Title: The efficacy and mechanism of trientine in patients with hypertrophic cardiomyopathy
Funder: Medical Research Council

Abstract: Background_x000D_ Hypertrophic cardiomyopathy (HCM) is the most common inherited heart condition, affecting around 1 in 200 adults. It leads to abnormal thickening and scarring of the walls of the heart. As a result, the heart can have trouble pumping blood as well as it should. This causes patients to develop breathing difficulties, chest pain and fainting, which often get worse with physical exertion, and therefore limit physical activity. HCM can also cause abnormal heart rhythms, which can cause people to die suddenly, in fact it is the leading cause of sudden death in people under 35._x000D_ _x000D_ Current treatments only aim to alleviate symptoms. There are no treatments that correct the underlying damage to the heart and no treatments that improve prognosis. Patients, caregivers and researchers have identified a “critical need” for trials of medicines that target the HCM disease process. _x000D_ _x000D_ Several studies in other diseases have shown that copper imbalance is associated with heart thickening similar to HCM, and that treatment with trientine, an oral medicine that increases copper elimination in urine, can reverse this thickening. _x000D_ _x000D_ We have established proof of concept in an earlier study to suggest that use of trientine may be beneficial in patients with HCM._x000D_ _x000D_ Aims_x000D_ To investigate if trientine reduces heart muscle thickening, improves exercise capacity, improves heart function and reduces abnormal heart rhythms in patients with HCM. The study will also assess how trientine works in HCM._x000D_ _x000D_ Design and methods_x000D_ Patients with HCM will be given trientine or a dummy drug (placebo) for 1 year. The change in heart muscle thickening, exercise capacity, heart function and heart rhythm will be compared between those receiving trientine and those receiving placebo._x000D_ _x000D_ In order to understand how trientine works in HCM, we will assess heart energy function, heart muscle scarring and urine copper levels before and after treatment. Patients in trientine and placebo groups will be compared. _x000D_ _x000D_ Patient and public involvement_x000D_ The study represents an active partnership between patients with HCM and the research team. We successfully applied for a patient involvement grant which allowed us to set up a Patient Advisory Group. We have also received feedback from patients who took part in our earlier study. _x000D_ _x000D_ This study has been identified as a priority by the Group. Group members helped frame the research question, affirmed its importance, shaped the design of the study and helped write this summary. Group members will help develop information resources and be actively involved in the management of the study and disseminating the results. _x000D_ _x000D_ Dissemination_x000D_ If trientine is able to slow or reverse HCM and improve exercise capacity, it would significantly improve the quality of life of patients with HCM and will lead on to a larger trial assessing whether it improves prognosis._x000D_ _x000D_ Video and written summaries of the results, made in conjunction with patients involved with the research, will be put onto a website that will be built for the trial. Results will also be published in scientific journals, presented at scientific meetings and patients involved with the research will take part in presentations to patient groups.

Lay abstract: Research question_x000D_ 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?_x000D_ _x000D_ Background_x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ Aims and objectives_x000D_ Aims: To evaluate the clinical efficacy and mechanism of action of trientine in HCM._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ Methods_x000D_ 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._x000D_ _x000D_ 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_x000D_ _x000D_ Timelines for delivery_x000D_ 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_x000D_ _x000D_ Anticipated impact and dissemination_x000D_ 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

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR