Clinical trial NCT02501811: Combination of Mesenchymal and C-kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure
Official title: A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, & Efficacy of Autologous Mesenchymal Stem Cells & C-kit+ Cardiac Stem Cells, Alone or in Combination, Administered Transendocardially in Subjects With Ischemic HF
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischemic Cardiomyopathy
Keywords: Heart Failure
Ischemia
Autologous Stem Cells
LV dysfunction
Mesenchymal Stem Cells
c-kit+ Cells
Combination Cell Therapy
LV function
Functional status
Lead sponsor: The University of Texas Health Science Center, Houston
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2015-07-17
Enrollment: 125
Sex: ALL
Minimum age (years): 21
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase II, randomized, placebo-controlled clinical trial designed to assess feasibility, safety, and effect of autologous bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cells both alone and in combination (Combo), compared to placebo (cell-free Plasmalyte-A medium) as well as each other, administered by transendocardial injection in subjects with ischemic cardiomyopathy.

Detailed description: This is a randomized, placebo-controlled clinical trial designed to evaluate the feasibility, safety, and effect of Combo, MSCs alone, and c-kit+ cells alone compared with placebo as well as each other in subjects with heart failure of ischemic etiology. Following a successful lead-in phase, a total of one hundred forty-four (144) subjects will be randomized (1:1:1:1) to receive Combo, MSCs, c-kit+ cells, or placebo. After randomization, baseline imaging, relevant harvest procedures, and study product injection, subjects will be followed up at 1 day, 1 week, 1 month, 3 months, 6 months and 12 months post study product injection. All subjects will receive study product injection (cells or placebo) using the NOGA® XP Mapping and Navigation System. Subjects will have delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and LV function and structure at baseline and at 6 and 12 months post study product administration. All endpoints will be assessed at the 6 and 12 month visits which will occur 180 ±30 days and 365 ±30 days respectively from the day of study product injection (Day 0). For the purpose of the endpoint analysis and safety evaluations, the Investigators will utilize an "intention-to-treat" study population, however an as treated analysis will also be conducted.

Eligibility criteria: Inclusion Criteria:

1. Be ≥ 21 and \<80 years of age
2. Have documented coronary artery disease (CAD) with evidence of myocardial injury, LV dysfunction, and clinical evidence of HF
3. Have a "detectable" area of myocardial injury defined as ≥ 5% LV involvement (infarct volume) and any subendocardial involvement by cMRI
4. Have an EF ≤ 40% by cMRI
5. Be receiving guideline-driven medical therapy for heart failure at stable and tolerated doses for ≥ 1 month prior to consent. For beta-blockade "stable" is defined as no greater than a 50% reduction in dose or no more than a 100% increase in dose.
6. Be a candidate for cardiac catheterization
7. Have NYHA class I, II, or III heart failure symptoms
8. If a female of childbearing potential, be willing to use one form of birth control for the duration of the study, and undergo a pregnancy test at baseline and within 36 hours prior to injection

Exclusion Criteria:

1. Indication for standard-of-care surgery (including valve surgery, placement of left-ventricular assist device, or imminent heart transplantation), coronary artery bypass grafting (CABG) procedure, and/or percutaneous coronary intervention (PCI) for the treatment of ischemic and/or valvular heart disease. Subjects who require or undergo PCI should undergo these procedures a minimum of 3 months in advance of randomization. Subjects who require or undergo CABG should undergo these procedures a minimum of 4 months in advance of randomization. In addition, subjects who develop a need for revascularization following enrollment should undergo revascularization without delay. Indication for imminent heart transplantation is defined as a high likelihood of transplant prior to collection of the 12 month study endpoint. Candidates cannot be UNOS status 1A or 1B, and they must have documented low probability of being transplanted
2. Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe (any valve) insufficiency/regurgitation within 12 months of consent
3. Aortic stenosis with valve area ≤ 1.5 cm2
4. History of ischemic or hemorrhagic stroke within 90 days of consent
5. History of a left ventricular remodeling surgical procedure utilizing prosthetic material
6. Presence of a pacemaker and/or implantable cardioverter-defibrillator (ICD) generator with any of the following limitations/conditions:

   * manufactured before the year 2000
   * leads implanted \< 6 weeks prior to consent
   * non-transvenous epicardial, or abandoned leads
   * subcutaneous ICDs
   * leadless pacemakers
   * any other condition that, in the judgment of device-trained staff, would deem an MRI contraindicated
7. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded)
8. A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent
9. Other MRI contraindications (e.g. patient body habitus incompatible with MRI)
10. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent
11. Ventricular tachycardia ≥ 20 consecutive beats without an ICD within 3 months of consent, or symptomatic Mobitz II or higher degree atrioventricular block without a functioning pacemaker within 3 months of consent
12. Presence of LV thrombus
13. Evidence of active myocarditis
14. Baseline maximal oxygen consumption (VO2 max) greater than 75% of age and gender based predictive values
15. Baseline eGFR \<35 ml/min/1.73m2
16. Blood glucose levels (HbA1c) \>10%
17. Hematologic abnormality evidenced by hematocrit \< 25%, white blood cell \< 2,500/ul or platelet count \< 100,000/ul
18. Liver dysfunction evidenced by enzymes (AST and ALT) ˃ 3 times the upper limit of normal (ULN)
19. Coagulopathy (INR ≥ 1.3) not due to a reversible cause (e.g., warfarin and/or Factor Xa inhibitors). Subjects who cannot be withdrawn from anticoagulation will be excluded.
20. HIV and/or active hepatitis B virus (HBV) or hepatitis C virus (HCV)
21. Allergy to radiographic contrast material that cannot adequately be managed by premedication
22. Known history of anaphylactic reaction to penicillin or streptomycin
23. Received gene or cell-based therapy from any source within the previous 12 months
24. History of malignancy within 5 years (i.e., subjects with prior malignancy must be disease free for 5 years), excluding basal cell carcinoma and cervical carcinoma in situ which have been definitively treated
25. Condition that limits lifespan to \< 1 year
26. History of drug abuse (illegal "street" drugs except marijuana, or prescription medications not being used appropriately for a pre-existing medical condition) or alcohol abuse (≥ 5 drinks/day for ˃ 3 months), or documented medical, occupational, or legal problems arising from the use of alcohol or drugs within the past 24 months
27. Participation in an investigational therapeutic or device trial within 30 days of consent
28. Cognitive or language barriers that prohibit obtaining informed consent or any study elements
29. Pregnancy or lactation or plans to become pregnant in the next 12 months
30. Any other condition that, in the judgment of the Investigator or Sponsor, would impair enrollment, study product administration, or follow-up

