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 Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Respiratory Distress Syndrome, Adult
• Interventions: Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells; Biological: Plasma-Lyte A
• Enrollment: 60

Participant Flow

Recruitment Details	From March 24, 2014, to Feb 9, 2017, 1038 patients were screened for eligibility, of whom 975 were excluded, and 63 were randomly assigned to a treatment group. Three patients were not eligible for treatment after randomization and, therefore, 40 patients received human mesenchymal stem cells and 20 patients received placebo.
Pre-assignment Details	Three patients who were randomly assigned to receive human mesenchymal stem cells, were excluded: 2 did not meet baseline stability criteria; 1 patient's PaO2:FiO2 > 200 mmHg.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Period Title: Overall Study
Started	40	20
Completed	40	20
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Human Mesenchymal Stem Cells (hMSCs)	Plasma-Lyte A (Placebo)	Total
Arm/Group Description		A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.	Total of all reporting groups
Overall Number of Baseline Participants		40	20	60
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	20 participants	60 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	30 75.0%	12 60.0%	42 70.0%
	>=65 years	10 25.0%	8 40.0%	18 30.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	40 participants	20 participants	60 participants
		55 (17)	55 (20)	55 (18)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	20 participants	60 participants
	Female	23 57.5%	10 50.0%	33 55.0%
	Male	17 42.5%	10 50.0%	27 45.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	20 participants	60 participants
	Hispanic or Latino	4 10.0%	2 10.0%	6 10.0%
	Not Hispanic or Latino	31 77.5%	16 80.0%	47 78.3%
	Unknown or Not Reported	5 12.5%	2 10.0%	7 11.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	20 participants	60 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	2 5.0%	2 10.0%	4 6.7%
	Native Hawaiian or Other Pacific Islander	3 7.5%	0 0.0%	3 5.0%
	Black or African American	4 10.0%	1 5.0%	5 8.3%
	White	27 67.5%	13 65.0%	40 66.7%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	4 10.0%	4 20.0%	8 13.3%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	40 participants	20 participants	60 participants
		40	20	60
Cause of Acute Respiratory Distress Syndrome (ARDS); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	20 participants	60 participants
	Sepsis with pneumonia	19 47.5%	12 60.0%	31 51.7%
	Sepsis without pneumonia	5 12.5%	2 10.0%	7 11.7%
	Pneumonia without sepsis	11 27.5%	5 25.0%	16 26.7%
	Aspiration only	4 10.0%	1 5.0%	5 8.3%
	Other	1 2.5%	0 0.0%	1 1.7%
Arterial pressure; Mean (Standard Deviation); Unit of measure: Mm Hg
	Number Analyzed	40 participants	20 participants	60 participants
		75 (10)	76 (9)	75 (10)
Taking vasopressors at the time of infusion; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	20 participants	60 participants
		24 60.0%	9 45.0%	33 55.0%
Sequential Organ Failure Assessment (SOFA) [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	40 participants	19 participants	59 participants
		8.1 (3.3)	6.9 (2.7)	7.7 (3.2)
		[1] Measure Description: SOFA score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 24 (worst).; [2] Measure Analysis Population Description: Data not recorded in one patient treated with Plasma-Lyte A (placebo).
Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) III score [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	40 participants	19 participants	59 participants
