Reassessing Phase II Heart Failure Clinical Trials

Abstract

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue regarding the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17th 2016 represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

“…An improvement in EF has historically been associated with a clinically meaningful improvement 27. Interestingly, this study provides evidence against that paradigm because both groups experienced improvements in quality of life, highlighting the importance of evaluating a variety of efficacy end points rather than a single functional parameter to determine the overall benefit from cell‐based therapies, an idea supported by several investigators in the field 27, 28, 29, 30. Similarly, several clinical trials evaluating cell‐based therapies for both forms of HF found that stem cells improved quality of life and functional parameters without sustained improvements in EF 31, 32, 33, 34.…”

“…The mechanisms by which MSCs may have improved cardiac function in patients with DCM include the restoration of endothelial function, which enhances coronary circulation,6, 38 and the reduction of fibrosis and tumor necrosis factor–α, an inflammatory biomarker associated with worsening HF and contractility 39, 40. Those with ICM likely benefit mostly from the stem cells’ antifibrotic properties through reduction in scar size and subsequent reverse remodeling as indicated by a reduction in SI and ESV 7, 29. This may be explained in part by the enhancement of endogenous cardiomyocyte proliferation and a subsequent increase in ventricular mass 5…”

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure

“…Although any individual surrogate endpoint and efficacy markers by themselves in phase II may not be sufficient to inform prospects of success in phase III trials, a combination of markers provides better cumulative information to guide downstream research endeavors 33 , and as such, the results seen in the 12-week anakinra group are promising.…”

Unique Aspects of the Design of Phase I/II Clinical Trials of Stem Cell Therapy

“…As with any traditional new drug, establishing the optimal dose and delivery method is a critical part of the development of new stem cell therapies [36,37,116]. In a phase II-a study, drug development normally comprises an estimate of a non-effective dose and the highest tolerated dose, whereas in a phase II-b the objective is to determine the dose-response relationship by testing doses ranging from clinically non-effective to the highest tolerated.…”