START: Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome

• Sponsor: Michael A. Matthay (Other)
• Overall Status: Completed
• CT.gov ID: NCT01775774
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Massachusetts General Hospital (Other), Stanford University (Other), University of Pittsburgh (Other), University of Minnesota (Other)
• Enrollment: 9
• Locations: 4
• Arm: 1
• Duration (Months): 19.1
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 1, open label, dose escalation, multi-center clinical trial of Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells (hMSCs) for the treatment of Acute Respiratory Distress Syndrome (ARDS). The purpose of this study is to assess the safety of hMSCs in patients with ARDS.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome	Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells	Phase 1

Detailed Description

The primary objective of this study is to assess the safety of intravenous infusion of Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells (hMSCs) in patients with ARDS.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Multi-center Clinical Trial of Allogeneic Bone Marrow-derived Human Mesenchymal Stem Cells for the Treatment of Acute Respiratory Distress Syndrome
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells A dose-escalation with 3 cohorts with 3 subjects/cohort who receive doses of 1, 5 and 10 million cells/kg predicted body weight (PBW). Proceed from lower dose to next higher dose if no safety concerns for each cohort.	Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells; Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously.

Outcome Measures

Primary Outcome Measures

1. Incidence of Pre-specified Infusion Associated Adverse Events [24 hours]

   Any of the following occurring within 6 h of mesenchymal stem-cell infusion: Addition of a third vasopressor or an increase in vasopressor dose greater than or equal to the following: Norepinephrine: 10 μg per min Phenylephrine: 100 μg per min Dopamine: 10 μg/kg per min Epinephrine: 0·1 μg/kg per min Hypoxaemia requiring an increase in the fraction of inspired oxygen of ≥0·2 and increase in positive end-expiratory airway pressure level of 5 cm H2O or more to maintain transcutaneous oxygen saturations in the target range of 88-95% New cardiac arrhythmia requiring cardioversion New ventricular tachycardia, ventricular fi brillation, or asystole A clinical scenario consistent with transfusion incompatibility or transfusion-related infection Cardiac arrest or death within 24 h of mesenchymal stem-cell infusion

Secondary Outcome Measures

1. Incidence of Severe Adverse Events (SAEs) [Investigators conducted daily assessments for the presence of adverse events (AE) from enrollment through study day 28 or hospital discharge, whichever occurred first.]

   The number of participants with a severe adverse event during the study was assessed.

2. Ventilator Free Days at Study Day 28 [time of initiating unassisted breathing to day 28]

   Ventilator Free Days (VFDs) to day 28 were defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject received assisted breathing at day 27 or died prior to day 28, a value of zero VFDs was given.

3. Duration of Vasopressor Use (Days) [28 days]

   Days on vasopressor to day 28 after study enrollment

4. ICU Free Days to Day 28 [28 days after study enrollment]

5. Hospital Survival to Day 60 [60 days after randomization]

   The number of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60.

6. Mortality at Hospital Discharge [From study enrollment to Hospital discharge]

   The number of patients expired at hospital discharge.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

In addition to meeting inclusion criteria, enrollment must occur within 96-hours of first meeting ARDS criteria per the Berlin definition of ARDS.

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. 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

	Site	City	State	Country	Postal Code
1	University of California San Francisco Medical Center	San Francisco	California	United States	94143
2	Stanford University Medical Center	Stanford	California	United States	94305
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	University of Pittsburgh Medical Center	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

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Michael A. Matthay, Prinicpal Investigator, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01775774
• Other Study ID Numbers: ARDS MSC 001; 1U01HL108713-01
• First Posted: Jan 25, 2013
• Last Update Posted: Aug 14, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Michael A. Matthay, Prinicpal Investigator, University of California, San Francisco: Acute Respiratory Distress Syndrome; Acute Lung Injury; Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome

Study Results

Participant Flow

Recruitment Details	This dose-escalation Phase 1 clinical trial with 3 cohorts with 3 subjects/cohort was performed in 7 centers in USA between July 2013 to January 2014.

