Safety & Efficacy of Intramyocardial Injection of Mesenchymal Precursor Cells on Myocardial Function in LVAD Recipients

• Sponsor: Annetine Gelijns (Other)
• Overall Status: Completed
• CT.gov ID: NCT02362646
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 159
• Locations: 19
• Arms: 2
• Duration (Months): 49.7
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The main purpose of this research is to determine whether injecting mesenchymal precursor cells (MPC) into the heart during surgery to implant a left ventricular assist device (LVAD) is safe. MPCs are normally present in human bone marrow and have been shown to increase the development of blood vessels and new heart muscle cells in the heart. In addition, this research is being done to test whether injecting the MPCs into the heart is effective in improving heart function.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure; Cardiomyopathy; Ventricular Dysfunction	Biological: MPC Intramyocardial Injection; Drug: Control Solution	Phase 2

Detailed Description

Intramyocardial injection of mesenchymal precursor cells (MPC) in patients with advanced heart failure who are treated with left ventricular assist device (LVAD) implantation may result in a renewable source of proliferating functional cardiomyocytes; induce development of capillaries and larger-size blood vessels to supply oxygen and nutrients to endogenous myocardium and newly-implanted cardiomyocytes; and release factors capable of paracrine signaling.

Study Design

• Study Type: Interventional
• Actual Enrollment: 159 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Safety & Efficacy of Intramyocardial Injection of Mesenchymal Precursor Cells on Myocardial Function in LVAD Recipients
• Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Aug 10, 2018
• Actual Study Completion Date: Aug 23, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MPC Intramyocardial Injection Intramyocardial injections of 150 million MPCs	Biological: MPC Intramyocardial Injection; Intramyocardial injection of 150 million mesenchymal precursor cells at the time of LVAD implantation; Other Names: Mesenchymal Precursor Cell Injection RevascorTM
Sham Comparator: Control Solution Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO	Drug: Control Solution; Other Names: 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO Cryoprotective media

Outcome Measures

Primary Outcome Measures

1. Number of Temporary Weans From LVAD Support Tolerated [up to 6 months]

   functional status, defined by the number of temporary weans from LVAD support tolerated over the 6 months post-randomization. A successful wean is the ability to tolerate temporary weaning from LVAD support for 30 minutes without sustained symptoms of worsening heart failure. Wean failures are defined as inability to tolerate the temporary wean for 30 minutes; death; or patient too unstable, in the judgment of the primary heart failure cardiologist, to tolerate the wean attempt.

2. Number of Participants With Adverse Events [up to 6 months]

   Safety as assessed by number of study intervention-related adverse events

Secondary Outcome Measures

1. Physiologic Assessments [up to 12 months]

   Echocardiographic assessments of the myocardial size and function by transthoracic echocardiography with LVAD at full support, and as tolerated following 6-Minute Walk Test (MWT) while weaned from LVAD support (for patients who tolerate wean from LVAD support for 30 minutes)

2. Histopathological Assessments of Myocardial Tissue [up to 12 months]

3. Overall Survival [up to 12 months]

4. Change in Quality of Life (QoL) [6 months and 12 months]

   Quality of life will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), a widely used tool in heart failure populations, and the Short Form 12 (SF12), a widely used overall health status measure.

5. Hopkins Verbal Learning Test [3 months and 12 months]

   Cognitive performance will be assessed Hopkins Verbal Learning Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.

6. Trailmaking Tests A and B [3 months and 12 months]

   Cognitive performance will be assessed using Trailmaking Tests A and B. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.

7. MCG Complex Figures [3 months and 12 months]

   Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.

8. Digit Span [3 months and 12 months]

   Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.

9. Digit Symbol Substitution Test [3 months and 12 months]

   Cognitive performance will be assessed using the Digit Symbol Substitution Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.

10. Controlled Oral Word Association [3 months and 12 months]

    Cognitive performance will be assessed using the Controlled Oral Word Association. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.