		104 (31)	89 (33)	99 (32)
		[1] Measure Description: The range of APACHE III is from 0 to 299. The higher score, the worse clinical outcome.; [2] Measure Analysis Population Description: Data not recorded in one patient treated with Plasma-Lyte (placebo).
Minute ventilation; Mean (Standard Deviation); Unit of measure: L/min
	Number Analyzed	40 participants	20 participants	60 participants
		11.1 (3.2)	9.6 (2.4)	10.6 (3.0)
Respiratory rate; Mean (Standard Deviation); Unit of measure: Breaths/min
	Number Analyzed	40 participants	20 participants	60 participants
		27.8 (6.6)	24.5 (6.3)	26.7 (6.6)
Tidal volume [1]; Mean (Standard Deviation); Unit of measure: mL/kg predicted body weight
	Number Analyzed	39 participants	20 participants	59 participants
		6.3 (0.9)	6.1 (0.7)	6.2 (0.9)
		[1] Measure Analysis Population Description: Data not recorded in one patient treated with hMSCs.
Mean airway pressure [1]; Mean (Standard Deviation); Unit of measure: Cm H2O
	Number Analyzed	37 participants	19 participants	56 participants
		17.8 (4.9)	16.4 (3.6)	17.4 (4.6)
		[1] Measure Analysis Population Description: Data not recorded in three patients treated with hMSCs and one patient treated with Plasma-Lyte A (placebo).
Plateau airway pressure [1]; Mean (Standard Deviation); Unit of measure: Cm H2O
	Number Analyzed	30 participants	15 participants	45 participants
		26.4 (5.7)	23.7 (5.1)	25.5 (5.6)
		[1] Measure Analysis Population Description: 15 patients did not have baseline plateau pressure recorded.
Positive end-expiratory pressure (PEEP); Mean (Standard Deviation); Unit of measure: Cm H2O
	Number Analyzed	40 participants	20 participants	60 participants
		12.4 (3.7)	10.8 (2.6)	11.8 (3.4)
Driving pressure [1]; Mean (Standard Deviation); Unit of measure: Cm H2O
	Number Analyzed	30 participants	15 participants	45 participants
		14.0 (4.1)	12.5 (4.3)	13.5 (4.2)
		[1] Measure Analysis Population Description: Data not recorded in 10 patients treated with hMSCs and in 5 patients treated with Plasma-Lyte (placebo).
PaO2/FiO2; Mean (Standard Deviation); Unit of measure: kPa
	Number Analyzed	40 participants	20 participants	60 participants
		18.1 (4.3)	19.1 (5.2)	18.4 (4.6)
Oxygenation index [1] [2]; Mean (Standard Deviation); Unit of measure: kPa
	Number Analyzed	37 participants	19 participants	56 participants
		108.1 (45.9)	95.7 (41.2)	103.9 (44.4)
		[1] Measure Description: Oxygenation index calculated as: FiO2 (%) x Mean Airway Pressure / PaO2; [2] Measure Analysis Population Description: Data not recorded in 3 patients treated with hMSCs and 1 patient treated with Plasma-Lyte (placebo).
Lung injury score (LIS) [1]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	40 participants	20 participants	60 participants
		3.1 (0.4)	3.0 (0.5)	3.1 (0.4)
		[1] Measure Description: LIS is a composite 4-point scoring system including the PaO2/FiO2, PEEP, lung compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used.
Ventilation mode; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	20 participants	60 participants
	Volume control	37 92.5%	17 85.0%	54 90.0%
	Pressure-regulated volume control	1 2.5%	2 10.0%	3 5.0%
	Other	2 5.0%	1 5.0%	3 5.0%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells (hMSCs)	Plasma-Lyte A (Placebo)
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	40	20
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells (hMSCs)	Plasma-Lyte A (Placebo)
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	40	20
Measure Type: Count of Participants; Unit of Measure: Participants
	1 2.5%	0 0.0%

