillation or asystole New cardiac arrhythmia requiring cardioversion Hypoxaemia requiring an increase in FiO2 of 0·2 or more and an increase in PEEP of 5·0 or more to maintain SpO2 in the target range of 88-95% Clinical scenario consistent with transfusion incompatibility or transfusion-related infection (eg, urticaria, new bronchospasm) | 6 hours | 
| Numbers of Patients Occurred Any Cardiac Arrest or Death Within 24 Hours of Study Infusion | Within 24 h of study product infusion • Any cardiac arrest or death | 24 hours | 
| Numbers of Patients Occurred Any Unexpected Severe Adverse Events (Including All-cause Deaths) | Safety endpoint: Any unexpected severe adverse events in two groups | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PaO2:FiO2 Change From Baseline to Day 3 | Efficacy endpoint: PaO2:FiO2 change from baseline to day 3 | baseline and day 3 | 
| Lung Injury Score From Baseline to Day 3 | Murray score for acute lung injury. The range is 0 to 4. The higher score, the worst outcome. | baseline and day 3 | 
| Oxygenation Index Change From Baseline to Day 2 | Oxygenation index with the following validated measure of respiratory function: FiO2 (%) x mean airway pressure / PaO2 | baseline and day 2 | 
| SOFA Score Change From Baseline to Day 3 | Sequential organ failure assessment score (SOFA). The SOFA score ranges from 0 to 24. The higher, the worse. | baseline and day 3 | 
| Number of Patients Death to Day 28 | Efficacy endpoint: all-cause mortality at day 28 | 28 days | 
| Mortality to Day 60 | Efficacy endpoint: all-cause mortality at day 60 | 60 days | 
| Number of Ventilator-free Days to Day 28 | Efficacy endpoint: Number of ventilator-free days to day 28. | 28 days | 
| Non-pulmonary Organ-failure-free Days to Day 28 | Efficacy endpoint: Non-pulmonary organ-failure-free days to day 28 | 28 days | 
| Angiopoietin 2 Change From Baseline to 6 h | Biological markers of endothelial injury: angiopoietin 2 | baseline and 6 hours | 
| Angiopoietin 2 Change From Baseline to 24 h | Biological markers of endothelial injury: angiopoietin 2 | baseline and 24 hours | 
| Interleukin 6 Change From Baseline to 6 h | Biological markers of inflammation: interleukin 6 | baseline and 6 hours | 
| Interleukin 6 Change From Baseline to 24 h | Biological markers of inflammation: interleukin 6 | baseline and 24 hours | 
| Interleukin 8 Change From Baseline to 6 h | Biological markers of inflammation: interleukin 8 | baseline and 6 hours | 
| Interleukin 8 Change From Baseline to 24 h | Biological markers of inflammation: interleukin 8 | baseline and 24 hours | 
| RAGE Change From Baseline to 6 h | Biological markers of alveolar epithelial injury: receptor for advanced glycation end products (RAGE) | baseline and 6 hours | 
| RAGE Change From Baseline to 24 h | Biological markers of alveolar epithelial injury: receptor for advanced glycation end products (RAGE) | baseline and 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells, Acute Respiratory Distress Syndrome