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

Tracking Information

• First Submitted Date: March 19, 2014
• First Posted Date: March 27, 2014
• Results First Submitted Date: January 15, 2019
• Results First Posted Date: April 10, 2019
• Last Update Posted Date: April 10, 2019
• Actual Study Start Date: March 15, 2014
• Actual Primary Completion Date: March 9, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 18, 2019)

• 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)
• 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
• 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

Original Primary Outcome Measures (submitted: March 24, 2014)

• Incidence of pre-specified infusion associated events occurring within 6 hours of study infusion [ Time Frame: 6 hours ]
• Any cardiac arrest or death within 24 hours of study infusion [ Time Frame: 24 hours ]
• Any unexpected severe adverse events in two groups [ Time Frame: 12 months ]

Current Secondary Outcome Measures (submitted: March 18, 2019)

• PaO2:FiO2 Change From Baseline to Day 3 [ Time Frame: baseline and day 3 ]
  Efficacy endpoint: PaO2:FiO2 change from baseline to day 3
• 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.
• 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
• 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.
• Number of Patients Death to Day 28 [ Time Frame: 28 days ]
  Efficacy endpoint: all-cause mortality at day 28
• Mortality to Day 60 [ Time Frame: 60 days ]
  Efficacy endpoint: all-cause mortality at day 60
• Number of Ventilator-free Days to Day 28 [ Time Frame: 28 days ]
  Efficacy endpoint: Number of ventilator-free days to day 28.
• Non-pulmonary Organ-failure-free Days to Day 28 [ Time Frame: 28 days ]
  Efficacy endpoint: Non-pulmonary organ-failure-free days to day 28
• Angiopoietin 2 Change From Baseline to 6 h [ Time Frame: baseline and 6 hours ]
  Biological markers of endothelial injury: angiopoietin 2
• Angiopoietin 2 Change From Baseline to 24 h [ Time Frame: baseline and 24 hours ]
  Biological markers of endothelial injury: angiopoietin 2
• Interleukin 6 Change From Baseline to 6 h [ Time Frame: baseline and 6 hours ]
  Biological markers of inflammation: interleukin 6
• Interleukin 6 Change From Baseline to 24 h [ Time Frame: baseline and 24 hours ]
  Biological markers of inflammation: interleukin 6
• Interleukin 8 Change From Baseline to 6 h [ Time Frame: baseline and 6 hours ]
  Biological markers of inflammation: interleukin 8
• Interleukin 8 Change From Baseline to 24 h [ Time Frame: baseline and 24 hours ]
  Biological markers of inflammation: interleukin 8
• 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)
• 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)

Original Secondary Outcome Measures (submitted: March 24, 2014)

• Respiratory efficacy endpoints which include lung injury score, PaO2/FiO2 ratio and oxygenation index at day 3. [ Time Frame: 28 days ]
• Systemic efficacy endpoints which include SOFA score, ventilator-free days, organ failure free days, mortality, et al. [ Time Frame: 60 days ]
• Biological efficacy endpoints which includes serial levels of plasma and urine biomarkers. [ Time Frame: 3 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Human Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (START)
• 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)
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Respiratory Distress Syndrome, Adult

Intervention

• 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.
• Biological: Plasma-Lyte A
  Plasma-Lyte A placebo was administered intravenously over approximately 60-80 minutes.

Study Arms

• 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.
  Intervention: Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells
• Placebo Comparator: Plasma-Lyte A (placebo)
  A single dose of Plasma-Lyte A was administered intravenously over approximately 60-80 minutes.
  Intervention: Biological: Plasma-Lyte A

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 24, 2014): 60
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: February 9, 2018
• Actual Primary Completion Date: March 9, 2017 (Final data collection date for primary outcome measure)

Eligibility 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02097641
• Other Study ID Numbers: UCSF-hMSC-ARDS-P2; 1U01HL108713-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Michael A. Matthay, University of California, San Francisco
• Original Responsible Party: Same as current
• Current Study Sponsor: Michael A. Matthay
• Original Study Sponsor: Same as current

Collaborators

• 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

• PRS Account: University of California, San Francisco
• Verification Date: March 2019