Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Abstract

Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy. Although most cardiovascular outcomes trials continue to use time-to-first event analyses to assess the primary efficacy end point, such analyses do not adequately reflect the impact of new treatments on the totality of the chronic disease burden. Consequently, patient enrichment and other strategies for ongoing clinical trial design, as well as new statistical methodologies, are important considerations, particularly when studying a population with advanced chronic HF. The DREAM-HF trial (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Advanced Heart Failure) is an ongoing, randomized, sham-controlled phase 3 study of the efficacy and safety of mesenchymal precursor cells as immunotherapy in patients with advanced chronic HF with reduced ejection fraction. Mesenchymal precursor cells have a unique multimodal mechanism of action that is believed to result in polarization of proinflammatory type 1 macrophages in the heart to an anti-inflammatory type 2 macrophage state, inhibition of maladaptive adverse left ventricular remodeling, reversal of cardiac and peripheral endothelial dysfunction, and recovery of deranged vasculature. The objective of DREAM-HF is to confirm earlier phase 2 results and evaluate whether mesenchymal precursor cells will reduce the rate of nonfatal recurrent HF-related major adverse cardiac events while delaying or preventing progression of HF to terminal cardiac events. DREAM-HF is an example of an ongoing contemporary events-driven cardiovascular cell-based immunotherapy study that has utilized the concepts of baseline disease enrichment, prognostic enrichment, and predictive enrichment to improve its efficiency by using accumulating data from within as well as external to the trial. Adaptive enrichment designs and strategies are important components of a rational approach to achieve clinical research objectives in shorter clinical trial timelines and with increased cost-effectiveness without compromising ethical standards or the overall statistical integrity of the study. The DREAM-HF trial also presents an alternative approach to traditional composite time-to-first event primary efficacy end points. Statistical methodologies such as the joint frailty model provide opportunities to expand the scope of events-driven HF with reduced ejection fraction clinical trials to utilize time to recurrent nonfatal HF-related major adverse cardiac events as the primary efficacy end point without compromising the integrity of the statistical analyses for terminal cardiac events. In advanced chronic HF with reduced ejection fraction studies, the joint frailty model is utilized to reflect characteristics of the high-risk patient population with important unmet therapeutic needs. In some cases, use of the joint frailty model may substantially reduce sample size requirements. In addition, using an end point that is acceptable to the Food and Drug Administration and the European Medicines Agency, such as recurrent nonfatal HF-related major adverse cardiac events, enables generation of clinically relevant pharmacoeconomic data while providing comprehensive views of the patient's overall cardiovascular disease burden. The major goal of this review is to provide lessons learned from the ongoing DREAM-HF trial that relate to biologic plausibility and flexible clinical trial design and are potentially applicable to other development programs of innovative therapies for patients with advanced cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02032004.

Keywords: clinical trial; goals; heart failure; humans; immunotherapy; inflammation.

Figures

Figure 1.

Relationships between multiple key factors that affect progression of heart failure with reduced ejection fraction (HFrEF) severity.

Figure 2.

Proposed key components of the mesenchymal precursor cell mechanisms of action in chronic heart failure (HF). Ang-1 indicates angiopoietin-1; FGF2, fibroblast growth factor 2; IDO, indoleamine dioxygenase; IL, interleukin; M1, macrophage (type 1); M2, macrophage (type 2); MPC, mesenchymal precursor cell; NF-κB, nuclear factor κB; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; SDF-1, stromal cell-derived factor-1; TNF-α, tumor necrosis factor-α; and VEGF, vascular endothelial growth factor.

Figure 3.

Phase 2 randomized dose-finding sham-controlled trial in New York Heart Association class II/III heart failure with reduced ejection fraction patients.A, The 150-million mesenchymal precursor cell group (MPC-150M) showed durable (36 mo) protection against heart failure–related major adverse cardiac events (HF-MACE) following single intracardiac injection. Left, All MPC-150M and control subjects.Right, MPC-150M and control subjects enriched for baseline left ventricular end-systolic volume (LVESV) >100 mL.B, Therapeutic benefit of MPCs on left ventricular remodeling at 6 mo enhanced in subjects with baseline LVESV >100 mL. LVEDV indicates left ventricular end-diastolic volume; and MPC, mesenchymal precursor cells.

Figure 4.

Illustrative example of recurrent events analysis for assessment of patients’ comprehensive healthcare journey. HF indicates heart failure; HF-MACE, heart failure–related major adverse cardiac events; TTFE, time-to-first event; and VF, ventricular fibrillation.