Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Abstract

Aims: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.

Methods and results: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death.

Conclusion: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Keywords: Cardiopoiesis; Cardiovascular disease; Disease severity; Marker; Precision medicine; Regenerative medicine; Stem cell; Target population.

Figure 1

Consolidated standards of reporting trials diagram of the CHART-1 study. This figure depicts the patient flow through the trial. Eighteen (11.5%) patients randomized to active treatment and 7 (4.4%) patients randomized to control did not undergo the study procedure: 10 (6.4%) and 6 (3.8%) patients died, and 2 (1.3%) and 1 (0.6%) patients withdrew consent in the active and control groups, respectively. Six (3.8%) patients randomized to active treatment were discontinued because of procedural contraindications including left ventricular thrombus and aortic stenosis not identified at screening. Cell release specifications were not achieved in 18 (11.5%) patients randomized to active treatment; these patients and one additional patient for whom the injection procedure was deemed unsafe underwent a sham procedure and were followed separately. The remaining 120 patients underwent injection of cardiopoietic cells. ^aOther reasons patients were withdrawn after screening but before bone marrow harvest included: withdrawal from the study by investigator or sponsor; patient missing or lost to follow-up; or other miscellaneous. ^bForty-eight (13.8%) patients who failed the first bone marrow harvest (1 due to inadequate sample volume, 8 due to improper harvesting or transport process, 21 because the sample was contaminated, and 18 because of inadequate expansion of MSCs) were eligible for a repeat harvest. Thirty-two patients underwent the second bone marrow harvest. Of the 16 who did not have a repeat, 5 were because the patient refused, 2 were due to SAEs (1 patient had a stroke and another was hospitalized for heart failure), and the rest for sponsor reason (either cell-process related or because study enrollment was nearing completion). ^cOther reasons patients were withdrawn after bone marrow harvest but before randomization included: withdrawal from the study by sponsor or other miscellaneous.

Figure 2

Primary efficacy outcome. Panel A depicts the primary efficacy outcome in the total population. The Mann–Whitney estimator, or the probability that the treatment group had a better outcome on the composite primary endpoint, was 0.54 (95% CI 0.47–0.61), P = 0.27 (a value > 0.5 favours the active treatment). The corresponding Mann–Whitney odds was 1.17 (95% 0.89–1.55). Panel B depicts the primary efficacy outcome in the subgroup of patients with LVEDV 200–370 mL. The Mann–Whitney estimator, or the probability that the treatment group had a better outcome on the composite primary endpoint, was 0.61 (95% CI 0.52–0.70), P = 0.015 (a value > 0.5 favours the active treatment). The corresponding Mann–Whitney odds was 1.57 (95% 1.09–2.35).

Figure 3

Primary efficacy outcome by markers of disease severity. This figure shows the Mann–Whitney estimator, or the probability that the treatment group had a better outcome on the composite primary endpoint, for patients above and below the median values for LVEDV, LVESV, MLHFQ score, and 6-min walk distance, and for LVEF above and below a cutpoint of 30%.

Figure 4

Subpopulation treatment effect pattern plot by markers of disease severity. Subpopulation Treatment Effect Pattern Plots (STEPPs) were used to further evaluate the potential effect of treatment according to baseline markers of disease severity. This figure shows the STEPP results according to baseline MLHFQ score (panel A), baseline LVEDV (panel B), baseline 6-min walk distance (panel C), and baseline LVESV (panel D).