Clinical trial NCT02097641: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Respiratory Distress Syndrome, Adult
Keywords: Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells
Acute Respiratory Distress Syndrome
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Massachusetts General Hospital
name: Stanford University
name: University of Pittsburgh
name: University of Minnesota
name: Ohio State University
First posted: 2014-03-27
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Numbers of Patients Occurred Pre-specified Infusion Associated Events Occurring Within 6 Hours of Study Infusion
timeFrame: 6 hours
measure: Numbers of Patients Occurred Any Cardiac Arrest or Death Within 24 Hours of Study Infusion
timeFrame: 24 hours
measure: Numbers of Patients Occurred Any Unexpected Severe Adverse Events (Including All-cause Deaths)
timeFrame: 12 months
Secondary outcomes:
measure: PaO2:FiO2 Change From Baseline to Day 3
timeFrame: baseline and day 3
measure: Lung Injury Score From Baseline to Day 3
timeFrame: baseline and day 3
measure: Oxygenation Index Change From Baseline to Day 2
timeFrame: baseline and day 2
measure: SOFA Score Change From Baseline to Day 3
timeFrame: baseline and day 3
measure: Number of Patients Death to Day 28
timeFrame: 28 days
measure: Mortality to Day 60
timeFrame: 60 days
measure: Number of Ventilator-free Days to Day 28
timeFrame: 28 days
measure: Non-pulmonary Organ-failure-free Days to Day 28
timeFrame: 28 days
measure: Angiopoietin 2 Change From Baseline to 6 h
timeFrame: baseline and 6 hours
measure: Angiopoietin 2 Change From Baseline to 24 h
timeFrame: baseline and 24 hours
measure: Interleukin 6 Change From Baseline to 6 h
timeFrame: baseline and 6 hours
measure: Interleukin 6 Change From Baseline to 24 h
timeFrame: baseline and 24 hours
measure: Interleukin 8 Change From Baseline to 6 h
timeFrame: baseline and 6 hours
measure: Interleukin 8 Change From Baseline to 24 h
timeFrame: baseline and 24 hours
measure: RAGE Change From Baseline to 6 h
timeFrame: baseline and 6 hours
measure: RAGE Change From Baseline to 24 h
timeFrame: baseline and 24 hours
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Paul
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of California, San Francisco
name: Michael A Matthay, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.