Considerations for drug trials in hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition with potentially serious manifestations. Management has traditionally comprised therapies to palliate symptoms and implantable cardioverter-defibrillators to prevent sudden cardiac death. The need for disease-modifying therapies has been recognized for decades. More recently, an increasing number of novel and repurposed therapies hypothesized to target HCM disease pathways have been evaluated, culminating in the recent regulatory approval of mavacamten, a novel oral myosin inhibitor. HCM poses several unique challenges for clinical trials, which are important to recognize when designing trials and interpreting findings. This manuscript discusses the key considerations in the context of recent and ongoing randomized trials, including the roles of genotype, phenotype and symptom status in patient selection, the evidence base for clinical and mechanistic outcome measurements, trial duration and sample size.

Keywords: Clinical trials; Disease‐modifying therapy; Hypertrophic cardiomyopathy; Patient selection; Trial endpoints.

Figure 1

The challenges to consider when designing clinical trials and interpreting findings. BOLD, blood oxygenation level dependent imaging; DTI, diffusion tensor imaging; LV, left ventricle; PCr/ATP, phosphocreatine/adenosine triphosphate; VO₂ max, maximum rate of oxygen consumption.