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	40	20
Measure Type: Count of Participants; Unit of Measure: Participants
	20 50.0%	5 25.0%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values of PaO2:FiO2 were not available in 10 patients treated with hMSCs and in 2 patients treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	30	18
Median (Inter-Quartile Range); Unit of Measure: kPa
	3.7; (-1.2 to 10.8)	3.5; (-2.7 to 8.3)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values were missing in 9 hMSC patients and 2 placebo patients.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	31	18
Median (Inter-Quartile Range); Unit of Measure: units on a scale
	-0.50; (-1.00 to -0.25)	-0.33; (-0.67 to -0.08)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values were missing in 16 patients treated by MSC and 6 patients treated by placebo

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	24	14
Median (Inter-Quartile Range); Unit of Measure: kPa
	-30.3; (-67.9 to 14.9)	-19.5; (-47.8 to 10.9)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values were missing in 3 MSC patients and 1 placebo patient.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	37	19
Median (Inter-Quartile Range); Unit of Measure: units on a scale
	-2; (-4 to 0)	-1; (-4 to 1)

8. Secondary Outcome

Title	Number of Patients Death to Day 28
Description	Efficacy endpoint: all-cause mortality at day 28
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	40	20
Measure Type: Count of Participants; Unit of Measure: Participants
	12 30.0%	3 15.0%

9. Secondary Outcome

Title	Mortality to Day 60
Description	Efficacy endpoint: all-cause mortality at day 60
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	40	20
Measure Type: Count of Participants; Unit of Measure: Participants
	15 37.5%	5 25.0%

10. Secondary Outcome

Title	Number of Ventilator-free Days to Day 28
Description	Efficacy endpoint: Number of ventilator-free days to day 28.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	40	20
Median (Inter-Quartile Range); Unit of Measure: days
	2; (0 to 23)	17; (0 to 24)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	40	20
Median (Inter-Quartile Range); Unit of Measure: days
	12; (4 to 24)	8; (4 to 15)

12. Secondary Outcome

Title	Angiopoietin 2 Change From Baseline to 6 h
Description	Biological markers of endothelial injury: angiopoietin 2
Time Frame	baseline and 6 hours

Outcome Measure Data

Analysis Population Description

The biomarker values were missing in one patient treated with hMSC and one patient treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	39	19
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-1120; (-4706 to -66)	287; (-1005 to 2374)

13. Secondary Outcome

Title	Angiopoietin 2 Change From Baseline to 24 h
Description	Biological markers of endothelial injury: angiopoietin 2
Time Frame	baseline and 24 hours

Outcome Measure Data

Analysis Population Description

The values were not available in two patients treated with hMSC and two patients treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	38	18
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-2080; (-6404 to 47)	-537; (-4294 to 1029)

14. Secondary Outcome

Title	Interleukin 6 Change From Baseline to 6 h
Description	Biological markers of inflammation: interleukin 6
Time Frame	baseline and 6 hours

Outcome Measure Data

Analysis Population Description

The values were not available in one patient treated with hMSC and one patient treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	39	19
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-51; (-124 to 4)	-20; (-71 to 17)

15. Secondary Outcome

Title	Interleukin 6 Change From Baseline to 24 h
Description	Biological markers of inflammation: interleukin 6
Time Frame	baseline and 24 hours

Outcome Measure Data

Analysis Population Description

The values were not available in two patients treated with hMSC and two patients treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	38	18
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-34; (-137 to 4)	-43; (-165 to 39)

16. Secondary Outcome

Title	Interleukin 8 Change From Baseline to 6 h
Description	Biological markers of inflammation: interleukin 8
Time Frame	baseline and 6 hours

Outcome Measure Data

Analysis Population Description

The values were not available in one patient treated with hMSC and one patient treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	39	19
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-2; (-24 to 3)	-1; (-8 to 1)

17. Secondary Outcome

Title	Interleukin 8 Change From Baseline to 24 h
Description	Biological markers of inflammation: interleukin 8
Time Frame	baseline and 24 hours

Outcome Measure Data

Analysis Population Description

The values were not available in two patients treated with hMSC and two patients treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	38	18
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-5; (-34 to 4)	-5; (-17 to -1)

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values were not available in one patient treated with hMSC and one patient treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	39	19
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-326; (-888 to -45)	-322; (-624 to -93)

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values were not available in two patients treated with hMSC and two patients treated with placebo.

Arm/Group Title	Human Mesenchymal Stem Cells	Plasma-Lyte A
Arm/Group Description:	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.	A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
Overall Number of Participants Analyzed	38	18
Median (Inter-Quartile Range); Unit of Measure: pg/mL
	-393; (-1118 to -78)	-411; (-1057 to -110)