Arm/Group Title	Human Mesenchymal Stem Cells 1 Million Cells/kg PBW	Human Mesenchymal Stem Cells 5 Million Cells/kg PBW	Human Mesenchymal Stem Cells 10 Million Cells/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Period Title: Overall Study
STARTED	3	3	3
COMPLETED	3	3	3
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Human Mesenchymal Stem Cells 1 Million Cells/kg PBW	Mesenchymal Stem Cells 5 Million Cells/kg PBW	Mesenchymal Stem Cells 10 Million Cells/kg PBW	Total
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Total of all reporting groups
Overall Participants	3	3	3	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	2 66.7%	3 100%	7 77.8%
>=65 years	1 33.3%	1 33.3%	0 0%	2 22.2%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	58.0	58.3	48.3	54.9
Sex: Female, Male (Count of Participants)
Female	3 100%	3 100%	1 33.3%	7 77.8%
Male	0 0%	0 0%	2 66.7%	2 22.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 66.7%	0 0%	2 22.2%
Not Hispanic or Latino	3 100%	1 33.3%	3 100%	7 77.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 33.3%	0 0%	0 0%	1 11.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	2 66.7%	3 100%	2 66.7%	7 77.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 33.3%	1 11.1%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	3 100%	9 100%
APACHE III Score (scores on a scale) [Mean (Full Range) ]
Mean (Full Range) [scores on a scale]	91.7	89.7	88.3	89.9
Primary cause of ARDS (participants) [Number]
Pneumonia	1 33.3%	1 33.3%	2 66.7%	4 44.4%
Aspiration	1 33.3%	2 66.7%	0 0%	3 33.3%
Sepsis	0 0%	0 0%	1 33.3%	1 11.1%
Pre-eclampsia	1 33.3%	0 0%	0 0%	1 11.1%

Outcome Measures

1. Primary Outcome

Title	Incidence of Pre-specified Infusion Associated Adverse Events
Description	Any of the following occurring within 6 h of mesenchymal stem-cell infusion: Addition of a third vasopressor or an increase in vasopressor dose greater than or equal to the following: Norepinephrine: 10 μg per min Phenylephrine: 100 μg per min Dopamine: 10 μg/kg per min Epinephrine: 0·1 μg/kg per min Hypoxaemia requiring an increase in the fraction of inspired oxygen of ≥0·2 and increase in positive end-expiratory airway pressure level of 5 cm H2O or more to maintain transcutaneous oxygen saturations in the target range of 88-95% New cardiac arrhythmia requiring cardioversion New ventricular tachycardia, ventricular fi brillation, or asystole A clinical scenario consistent with transfusion incompatibility or transfusion-related infection Cardiac arrest or death within 24 h of mesenchymal stem-cell infusion
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Measure Participants	3	3	3
Number [participants]	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Incidence of Severe Adverse Events (SAEs)
Description	The number of participants with a severe adverse event during the study was assessed.
Time Frame	Investigators conducted daily assessments for the presence of adverse events (AE) from enrollment through study day 28 or hospital discharge, whichever occurred first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Measure Participants	3	3	3
Number [participants]	2 66.7%	1 33.3%	0 0%

3. Secondary Outcome

Title	Ventilator Free Days at Study Day 28
Description	Ventilator Free Days (VFDs) to day 28 were defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject received assisted breathing at day 27 or died prior to day 28, a value of zero VFDs was given.
Time Frame	time of initiating unassisted breathing to day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Measure Participants	3	3	3
Median (Full Range) [day]	18	22	20

4. Secondary Outcome

Title	Duration of Vasopressor Use (Days)
Description	Days on vasopressor to day 28 after study enrollment
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Measure Participants	3	3	3
Median (Full Range) [day]	4	2	0

5. Secondary Outcome

Title	ICU Free Days to Day 28
Time Frame	28 days after study enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Measure Participants	3	3	3
Median (Full Range) [day]	14	21	18

6. Secondary Outcome

Title	Hospital Survival to Day 60
Description	The number of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60.
Time Frame	60 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Measure Participants	3	3	3
Number [participants]	2 66.7%	2 66.7%	3 100%

7. Secondary Outcome

Title	Mortality at Hospital Discharge
Description	The number of patients expired at hospital discharge.
Time Frame	From study enrollment to Hospital discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW	Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts.
Measure Participants	3	3	3
Number [participants]	1 33.3%	1 33.3%	0 0%

Adverse Events

Time Frame	1 year
Arm/Group Title	Human Mesenchymal Stem Cells: 1 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 5 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 10 Million Cells/kg PBW
Arm/Group Description	Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously.		Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously.		Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously.
All Cause Mortality
	Human Mesenchymal Stem Cells: 1 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 5 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 10 Million Cells/kg PBW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Human Mesenchymal Stem Cells: 1 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 5 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 10 Million Cells/kg PBW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Multiorgan failure	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)
Vascular disorders
Infarcts of kidneys, spleen and brain	1/3 (33.3%)		0/3 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Human Mesenchymal Stem Cells: 1 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 5 Million Cells/kg PBW		Human Mesenchymal Stem Cells: 10 Million Cells/kg PBW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)
Hepatobiliary disorders
Elevated liver function tests	0/3 (0%)		1/3 (33.3%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/3 (0%)		0/3 (0%)		1/3 (33.3%)

Limitations/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.