The Efficacy and Mechanism of Trientine in Patients With Hypertrophic Cardiomyopathy

HCM is the most common inherited cardiovascular disorder. It is characterised by left ventricular (LV) myocardial hypertrophy and fibrosis. Patients can experience symptoms of effort intolerance, progressive heart failure and abnormal heart rhythms. 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. Proof of concept has been established through an MRC-funded study to suggest that use of trientine may also be beneficial in HCM.

Inclusion criteria

• Written informed consent.
• Age 18-75 inclusive.
• Hypertrophic cardiomyopathy (HCM), as defined by the European Society of Cardiology HCM guidelines as: "a wall thickness ≥15 mm in one or more LV myocardial segments that is not explained solely by loading conditions". The same definition is applied to first-degree relatives of patients with HCM i.e. all participants are required to have a LV wall thickness ≥15 mm. Wall thickness is as measured on the most recent cardiovascular magnetic resonance (CMR) scan performed prior to the baseline visit. If CMR has not been performed previously, wall thickness measurement should be taken from the most recent echocardiogram performed prior to the baseline visit. (It is recognised that in the European Society of Cardiology guidelines a clinical diagnosis of HCM in first-degree relatives requires a wall thickness that is less than this value, however ≥15 mm is applied here in order to ensure that all participants have an unequivocal phenotype).
• New York Heart Association class I, II or III at the most recent clinical assessment performed prior to the baseline visit.

Exclusion criteria

• Previous or planned septal reduction therapy.
• Previously documented myocardial infarction or severe coronary artery disease.
• Uncontrolled hypertension, defined as a systolic blood pressure of >180mmHg or a diastolic blood pressure of > 100mmHg at Visit 1.
• Known LV EF < 50%, as measured on the most recent CMR scan performed prior to the baseline visit. If CMR has not been performed previously, the most recent echocardiogram performed prior to the baseline visit should be used.
• Previously documented persistent atrial fibrillation.
• Anaemia, defined as haemoglobin being below the local site normal reference range, at Visit 1.
• Iron deficiency, defined as serum iron being below the local site normal reference range, at Visit 1.
• Copper deficiency, defined as serum copper being below the normal reference range, at Visit 1.
• Pacemaker or implantable cardioverter defibrillator.
• Known severe valvular heart disease, as demonstrated on the most recent heart imaging performed prior to the baseline visit.
• Previously documented other cardiomyopathic cause of myocardial hypertrophy (e.g. amyloidosis, Fabry disease, mitochondrial disease).
• History of hypersensitivity to any of the components of the investigational medicinal product (IMP).
• Known contraindication to MRI scanning.
• Pregnancy, lactation or planning pregnancy. Women of childbearing capacity are required to have a negative serum pregnancy test before treatment, must agree to pregnancy tests at study visits as defined in the Section 8 and must agree to maintain highly effective contraception as defined in Section 8 during the study.
• Any medical condition, which in the opinion of the Investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.