Extra energy for hearts with a genetic defect: ENERGY trial

Hypertrophic cardiomyopathy (HCM) is the most frequent and lethal genetic heart
disease. It is caused by mutations in sarcomeric proteins, the building blocks
of the heart. Individuals are at high-risk for ventricular arrhythmias and
sudden cardiac death, or develop cardiomyopathy at a young age. The current
treatment options are insufficient to prevent the disease. In the ENERGY trial
we will investigate if metabolic therapy with trimetazidine reverses the
reduced myocardial efficiency in asymptomatic mutation carriers. This trial is
based on our preclinical and clinical studies, which revealed that 1) mutant
proteins cause an energetic deficiency of the heart and 2) this energetic
deficit is already observed in human mutation carriers without cardiomyopathy.
The mutation-induced energy deficiency of the heart causes hypertrophy and
dysfunction of the heart. Approach: We will treat asymptomatic mutation
carriers with trimetazidine or placebo and measure cardiac efficiency at
baseline and after 2 months of treatment. Impact: Our study will establish if
energy deficiency represents a novel HCM drug target before onset of cardiac
hypertrophy. This phase II clinical trial builds proof for a multicenter phase
III clinical trial to study if metabolic therapy prevents cardiac hypertrophy,
acute cardiac arrest and development of cardiomyopathy in asymptomatic mutation
carriers.

Main objective: to measure the effect of trimetazidine on myocardial external
efficiency in asymptomatic MYH7, MYBPC3 or TNNT2 mutation carriers Secondary
objectives: to study the effect of trimetazidine on diastolic function, left
ventricle and left atrial volume parameters, exercise capacity, and
electrophysiological properties of the heart

randomized, double blind, placebo-controlled trial

Trimetazidine 20mg three times daily, or placebo 20mg three times daily

Burden associated with participation:
Patients will be asked to visit the hospital 5 times. After the first visit,
subjects will receive information about the study and will be given time (>48
hours) to decide if they want to participate.
Approximately two days after the first visit, subjects will be called to ask if
they want to participate in the study. If yes, an appointment will be made for
the second visit. During this visit informed consent will be signed and a
subjects will undergo an echo, ECG and venapunction to determine whether the
subject is eligible to participate in the trial (see 3.3 exclusion criteria).
On visits 3 and 5, subjects will visit the VUmc to undergo PET- and MRI-
investigations in supine position for a maximum of 1.5 hours per investigation.
To minimize the burden of travelling, both procedures will be carried out on
the same day. For intravenous administration of the contrast-agent
Gadolinium-DTPA (Dotarem©), a venflon will be inserted in the vena brachialis.
An ECG, echo, and exercise test and a survey will also be taken. From the
intravenous line, vials of blood will be drawn for research purposes.
On visit 4 a research nurse will perform a clinical check-up, echo, ecg and
venapunction.
Risk associated with participation:
Trimetazidine is a drug with mild and reversible side-effects. We estimate
minimal health risk by participation in this study.
Patients with renal failure (glomerular filtration rate (GFR) < 30 ml/min) will
be excluded to avoid development of Gadolinium-DTPA induced nephrogenic
systhemic fibrosis (NSF).
The total radiation dose for study participants is 6 mSv, falls in the risk
category IIb and represents low risk. The range of 1 to 10 mSv corresponds with
a maximum risk of one in ten thousand, and is of the same order of magnitude as
the annual natural background radiation in some parts of the world.
(Netherlands commission on radiation dosimetry, 9 september 2015).which is well
below the threshold of 10 mSv for negligible risk.
Group relatedness:
This study will be done in MYH7, MYBPC3 and TNNT2 mutation carriers as previous
research showed these mutation carriers have an energetic defect of >20%
difference in myocardial energy efficiency compared to healthy controls. To
reveal a 15% beneficial effect of trimetazidine on MEE, taking into account a
standard deviation of 15% based on our previous studies of MEE in HCM mutation
carriers, a number of 20 carriers should be included in each group (with
metabolic therapy or placebo) to reach a power of 80%
Benefit:
This study aims to find a preventive treatment for HCM, which currently does
not exist.