Primary outcomes:
measure: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Global Strain (HARP MRI)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Regional Strain (HARP MRI)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Left Ventricular Sphericity Index
timeFrame: Baseline to 6 months
measure: Change From Baseline in Scar Size Percent (DEMRI)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Scar Tissue Mass (DEMRI)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Maximal Oxygen Consumption (Peak VO2)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Exercise Tolerance (Six Minute Walk Test)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score
timeFrame: Baseline to 6 months
measure: Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)
timeFrame: Baseline to 6 months
measure: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Global Strain (HARP MRI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Regional Strain (HARP MRI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, 12 months)
measure: Change From Baseline in Left Ventricular Sphericity Index-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Scar Size Percent (DEMRI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Scar Tissue Mass (DEMRI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Maximal Oxygen Consumption (Peak VO2)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Participants With Major Adverse Cardiac Events (MACE)
timeFrame: Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection
measure: Participants Experiencing Other Significant Clinical Events
timeFrame: Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection
measure: Cumulative Days Alive and Out of Hospital for Heart Failure
timeFrame: Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection
Secondary outcomes:
Other outcomes:
measure: Subjects With Events Between Randomization and Study Product Injection (SPI) That Preclude the Receipt of Product
timeFrame: Randomization to SPI, an average of 14 weeks
measure: Subjects Who Have a Failed Bone Marrow Aspiration Procedure
timeFrame: During bone marrow aspiration procedure
measure: Subjects Who Have a Failed Endomyocardial Biopsy Procedure
timeFrame: During endomyocardial biopsy procedure
measure: Subject MSC Products Which Failed Release Criteria
timeFrame: Harvest to Study Product Injection Procedure
measure: Subject CPC Products Which Failed Release Criteria
timeFrame: Harvest to Study Project Injection procedure
measure: Subjects Who Receive Less Than 15 Injections During SPI
timeFrame: During SPI procedure
measure: Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable
timeFrame: Baseline to 12 months
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine (Falk Cardiovascular Research Center)
state: California
city: Gainesville
country: United States
facility: University of Florida-Department of Medicine
state: Florida
city: Miami
country: United States
facility: University of Miami-Interdisciplinary Stem Cell Institute
state: Florida
city: Indianapolis
country: United States
facility: Indiana Center for Vascular Biology and Medicine
state: Indiana
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Houston
country: United States
facility: Texas Heart Institute
state: Texas
Study officials:
affiliation: CCTRN Steering Committee Chair
name: Robert Simari, MD
role: STUDY_CHAIR
References:
citation: Hare JM, Bolli R, Cooke JP, Gordon DJ, Henry TD, Perin EC, March KL, Murphy MP, Pepine CJ, Simari RD, Skarlatos SI, Traverse JH, Willerson JT, Szady AD, Taylor DA, Vojvodic RW, Yang PC, Moye LA; Cardiovascular Cell Therapy Research Network. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation. 2013 Apr 16;127(15):1630-5. doi: 10.1161/CIRCULATIONAHA.112.000779. No abstract available.
citation: Nazarian S, Halperin HR. How to perform magnetic resonance imaging on patients with implantable cardiac arrhythmia devices. Heart Rhythm. 2009 Jan;6(1):138-43. doi: 10.1016/j.hrthm.2008.10.021. Epub 2008 Oct 22. No abstract available.
citation: Bolli R, Hare JM, March KL, Pepine CJ, Willerson JT, Perin EC, Yang PC, Henry TD, Traverse JH, Mitrani RD, Khan A, Hernandez-Schulman I, Taylor DA, DiFede DL, Lima JAC, Chugh A, Loughran J, Vojvodic RW, Sayre SL, Bettencourt J, Cohen M, Moye L, Ebert RF, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure). Circ Res. 2018 Jun 8;122(12):1703-1715. doi: 10.1161/CIRCRESAHA.118.312978. Epub 2018 Apr 27.
citation: Kato Y, Kizer JR, Ostovaneh MR, Lazar J, Peng Q, van der Geest RJ, Lima JAC, Ambale-Venkatesh B. Extracellular volume-guided late gadolinium enhancement analysis for non-ischemic cardiomyopathy: The Women's Interagency HIV Study. BMC Med Imaging. 2021 Jul 27;21(1):116. doi: 10.1186/s12880-021-00649-6.