The efficacy and mechanism of trientine in patients with hypertrophic cardiomyopathy

Research question Does trientine slow or reverse phenotypic expression of hypertrophic cardiomyopathy (HCM), improve exercise capacity, reduce arrhythmia burden and improve cardiac function, and by what mechanism? Background HCM is the most common inherited cardiovascular disorder. It is characterised by left ventricular (LV) myocardial hypertrophy and fibrosis. Mean age at diagnosis is around 40. Patients can experience symptoms of effort intolerance, progressive heart failure and abnormal heart rhythms; indeed it is the leading cause of sudden death in people under 35. There are currently no treatments that alter the natural history of HCM. Patients and the cardiovascular field have identified a “critical need” for clinical studies of drug therapies that target HCM pathophysiological mechanisms. Trientine dihydrochloride is a copper-chelating agent licensed for Wilson disease, a genetic disorder of copper excretion, in which patients exhibit a cardiac phenotype that mimics HCM. We have established proof of concept through an MRC-funded study to suggest that use of trientine may also be beneficial in HCM. Aims and objectives Aims: To evaluate the clinical efficacy and mechanism of action of trientine in HCM. Primary efficacy objective: To determine whether trientine compared to placebo leads to regression of LV hypertrophy. Secondary efficacy objectives include determining whether trientine compared to placebo increases urine copper excretion, improves exercise capacity, reduces arrhythmia burden, and improves cardiac function. Mechanistic objectives: To determine whether the reduction in LV hypertrophy is mediated by a reduction in myocardial cellular mass, fibrosis or improved myocardial energetics, and whether these are in turn determined by copper excretion. Methods A phase II double-blind, parallel group, 1:1 randomised placebo-controlled multicentre trial of 52 weeks of trientine vs. placebo in 172 patients with HCM. A subgroup of 84 patients (42 in each treatment group) will undergo magnetic resonance spectroscopy as part of the mechanistic evaluation. The primary outcome measure is change in left ventricular mass indexed to body surface area (grams/m2), measured using cardiovascular magnetic resonance. Data from our pilot study have been used to calculate sample size. The study represents an active partnership between patients with HCM and the research team. We have established a Patient Advisory Group (PAG), who have helped frame the research question, affirmed its importance and shaped study design. PAG members will be actively involved in study management and dissemination Timelines for delivery Set up: month 1-11. Recruitment: month 12-35. Follow-up: month 36-47. Analysis and report writing: month 48-53. The project has 12 milestones linked to key deliverables regarding set up, recruitment, retention, dissemination and patient and public involvement Anticipated impact and dissemination This trial is an exciting opportunity to provide patients with HCM a disease-modifying treatment, for which one does not currently exist, and improve quality of life. It will open new avenues of clinical and biological research, provide the pharmaceutical industry with new therapeutic targets and reduce strain on NHS and Government budgets. Dissemination will be via our PAG, lay written and video summaries, websites, patient groups, journals, conference presentations, a dedicated symposium and media outlets