11. Length of Stay [up to 12 months]

    Length of stay of index hospitalization

12. Hospitalizations [up to 12 months]

    Frequency and cause of readmissions

13. Hospital Costs [up to 12 months]

    Hospital resource use

14. Functional Status [up to 12 months]

    functional status, defined by the number of temporary weans from LVAD support tolerated

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed informed consent, inclusive of release of medical information, and Health Insurance Portability and Accountability Act (HIPAA) documentation

• Age 18 years or older

• If the subject or partner is of childbearing potential, he or she must be willing to use adequate contraception (hormonal or barrier method or abstinence) from the time of screening and for a period of at least 16 weeks after procedure

• Female subjects of childbearing potential must have a negative serum pregnancy test at screening

• Admitted to the clinical center at the time of randomization

• Clinical indication and accepted candidate for implantation of an FDA-approved (US sites only) or Health Canada-approved (Canadian sites only) implantable, non-pulsatile LVAD as a bridge to transplantation or for destination therapy.

Exclusion Criteria:

• Planned percutaneous LVAD implantation

• Anticipated requirement for biventricular mechanical support

• Concomitant arrhythmia ablation at time of LVAD implantation

-- Planned aortic valve intervention for aortic insufficiency at the time of LVAD implantation

• Cardiothoracic surgery within 30 days prior to randomization

• Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as unstable plaque rupture, erosion or dissection within 30 days prior to randomization

• Prior cardiac transplantation, LV reduction surgery, or cardiomyoplasty

• Acute reversible cause of heart failure (e.g. myocarditis, profound hypothyroidism)

• Stroke within 30 days prior to randomization

• Platelet count < 100,000/ul within 24 hours prior to randomization

• Acute infectious process: acute bacterial, fungal, or viral disease OR acute exacerbation of chronic infectious disease such as hepatitis

• Presence of >10% anti-HLA antibody titers with known specificity to MPC donor HLA antigens

• A known hypersensitivity to dimethyl sulfoxide (DMSO), murine, and/or bovine products

• History of a known active malignancy within the past 3 years except for localized prostate cancer, cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that has been definitively treated

• Presence of human immunodeficiency virus (HIV)

• Received investigational intervention within 30 days prior to randomization

• Treatment and/or an incomplete follow-up treatment of any investigational cell based therapy within 6 months prior to randomization

• Active participation in other research therapy for cardiovascular repair/regeneration

• Prior recipient of stem precursor cell therapy for cardiac repair

• Pregnant or breastfeeding at time of randomization.

• History of known or suspected hypercoagulable state in the opinion of the investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California	Los Angeles	California	United States	90033
2	Stanford University School of Medicine	Stanford	California	United States	94305
3	University of Maryland	Baltimore	Maryland	United States	21201
4	University of Michigan	Ann Arbor	Michigan	United States	48109
5	Henry Ford Hospital	Detroit	Michigan	United States	48202
6	Montefiore Einstein Heart Center	Bronx	New York	United States	10467
7	Columbia University Medical Center	New York	New York	United States	10032
8	Duke University	Durham	North Carolina	United States	27710
9	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
10	Ohio State University	Columbus	Ohio	United States	43210
11	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
12	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
13	Baylor Research Institute	Plano	Texas	United States	75093
14	University of Utah	Salt Lake City	Utah	United States	84132
15	University of Virginia Health Systems	Charlottesville	Virginia	United States	22908
16	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin	United States	53726
17	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
18	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
19	Institut Universitaire de Cardiologie de Quebec (Hopital Laval)	Québec City	Quebec	Canada	G1V 4G5

Sponsors and Collaborators

• Annetine Gelijns
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Chair: Patrick O'Gara, MD, Brigham and Women's Hospital
• Study Chair: Richard Weisel, MD, Toronto General Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 15, 2018

More Information

Additional Information:

• Cardiothoracic Surgical Network Website

Publications

None provided.

• Responsible Party: Annetine Gelijns, Chair, Department of Population Health Science & Policy; Edmond A. Guggenheim Professor of Health Policy; Co-Director, InCHOIR, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT02362646
• Other Study ID Numbers: GCO 08-1078-0008; 2U01HL088942-07
• First Posted: Feb 13, 2015
• Last Update Posted: Nov 26, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Annetine Gelijns, Chair, Department of Population Health Science & Policy; Edmond A. Guggenheim Professor of Health Policy; Co-Director, InCHOIR, Icahn School of Medicine at Mount Sinai: Heart Failure; Left Ventricular Assist Device; Heart Transplantation; Cardiomyopathy, Destination Therapy; Cell Therapy; Bridge to Transplant
• Additional relevant MeSH terms: Heart Failure; Cardiomyopathies; Ventricular Dysfunction

Study Results

Participant Flow

Recruitment Details	Screening started in 2014. First patient randomized in July 2015. Last patient randomized in August 2017.

