The CardiAMP Heart Failure trial: A randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post–myocardial infarction heart failure: Trial rationale and study design

doi:10.1016/j.ahj.2018.03.016

American Heart Journal

Volume 201, July 2018, Pages 141-148

https://doi.org/10.1016/j.ahj.2018.03.016 Get rights and content

Abstract

Background

Heart failure following myocardial infarction is a common, disabling, and deadly condition. Direct injection of autologous bone marrow mononuclear cells into the myocardium may result in improved functional recovery, relieve symptoms, and improve other cardiovascular outcomes.

Methods

CardiAMP-HF is a randomized, double-blind, sham-controlled, pivotal trial designed to investigate the safety and efficacy of autologous bone marrow mononuclear cells treatment for patients with medically refractory and symptomatic ischemic cardiomyopathy. The primary end point is change in 6-minute walk distance adjusted for major adverse cardiovascular events at 12 months following treatment. Particularly novel aspects of this trial include a cell potency assay to screen subjects who have bone marrow cell characteristics that suggest a favorable response to treatment, a point-of-care treatment method, a high target dose of 200 million cells, and an efficient transcatheter intramyocardial delivery method that is associated with high cell retention.

Conclusions

This novel approach may lead to a new treatment for those with ischemic heart disease suffering from medically refractory heart failure.

Section snippets

Methods

CardiAMP-HF is a pivotal, randomized controlled trial to investigate the safety and efficacy of the CardiAMP cell therapy system (BioCardia, San Carlos, CA) in bone marrow potency selected patients with post–myocardial infarction NYHA functional class II-III heart failure (NCT02438306) enrolled in up to 40 clinical centers in the United States. The trial has 2 cohorts: (1) a roll-in phase with a prospective, open-label, uncontrolled patient cohort to evaluate on-site physician and coordinator

Discussion

The CardiAMP-HF trial is intended to expand and extend the results of the Phase II TAC-HFT study. The current study includes, to our knowledge, the first human use of a CPA to select patients who are likely to yield therapeutic cells and a high dose of BM MNC cells. It will test the hypothesis that intramyocardial delivery of high-dose BM MNCs isolated with a point-of-care device will improve a clinical composite of 6MWD and MACE in NYHA functional class II-III ischemic heart failure patients

Conclusion

The CardiAMP pivotal trial will test whether transendocardial injection of a high effective dose of autologous BM MNCs obtained from NYHA class II-III ischemic heart failure patients, who are selected by a novel bone marrow potency assay designed to assess the likelihood of a therapeutic effect, improves ambulatory function, quality of life, and survival. Success in this treatment approach may lead to a novel treatment option for those suffering with medically refractory ischemic heart failure.

Acknowledgments

The authors would like to acknowledge the contributions of Adrian Gee and April Durett of the Center for Cell & Gene Therapy, Baylor College of Medicine, Texas Children's Hospital in Houston, and Maria Cabreira of the Stem Cell Center, Texas Heart Institute, Houston, for their support of CardiAMP HF stem cell studies. In addition, Mary Jo Rizzo, Dr Lavanya Bellumkonda, Dr Lissa Sugeng, and Dr Alexandra Lansky of Yale University are acknowledged for their contributions to the echocardiographic

Disclosures

The CardiAMP-HF trial is sponsored, in part, by Biocardia Inc (San Carlos, CA). Authors E. D. and P. A. are employees of Biocardia Inc. The remaining authors are members of the executive steering committee for the CardiAMP-HF trial.

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Clinical trials of cell-based therapies for heart failure have resulted in significant strides forward in our understanding of the potential the failing heart has for regeneration and repair. Yet, two decades on, the need for novel cell-based therapies for heart failure has never been greater. The DREAM-HF trial, which was presented as a late-breaking trial at the American Heart Association Scientific Sessions 2021 did not meet the primary heart failure outcome, but did show a large, clinically significant reduction in major adverse cardiovascular events (MACE) in patients receiving cells, an effect that was most pronounced in patients with evidence of maladaptive inflammation. These results represent an important step forward in our understanding of how cell-based therapies can exert beneficial effects in patients with heart failure and should serve as a guide for future clinical efforts. In light of the results of DREAM-HF, this review serves to provide an understanding of the current state of cell-based therapies for heart failure, as well as to highlight major knowledge gaps and suggest guiding principles for clinical trials of cell therapy going forward. Using the knowledge gained from DREAM-HF along with the trials that preceded it, the potential for breakthrough cell-based therapies for heart failure in the coming decade is immense.
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Citation Excerpt :
The recently initiated, randomized sham-controlled, pivotal, CardiAMP Heart Failure (HF) clinical trial (NCT02438306) was conceived using knowledge gained from prior cell therapy trials. This trial was designed to test the hypothesis that intramyocardial delivery of a high dose of autologous BM MNCs in chronic post myocardial infarction HF patients, who meet pre-specified, evidence-based bone marrow cell potency criteria, will improve exercise capacity, clinical status and contractile function [23]. Herein, we report the 12-month results of the 10 patients enrolled into the pre-specified, open-label, “roll-in cohort” for protocol feasibility.
Heart failure following myocardial infarction (MI) is a potentially lethal problem with a staggering incidence. The CardiAMP Heart Failure trial represents the first attempt to personalize marrow-derived cell-based therapy to individuals with cell characteristics associated with beneficial responses in prior trials. Before the initiation of the randomized pivotal trial, an open-label “roll-in cohort” was completed to ensure the feasibility of the protocol's procedures.
Patients with chronic post-MI heart failure (NYHA class II-III) receiving stable, guideline-directed medical therapy with a left ventricular ejection fraction between 20 and 40% were eligible. Two weeks prior to treatment, a ~ 5 mL bone marrow aspiration was performed to examine “cell potency”. On treatment day, a 60 mL bone marrow aspiration, bone marrow mononuclear cell (BM MNC) enrichment and transendocardial injection of 200 million BM MNC's was performed in a single, point of care encounter. Patients were then followed to assess clinical outcomes.
The cell potency small volume bone marrow aspirate, the 60 mL bone marrow aspirate, and transendocardial injections were well tolerated in 10 patients enrolled. There were no serious adverse events related to bone marrow aspiration or cell delivery. Improvement in 6-min walk distance was observed at 6 months (+47.8 m, P = 0.01) and trended to improvement at 12 months (+46.4, P = 0.06). Similarly, trends to improved NYHA heart failure functional class, quality of life, left ventricular ejection fraction and recruitment of previously akinetic left ventricular wall segments were observed.
All CardiAMP HF protocol procedures were feasible and well tolerated. Favorable functional, echo and quality of life trends suggest this approach may offer promise for patients with post MI heart failure. The randomized CardiAMP Heart Failure pivotal trial is underway to confirm the efficacy of this approach.
https://clinicaltrials.gov/ct2/show/NCT02438306
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Citation Excerpt :
Such standardized endpoint definitions and event reporting has been widely adopted for prosthetic valve associated (Valve Academic Research Consortium [72]) and anti-thrombotic medication associated bleeding associated (Bleeding Academic Research Consortium [73]) events. The transendocardial injection method was used in the DREAM Heart Failure clinical trial [74] (NCT02032004) which has completed its enrollment phase, the actively enrolling CardiAMP Heart Failure pivotal trial [75] (NCT02438306) and soon to initiate CardiAMP Chronic Myocardial Ischemia pivotal trial (NCT03455725). The DREAM Heart Failure trial, which is testing the safety and efficacy of allogeneic mesenchymal precursor cells, used the EAM-SN delivery system.
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A systematic search was performed for trial publications using TIC. Procedure-associated adverse event data were abstracted, pooled and compared across catheters for active treatment and placebo injected patients. The transendocardial injection associated serious adverse events (TEI-SAE) was defined as the composite of death, myocardial infarction, stroke or transient ischemic attack within 30 days and cardiac perforation causing death or requiring evacuation, serious intraprocedural arrhythmias and serious coronary artery or peripheral vascular complications.
The search identified 4 TIC systems: a helical needle (HN), an electro-anatomically tracked straight needle (EAM-SN), a straight needle without tracking elements (SN), and a curved needle (CN). Of 1799 patients who underwent transendocardial injections, the combined TEI-SAE was 3.4% across all catheters, and 1.1%, 3.3%, 7.1%, and 8.3% for HN, EAM-SN, SN and CN, respectively. However, TIC procedure duration and post procedural cardiac biomarker levels were reported in only 24% and 36% of published trials, respectively.
Transendocardial injection is associated with varied TEI-SAE but the data are very limited. The HN catheter appeared to be associated with lower TEI-SAE, versus other catheters. Procedure duration and post procedure cardiac biomarker levels were under-reported. Clearly, standardized, procedure-related event reporting for trials involving transcatheter delivery would improve our understanding of complications across different systems.
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View all citing articles on Scopus

: Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02438306.

: Journal Subject Terms: Cell Therapy, Stem cells, Heart Failure, Chronic Ischemic Heart Disease, Treatment.

: RCT# NCT02438306.

View full text

Trial DesignThe CardiAMP Heart Failure trial: A randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post–myocardial infarction heart failure: Trial rationale and study design

Abstract

Background

Methods

Conclusions

Section snippets

Methods

Discussion

Conclusion

Acknowledgments

Disclosures

J Mol Cell Cardiol

EBioMedicine

J Am Coll Cardiol

Life Sci

J Am Soc Echocardiogr

Int J Cardiol

Lancet

J Am Coll Cardiol

Lancet

JACC Cardiovasc Interv

J Am Coll Cardiol

Cytotherapy

J Mol Cell Cardiol

Chest

J Am Coll Cardiol

Am J Cardiol

Heart disease and stroke statistics—2018 update: a report from the American Heart Association

Circulation

Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization

Circ Res

Isolation of putative progenitor endothelial cells for angiogenesis

Science

Bone marrow cells regenerate infarcted myocardium

Nature

Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function

Nat Med

Enhanced cytoprotection and angiogenesis by bone marrow cell transplantation may contribute to improved ischemic myocardial function

Eur J Cardiothorac Surg

Paracrine action accounts for marked protection of ischemic heart by akt-modified mesenchymal stem cells

Nat Med

Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury

Am J Physiol Heart Circ Physiol

Bone-marrow–derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences

Circ Res

Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation

Circ Res

Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines

Circulation

Paracrine effects of direct intramyocardial implantation of bone marrow derived cells to enhance neovascularization in chronic ischaemic myocardium

Eur J Heart Fail

A dosing study of bone marrow mononuclear cells for transendocardial injection in a pig model of chronic ischemic heart disease

Tex Heart Inst J

Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: A randomized study

J Cardiovasc Transl Res

Feasibility of trans-endocardial cell transplantation in chronic ischaemia

Heart

Transendocardial autologous bone marrow in chronic myocardial infarction using a helical needle catheter: 1-year follow-up in an open-label, nonrandomized, single-center pilot study (the TABMMI study)

Am Heart J

Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial)

Eur Heart J

Trial Design
The CardiAMP Heart Failure trial: A randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post–myocardial infarction heart failure: Trial rationale and study design