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

• ClinicalTrials.gov Identifier: NCT02097641
• Recruitment Status: Completed
• First Posted: March 27, 2014
• Results First Posted: April 10, 2019
• Last Update Posted: April 10, 2019
• Sponsor: Michael A. Matthay
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Massachusetts General Hospital; Stanford University; University of Pittsburgh; University of Minnesota; Ohio State University
• Information provided by (Responsible Party): Michael A. Matthay, University of California, San Francisco

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Respiratory Distress Syndrome, Adult	Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells; Biological: Plasma-Lyte A	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: March 15, 2014
• Actual Primary Completion Date: March 9, 2017
• Actual Study Completion Date: February 9, 2018

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Numbers of Patients Occurred Pre-specified Infusion Associated Events Occurring Within 6 Hours of Study Infusion [ Time Frame: 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)
2. Numbers of Patients Occurred Any Cardiac Arrest or Death Within 24 Hours of Study Infusion [ Time Frame: 24 hours ]

   Within 24 h of study product infusion

   • Any cardiac arrest or death

3. Numbers of Patients Occurred Any Unexpected Severe Adverse Events (Including All-cause Deaths) [ Time Frame: 12 months ]
   Safety endpoint: Any unexpected severe adverse events in two groups

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Locations

United States, California

University of California San Francisco

San Francisco, California, United States, 94143

Stanford University

Stanford, California, United States, 94305

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Minnesota

University of Minnesota Medical Center

Saint Paul, Minnesota, United States, 55108

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43210

United States, Pennsylvania

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

Michael A. Matthay

National Heart, Lung, and Blood Institute (NHLBI)

Massachusetts General Hospital

Stanford University

University of Pittsburgh

University of Minnesota

Ohio State University

Investigators

• Principal Investigator: Michael A Matthay, MD; University of California, San Francisco

  Study Documents (Full-Text)

Documents provided by Michael A. Matthay, University of California, San Francisco:

Study Protocol and Statistical Analysis Plan  [PDF] February 17, 2015

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Michael A. Matthay, Principal Investigator, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02097641
• Other Study ID Numbers: UCSF-hMSC-ARDS-P2; 1U01HL108713-01 ( U.S. NIH Grant/Contract )
• First Posted: March 27, 2014
• Results First Posted: April 10, 2019
• Last Update Posted: April 10, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Michael A. Matthay, University of California, San Francisco:

Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells; Acute Respiratory Distress Syndrome

Additional relevant MeSH terms:

Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome; Disease; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Plasma-lyte 148; Ophthalmic Solutions; Pharmaceutical Solutions