Arm/Group Title	MPC Intramyocardial Injection	Control Solution
Arm/Group Description	MPC Intramyocardial Injection: Intramyocardial injection of 150 million mesenchymal precursor cells (MPCs) at the time of LVAD implantation	Control Solution: Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO
Period Title: Overall Study
STARTED	106	53
COMPLETED	68	29
NOT COMPLETED	38	24

Baseline Characteristics

Arm/Group Title	MPC Intramyocardial Injection	Control Solution	Total
Arm/Group Description	MPC Intramyocardial Injection: Intramyocardial injection of 150 million mesenchymal precursor cells (MPCs) at the time of LVAD implantation	Control Solution: Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO	Total of all reporting groups
Overall Participants	106	53	159
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.5 (12.3)	56.9 (11.7)	56 (12.1)
Sex: Female, Male (Count of Participants)
Female	12 11.3%	6 11.3%	18 11.3%
Male	94 88.7%	47 88.7%	141 88.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 5.7%	0 0%	6 3.8%
Not Hispanic or Latino	100 94.3%	52 98.1%	152 95.6%
Unknown or Not Reported	0 0%	1 1.9%	1 0.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 1.9%	0 0%	2 1.3%
Asian	2 1.9%	5 9.4%	7 4.4%
Native Hawaiian or Other Pacific Islander	1 0.9%	0 0%	1 0.6%
Black or African American	16 15.1%	7 13.2%	23 14.5%
White	82 77.4%	40 75.5%	122 76.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 2.8%	1 1.9%	4 2.5%

Outcome Measures

1. Primary Outcome

Title	Number of Temporary Weans From LVAD Support Tolerated
Description	functional status, defined by the number of temporary weans from LVAD support tolerated over the 6 months post-randomization. A successful wean is the ability to tolerate temporary weaning from LVAD support for 30 minutes without sustained symptoms of worsening heart failure. Wean failures are defined as inability to tolerate the temporary wean for 30 minutes; death; or patient too unstable, in the judgment of the primary heart failure cardiologist, to tolerate the wean attempt.
Time Frame	up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MPC Intramyocardial Injection	Control Solution
Arm/Group Description	MPC Intramyocardial Injection: Intramyocardial injection of 150 million mesenchymal precursor cells (MPCs) at the time of LVAD implantation	Control Solution: Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO
Measure Participants	106	53
Mean (Standard Deviation) [number of weans]	0.61 (0.41)	0.58 (0.45)

2. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Safety as assessed by number of study intervention-related adverse events
Time Frame	up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MPC Intramyocardial Injection	Control Solution
Arm/Group Description	Intramyocardial injections of 150 million MPCs MPC Intramyocardial Injection: Intramyocardial injection of 150 million mesenchymal precursor cells at the time of LVAD implantation	Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO Control Solution
Measure Participants	106	53
Serious AE	88 83%	44 83%
Other than Serious AE	33 31.1%	12 22.6%

