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

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)

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).

Study Overview

• Status: Completed
• Conditions: Respiratory Distress Syndrome, Adult
• Intervention / Treatment: Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells; Biological: Plasma-Lyte A

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 Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Saint Paul, Minnesota, United States, 55108
      • University of Minnesota Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Human Mesenchymal Stromal Cells (hMSCs); 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; Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells was administered intravenously over approximately 60-80 minutes.
Placebo Comparator: Plasma-Lyte A (placebo); A single dose of Plasma-Lyte A was administered intravenously over approximately 60-80 minutes.	Biological: Plasma-Lyte A; Plasma-Lyte A placebo was administered intravenously over approximately 60-80 minutes.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Michael A. Matthay
• Collaborators: Massachusetts General Hospital; National Heart, Lung, and Blood Institute (NHLBI); University of Pittsburgh; Stanford University; Ohio State University; University of Minnesota
• Investigators: Principal Investigator: Michael A Matthay, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Liu KD, Wilson JG, Zhuo H, Caballero L, McMillan ML, Fang X, Cosgrove K, Calfee CS, Lee JW, Kangelaris KN, Gotts JE, Rogers AJ, Levitt JE, Wiener-Kronish JP, Delucchi KL, Leavitt AD, McKenna DH, Thompson BT, Matthay MA. Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome. Ann Intensive Care. 2014 Jul 3;4:22. doi: 10.1186/s13613-014-0022-z. eCollection 2014.
• Asmussen S, Ito H, Traber DL, Lee JW, Cox RA, Hawkins HK, McAuley DF, McKenna DH, Traber LD, Zhuo H, Wilson J, Herndon DN, Prough DS, Liu KD, Matthay MA, Enkhbaatar P. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax. 2014 Sep;69(9):819-25. doi: 10.1136/thoraxjnl-2013-204980. Epub 2014 Jun 2.
• Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, Rogers AJ, Gotts JE, Wiener-Kronish JP, Bajwa EK, Donahoe MP, McVerry BJ, Ortiz LA, Exline M, Christman JW, Abbott J, Delucchi KL, Caballero L, McMillan M, McKenna DH, Liu KD. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019 Feb;7(2):154-162. doi: 10.1016/S2213-2600(18)30418-1. Epub 2018 Nov 16.
• Wick KD, Leligdowicz A, Zhuo H, Ware LB, Matthay MA. Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS. JCI Insight. 2021 Jun 22;6(12):e148983. doi: 10.1172/jci.insight.148983.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2014
• Primary Completion (Actual): March 9, 2017
• Study Completion (Actual): February 9, 2018

Study Registration Dates

• First Submitted: March 19, 2014
• First Submitted That Met QC Criteria: March 24, 2014
• First Posted (Estimate): March 27, 2014

Study Record Updates

• Last Update Posted (Actual): April 10, 2019
• Last Update Submitted That Met QC Criteria: March 18, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Acute Respiratory Distress Syndrome; Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells
• 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; Pharmaceutical Solutions; Ophthalmic Solutions; Plasma-lyte 148
• Other Study ID Numbers: UCSF-hMSC-ARDS-P2; 1U01HL108713-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO