Back to resultsHuman Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (START) (START)
Primary Purpose
Respiratory Distress Syndrome, Adult
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells
Plasma-Lyte A
Sponsored by
About this trial
This is an interventional treatment trial for Respiratory Distress Syndrome, Adult focused on measuring Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells, Acute Respiratory Distress Syndrome
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:
- 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)
- Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph
- No clinical evidence of left atrial hypertension for bilateral pulmonary infiltrates.
Exclusion Criteria:
- Age less than 18 years
- Greater than 96 hours since first meeting ARDS criteria per the Berlin definition of ARDS
- Pregnant or breast-feeding
- Prisoner
- Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last 2 years
- Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%
- Moderate to severe liver failure (Childs-Pugh Score > 12)
- Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or the use of home oxygen
- 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)
- Major trauma in the prior 5 days
- Lung transplant patient
- No consent/inability to obtain consent
- Moribund patient not expected to survive 24 hours
- World Health Organization (WHO) Class III or IV pulmonary hypertension
- Documented deep venous thrombosis or pulmonary embolism within past 3 months
- No arterial line/no intent to place an arterial line
- No intent/unwillingness to follow lung protective ventilation strategy or fluid management protocol
- Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV)
Sites / Locations
- University of California San Francisco
- Stanford University
- Massachusetts General Hospital
- University of Minnesota Medical Center
- Ohio State University
- University of Pittsburgh
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Human Mesenchymal Stromal Cells (hMSCs)
Plasma-Lyte A (placebo)
Arm Description
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.
A single dose of Plasma-Lyte A was administered intravenously over approximately 60-80 minutes.
Outcomes
Primary Outcome Measures
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)
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
Numbers of Patients Occurred Any Unexpected Severe Adverse Events (Including All-cause Deaths)
Safety endpoint: Any unexpected severe adverse events in two groups
Secondary Outcome Measures
PaO2:FiO2 Change From Baseline to Day 3
Efficacy endpoint: PaO2:FiO2 change from baseline to 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.
Oxygenation Index Change From Baseline to 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
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
Efficacy endpoint: all-cause mortality at day 28
Mortality to Day 60
Efficacy endpoint: all-cause mortality at day 60
Number of Ventilator-free Days to Day 28
Efficacy endpoint: Number of ventilator-free days to day 28.
Non-pulmonary Organ-failure-free Days to Day 28
Efficacy endpoint: Non-pulmonary organ-failure-free days to day 28
Angiopoietin 2 Change From Baseline to 6 h
Biological markers of endothelial injury: angiopoietin 2
Angiopoietin 2 Change From Baseline to 24 h
Biological markers of endothelial injury: angiopoietin 2
Interleukin 6 Change From Baseline to 6 h
Biological markers of inflammation: interleukin 6
Interleukin 6 Change From Baseline to 24 h
Biological markers of inflammation: interleukin 6
Interleukin 8 Change From Baseline to 6 h
Biological markers of inflammation: interleukin 8
Interleukin 8 Change From Baseline to 24 h
Biological markers of inflammation: interleukin 8
RAGE Change From Baseline to 6 h
Biological markers of alveolar epithelial injury: receptor for advanced glycation end products (RAGE)
RAGE Change From Baseline to 24 h
Biological markers of alveolar epithelial injury: receptor for advanced glycation end products (RAGE)
Full Information
NCT ID
NCT02097641
First Posted
March 19, 2014
Last Updated
March 18, 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
1. Study Identification
Unique Protocol Identification Number
NCT02097641
Brief Title
Human Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (START)
Acronym
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
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
March 15, 2014 (Actual)
Primary Completion Date
March 9, 2017 (Actual)
Study Completion Date
February 9, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the 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
4. Oversight
Data Monitoring Committee
Yes
5. 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).
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Distress Syndrome, Adult
Keywords
Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells, Acute Respiratory Distress Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
60 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Human Mesenchymal Stromal Cells (hMSCs)
Arm Type
Experimental
Arm Description
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.
Arm Title
Plasma-Lyte A (placebo)
Arm Type
Placebo Comparator
Arm Description
A single dose of Plasma-Lyte A was administered intravenously over approximately 60-80 minutes.
Intervention Type
Biological
Intervention Name(s)
Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells
Intervention Description
Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells was administered intravenously over approximately 60-80 minutes.
Intervention Type
Biological
Intervention Name(s)
Plasma-Lyte A
Intervention Description
Plasma-Lyte A placebo was administered intravenously over approximately 60-80 minutes.
Primary Outcome Measure Information:
Title
Numbers of Patients Occurred Pre-specified Infusion Associated Events Occurring Within 6 Hours of Study Infusion
Description
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)
Time Frame
6 hours
Title
Numbers of Patients Occurred Any Cardiac Arrest or Death Within 24 Hours of Study Infusion
Description
Within 24 h of study product infusion
• Any cardiac arrest or death
Time Frame
24 hours
Title
Numbers of Patients Occurred Any Unexpected Severe Adverse Events (Including All-cause Deaths)
Description
Safety endpoint: Any unexpected severe adverse events in two groups
Time Frame
12 months
Secondary Outcome Measure Information:
Title
PaO2:FiO2 Change From Baseline to Day 3
Description
Efficacy endpoint: PaO2:FiO2 change from baseline to day 3
Time Frame
baseline and day 3
Title
Lung Injury Score From Baseline to Day 3
Description
Murray score for acute lung injury. The range is 0 to 4. The higher score, the worst outcome.
Time Frame
baseline and day 3
Title
Oxygenation Index Change From Baseline to Day 2
Description
Oxygenation index with the following validated measure of respiratory function: FiO2 (%) x mean airway pressure / PaO2
Time Frame
baseline and day 2
Title
SOFA Score Change From Baseline to Day 3
Description
Sequential organ failure assessment score (SOFA). The SOFA score ranges from 0 to 24. The higher, the worse.
Time Frame
baseline and day 3
Title
Number of Patients Death to Day 28
Description
Efficacy endpoint: all-cause mortality at day 28
Time Frame
28 days
Title
Mortality to Day 60
Description
Efficacy endpoint: all-cause mortality at day 60
Time Frame
60 days
Title
Number of Ventilator-free Days to Day 28
Description
Efficacy endpoint: Number of ventilator-free days to day 28.
Time Frame
28 days
Title
Non-pulmonary Organ-failure-free Days to Day 28
Description
Efficacy endpoint: Non-pulmonary organ-failure-free days to day 28
Time Frame
28 days
Title
Angiopoietin 2 Change From Baseline to 6 h
Description
Biological markers of endothelial injury: angiopoietin 2
Time Frame
baseline and 6 hours
Title
Angiopoietin 2 Change From Baseline to 24 h
Description
Biological markers of endothelial injury: angiopoietin 2
Time Frame
baseline and 24 hours
Title
Interleukin 6 Change From Baseline to 6 h
Description
Biological markers of inflammation: interleukin 6
Time Frame
baseline and 6 hours
Title
Interleukin 6 Change From Baseline to 24 h
Description
Biological markers of inflammation: interleukin 6
Time Frame
baseline and 24 hours
Title
Interleukin 8 Change From Baseline to 6 h
Description
Biological markers of inflammation: interleukin 8
Time Frame
baseline and 6 hours
Title
Interleukin 8 Change From Baseline to 24 h
Description
Biological markers of inflammation: interleukin 8
Time Frame
baseline and 24 hours
Title
RAGE Change From Baseline to 6 h
Description
Biological markers of alveolar epithelial injury: receptor for advanced glycation end products (RAGE)
Time Frame
baseline and 6 hours
Title
RAGE Change From Baseline to 24 h
Description
Biological markers of alveolar epithelial injury: receptor for advanced glycation end products (RAGE)
Time Frame
baseline and 24 hours
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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:
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)
Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph
No clinical evidence of left atrial hypertension for bilateral pulmonary infiltrates.
Exclusion Criteria:
Age less than 18 years
Greater than 96 hours since first meeting ARDS criteria per the Berlin definition of ARDS
Pregnant or breast-feeding
Prisoner
Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last 2 years
Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%
Moderate to severe liver failure (Childs-Pugh Score > 12)
Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or the use of home oxygen
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)
Major trauma in the prior 5 days
Lung transplant patient
No consent/inability to obtain consent
Moribund patient not expected to survive 24 hours
World Health Organization (WHO) Class III or IV pulmonary hypertension
Documented deep venous thrombosis or pulmonary embolism within past 3 months
No arterial line/no intent to place an arterial line
No intent/unwillingness to follow lung protective ventilation strategy or fluid management protocol
Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael A Matthay, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Minnesota Medical Center
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55108
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
30455077
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.
Results Reference
result
PubMed Identifier
33974564
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.
Results Reference
derived
PubMed Identifier
25593740
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.
Results Reference
derived
PubMed Identifier
24891325
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.
Results Reference
derived
Learn more about this trial
Human Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (START)
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