3. Secondary Outcome

Title	Physiologic Assessments
Description	Echocardiographic assessments of the myocardial size and function by transthoracic echocardiography with LVAD at full support, and as tolerated following 6-Minute Walk Test (MWT) while weaned from LVAD support (for patients who tolerate wean from LVAD support for 30 minutes)
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Histopathological Assessments of Myocardial Tissue
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Overall Survival
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Change in Quality of Life (QoL)
Description	Quality of life will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), a widely used tool in heart failure populations, and the Short Form 12 (SF12), a widely used overall health status measure.
Time Frame	6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Hopkins Verbal Learning Test
Description	Cognitive performance will be assessed Hopkins Verbal Learning Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time Frame	3 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Trailmaking Tests A and B
Description	Cognitive performance will be assessed using Trailmaking Tests A and B. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time Frame	3 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	MCG Complex Figures
Description	Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time Frame	3 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Digit Span
Description	Cognitive performance will be assessed using the MCG Complex Figures. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time Frame	3 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Digit Symbol Substitution Test
Description	Cognitive performance will be assessed using the Digit Symbol Substitution Test. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time Frame	3 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Controlled Oral Word Association
Description	Cognitive performance will be assessed using the Controlled Oral Word Association. Neurocognitive testing will be administered by clinical site personnel who have been trained and certified for test administration by the Neurocognitive Core lab personnel.
Time Frame	3 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Length of Stay
Description	Length of stay of index hospitalization
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Hospitalizations
Description	Frequency and cause of readmissions
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Hospital Costs
Description	Hospital resource use
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	Functional Status
Description	functional status, defined by the number of temporary weans from LVAD support tolerated
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	6 months for adverse events 12 months for mortality
Adverse Event Reporting Description	Trial specific protocol-defined adverse event
Arm/Group Title	MPC Intramyocardial Injection		Control Solution
Arm/Group Description	Intramyocardial injections of 150 million MPCs MPC Intramyocardial Injection: Intramyocardial injection of 150 million mesenchymal precursor cells at the time of LVAD implantation		Intramyocardial injections of 50% Alpha-MEM/42.5% ProFreeze NAO Freezing Medium/7.5% DMSO Control Solution
All Cause Mortality
	MPC Intramyocardial Injection		Control Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/106 (14.2%)		8/53 (15.1%)
Serious Adverse Events
	MPC Intramyocardial Injection		Control Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/106 (83%)		41/53 (77.4%)
Blood and lymphatic system disorders
Hemolysis	4/106 (3.8%)		2/53 (3.8%)
Venous Thromboembolism Event	2/106 (1.9%)		1/53 (1.9%)
Cardiac disorders
Sustained ventricular dysrhythmia requiring defibrillation or cardioversion	26/106 (24.5%)		8/53 (15.1%)
Sustained supraventricular dysrhythmia requiring drug treatment or cardioversion	12/106 (11.3%)		9/53 (17%)
Right heart failure	19/106 (17.9%)		10/53 (18.9%)
Pericardial Fluid Collection	8/106 (7.5%)		3/53 (5.7%)
Vasodilatory State	3/106 (2.8%)		0/53 (0%)
MI (Non-perioperative)	1/106 (0.9%)		0/53 (0%)
Sustained SVT dysrhytmia	14/106 (13.2%)		3/53 (5.7%)
General disorders
Bleeding	51/106 (48.1%)		28/53 (52.8%)
Potential Inflammatory Responses	1/106 (0.9%)		0/53 (0%)
Hepatobiliary disorders
Hepatic Dysfunction	1/106 (0.9%)		1/53 (1.9%)
Infections and infestations
Localized nondevice infection	20/106 (18.9%)		14/53 (26.4%)
Sepsis	14/106 (13.2%)		6/53 (11.3%)
Percutaneous site and/or pocket infection	6/106 (5.7%)		5/53 (9.4%)
Localized nondevice infection	16/106 (15.1%)		8/53 (15.1%)
Injury, poisoning and procedural complications
Pump thrombus confirmed	10/106 (9.4%)		3/53 (5.7%)
Pump thrombus suspected	9/106 (8.5%)		3/53 (5.7%)
Nonpump thrombus related	1/106 (0.9%)		0/53 (0%)
Minor device malfunction	2/106 (1.9%)		0/53 (0%)
Wound Dehiscence	1/106 (0.9%)		1/53 (1.9%)
Nervous system disorders
Toxic metabolic encephalopathy	5/106 (4.7%)		4/53 (7.5%)
Ischemic stroke	6/106 (5.7%)		1/53 (1.9%)
Intracranial hemorrhage	6/106 (5.7%)		0/53 (0%)
Transient ischemic attack	3/106 (2.8%)		1/53 (1.9%)
Other neurological dysfunction	5/106 (4.7%)		3/53 (5.7%)
Psychiatric disorders
Psychiatric Episode	1/106 (0.9%)		0/53 (0%)
Renal and urinary disorders
Renal dysfunction	10/106 (9.4%)		5/53 (9.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory Failure	16/106 (15.1%)		10/53 (18.9%)
Pleural Effusion	13/106 (12.3%)		6/53 (11.3%)
Pleural Effusion	6/106 (5.7%)		3/53 (5.7%)
Vascular disorders
Hypertension	4/106 (3.8%)		1/53 (1.9%)
Arterial Non-CNS Thromboembolism	1/106 (0.9%)		0/53 (0%)
Other (Not Including Serious) Adverse Events
	MPC Intramyocardial Injection		Control Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/106 (31.1%)		12/53 (22.6%)
Cardiac disorders
Sustained supraventricular dysrhythmia	14/106 (13.2%)		3/53 (5.7%)
Infections and infestations
Localized nondevice infection	16/106 (15.1%)		8/53 (15.1%)
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	6/106 (5.7%)		3/53 (5.7%)

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.