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

Phase 2

Completed

• Conditions: Respiratory Distress Syndrome, Adult
• Interventions: Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells; Biological: Plasma-Lyte A

• Registration Number: NCT02097641
• Lead Sponsor: Michael A. Matthay

Brief Summary

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

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.

Study Timeline

• Study Start: 2014-03-15
• Study First Submitted: 2014-03-19
• Study First Submitted QC: 2014-03-24
• Study First Posted: 2014-03-27
• Primary Completion: 2017-03-09
• Study Completion: 2018-02-09
• Results First Submitted: 2019-01-15
• Status Verified: 2019-03
• Results First Submitted QC: 2019-03-18
• Last Update Submitted: 2019-03-18
• Results First Posted: 2019-04-10
• Last Update Posted: 2019-04-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

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:

1. 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)
2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph
3. No clinical evidence of left atrial hypertension for bilateral pulmonary infiltrates.

Exclusion Criteria

1. Age less than 18 years
2. Greater than 96 hours since first meeting ARDS criteria per the Berlin definition of ARDS
3. Pregnant or breast-feeding
4. Prisoner
5. Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last 2 years
6. Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%
7. Moderate to severe liver failure (Childs-Pugh Score > 12)
8. Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or the use of home oxygen
9. 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)
10. Major trauma in the prior 5 days
11. Lung transplant patient
12. No consent/inability to obtain consent
13. Moribund patient not expected to survive 24 hours
14. World Health Organization (WHO) Class III or IV pulmonary hypertension
15. Documented deep venous thrombosis or pulmonary embolism within past 3 months
16. No arterial line/no intent to place an arterial line
17. No intent/unwillingness to follow lung protective ventilation strategy or fluid management protocol
18. Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Human Mesenchymal Stromal Cells (hMSCs)	Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells	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.
Plasma-Lyte A (placebo)	Plasma-Lyte A	A single dose of Plasma-Lyte A was administered intravenously over approximately 60-80 minutes.

Primary Outcome Measures

Name	Time	Method
Numbers of Patients Occurred Pre-specified Infusion Associated Events Occurring Within 6 Hours of Study Infusion	6 hours	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)
Numbers of Patients Occurred Any Cardiac Arrest or Death Within 24 Hours of Study Infusion	24 hours	Within 24 h of study product infusion; • Any cardiac arrest or death
Numbers of Patients Occurred Any Unexpected Severe Adverse Events (Including All-cause Deaths)	12 months	Safety endpoint: Any unexpected severe adverse events in two groups

Secondary Outcome Measures

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

Trial Locations

Locations (6)

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

Stanford University; 🇺🇸 Stanford, California, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Ohio State University; 🇺🇸 Columbus, Ohio, United States

University of Minnesota Medical Center; 🇺🇸 Saint Paul, Minnesota, United States