Adverse Events

Time Frame	60 days
Adverse Event Reporting Description	All-cause mortality by day 60 after study product infusion; Serious adverse events, expected and unexpected, also included any deaths through study day 28 (none of them were related to study product or study procedures per DSMB review); Please see our Lancet Resp Medicine 2018 publication (citation included) for further details including adjusted analyses of baseline differences between the MSC and placebo treated groups
Arm/Group Title	Human Mesenchymal Stem Cells		Plasma-Lyte A
Arm/Group Description	A single dose of 10 million cells/kg PBW (predicted body weight) Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells administered intravenously over approximately 60-80 minutes. Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously over approximately 60-80 minutes.		A single dose of Plasma-Lyte A will be administered intravenously over approximately 60-80 minutes. Plasma-Lyte A: Plasma-Lyte A placebo will be administered intravenously over approximately 60-80 minutes.
All-Cause Mortality
	Human Mesenchymal Stem Cells		Plasma-Lyte A
	Affected / at Risk (%)		Affected / at Risk (%)
Total	15/40 (37.50%)		5/20 (25.00%)
Serious Adverse Events
	Human Mesenchymal Stem Cells		Plasma-Lyte A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/40 (42.50%)		11/20 (55.00%)
Blood and lymphatic system disorders
Acute leukemia *	0/40 (0.00%)	0	1/20 (5.00%)	1
Diffuse alveolar hemorrhage *	1/40 (2.50%)	1	0/20 (0.00%)	0
Calvarial bone marrow abnormality *	1/40 (2.50%)	1	0/20 (0.00%)	0
Cardiac disorders
Death due to cardiac arrest *	1/40 (2.50%)	1	1/20 (5.00%)	1
Myocardial ischemia *	1/40 (2.50%)	1	0/20 (0.00%)	0
Bradycardia *	1/40 (2.50%)	1	0/20 (0.00%)	0
Tachycardia *	1/40 (2.50%)	1	0/20 (0.00%)	0
Pericardial effusion *	1/40 (2.50%)	1	0/20 (0.00%)	0
Heart block *	1/40 (2.50%)	1	0/20 (0.00%)	0
Ischemic stroke *	0/40 (0.00%)	0	1/20 (5.00%)	1
General disorders
Death due to multi-organ failure *	8/40 (20.00%)	8	2/20 (10.00%)	2
Hepatobiliary disorders
Liver abscess *	0/40 (0.00%)	0	1/20 (5.00%)	1
Acute pancreatitis *	0/40 (0.00%)	0	1/20 (5.00%)	1
Nervous system disorders
Lower extremity weakness *	0/40 (0.00%)	0	1/20 (5.00%)	1
Renal and urinary disorders
Acute renal failure *	1/40 (2.50%)	1	0/20 (0.00%)	0
Hospital readmission due to pyelonephritis *	0/40 (0.00%)	0	1/20 (5.00%)	1
Respiratory, thoracic and mediastinal disorders
Death due to worsening respiratory failure *	3/40 (7.50%)	3	0/20 (0.00%)	0
Worsening respiratory failure, recovered *	0/40 (0.00%)	0	1/20 (5.00%)	1
Aspiration pneumonitis *	1/40 (2.50%)	1	0/20 (0.00%)	0
Pulmonary embolism *	1/40 (2.50%)	1	2/20 (10.00%)	2
Surgical and medical procedures
Hospital readmission due to post-surgical pain *	0/40 (0.00%)	0	1/20 (5.00%)	1
* Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Human Mesenchymal Stem Cells		Plasma-Lyte A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/40 (5.00%)		2/20 (10.00%)
Blood and lymphatic system disorders
Acute anemia *	0/40 (0.00%)		1/20 (5.00%)
Hepatobiliary disorders
Hepatitis *	1/40 (2.50%)		0/20 (0.00%)
Renal and urinary disorders
Fecal and urinary incontinence *	0/40 (0.00%)		1/20 (5.00%)
Vascular disorders
Deep venous thrombosis *	1/40 (2.50%)		0/20 (0.00%)
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Michael A. Matthay, MD
• Organization: University of California San Francisco
• Phone: 415-502-7434
• EMail: michael.matthay@ucsf.edu

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, 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 Submitted: March 19, 2014
• First Posted: March 27, 2014
• Results First Submitted: January 15, 2019
• Results First Posted: April 10, 2019
• Last Update Posted: April 10, 2019