This is a pilot clinical trial to assess whether the administration of diltiazem may be able to decrease the development or progression of hypertrophic cardiomyopathy (HCM). Diltiazem is a commonly used medication for the treatment of high blood pressure and studies on animals with HCM suggest that diltiazem decreases disease development. This study specifically targets individuals in the "prehypertrophic" phase of HCM-- those with documented sarcomere gene mutations without echocardiographic or EKG evidence of LVH, and therefore without a clinical diagnosis of HCM.

The hypothesis of this study is that starting diltiazem administration early in life (in the prehypertrophic phase) will decrease the progression of HCM in individuals with sarcomere gene mutations. This will be assessed by looking at an improvement in the heart's ability to relax using echocardiography, as well as exploratory analyses of a broad range of features reflecting the heart's structure and function.

STUDY RATIONALE:

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by histopathologic findings of cardiac myocyte disarray and fibrosis, and clinical manifestations of unexplained left ventricular hypertrophy (LVH), diastolic dysfunction, and an increased risk for sudden death. It is a common disorder affecting approximately 1 in 1000 individuals in the general population. Dominantly-acting mutations in contractile proteins-genes encoding the elements of the sarcomere apparatus-- have been shown to be the genetic etiology of HCM. Contemporary management strategies for HCM focus on identification of individuals at high risk for sudden death and management of symptoms. There is no current therapy available which address disease prevention or phenotypic attenuation.

Dysregulation of intracellular calcium handling is a fundamental and early manifestation of sarcomere mutations. Animal models of HCM demonstrated abnormal Ca2+ cycling prior to the development of myocyte disarray or hypertrophy. Manipulation of intracellular Ca2+ handling in young, pre-hypertrophic mice with HCM via administration of the L-type Ca2+ channel blocker, diltiazem, attenuated the degree of hypertrophic remodeling and diminished the phenotypic manifestations of sarcomere mutations. Notably, if treatment was initiated later in life, after LVH was allowed to develop, there was no significant effect. Although this strategy has not yet been tested in humans, diltiazem is a commonly-used medication with a long track record of safety and tolerability.

Mutation carriers without discernible echocardiographic left ventricular hypertrophy (designated G+/LVH-) represent a unique population of individuals with early disease who are ideal candidates for preemptive strategies to attempt to attenuate phenotypic development. One clinical marker of early disease is a subtle abnormality of LV diastolic function, detectable by tissue Doppler echocardiography (TDI). Individuals with sarcomere mutations have evidence of abnormal diastolic function by TDI as demonstrated by a 13-19% reduction in early myocardial relaxation velocities (E'), as compared to healthy controls.

Since LVH develops in a age-dependent manner, genetic diagnosis provides a mechanism for early identification of individuals at risk for developing HCM, prior to the expression of diagnostic clinical manifestations. One goal for the next era of medicine is to evolve from contemporary symptom palliation of late stage disease to early preventive strategies which instead strive to alter the natural history of disease development.

STUDY OBJECTIVES:

The goal of this trial is to evaluate the safety, feasibility, and efficacy of diltiazem administration in attenuating the natural history of HCM, focusing on tolerability and impact on diastolic function. The primary efficacy endpoint will be an improvement in diastolic function in G+/LVH- subjects receiving active therapy as compared to placebo, as measured by improved mean tissue Doppler echocardiographic early diastolic velocity (E') in the diltiazem group compared to the placebo group 2 years after randomization. As a pilot trial, treatment effects on multiple related parameters including changes in LV dimensions and mass, development of overt LVH, development of cardiac magnetic resonance (CMR) evidence of fibrosis, and levels of serum biomarkers will be analyzed in an exploratory manner to more fully characterize potential treatment effect. The safety endpoint will be no excess of all cause death, cardiovascular death (including sudden death), heart failure requiring medication or hospitalization, or a significant difference in the development of symptoms/side effects which necessitate discontinuation of treatment in the active vs placebo arm.

STUDY DESIGN AND SCHEMA A placebo-controlled, randomized double-blind Pilot clinical trial.

Eligible G+/LVH- subjects will undergo baseline studies (physical examination, echocardiography, CMR, blood tests) and will be randomized to receive diltiazem or placebo in a double blind fashion. There is a 3 week titration phase to increase the dose of study drug to target. The total duration of the study protocol is 5 years: study drug will be continued for a total of 4 years and a 1 year post-treatment evaluation will be performed. The primary endpoint will be assessed after 2 years of treatment.

Study visits and data collection consist of echocardiography at 3, 6, 12, 18, 24, 36,48, and 60 months. Annual evaluations consisting of physical exam, echocardiography, EKG, and measurement of serum biomarkers will also be performed.

PATIENT POPULATION Eligible subjects will have an identified sarcomere mutation with no clinical evidence of LVH. Children age 15 years and older will be enrolled at Brigham and Women's Hospital; children age 5-15 years will be enrolled via Children's Hospital Boston.

Major Inclusion Criteria:

• Preclinical HCM as defined by above G+/LVH- criteria
• Able to provide informed consent (or parental consent)

Major Major Exclusion Criteria:

Contraindication to diltiazem administration, including the following pre-existing conditions:

• Second or third degree atrioventricular block
• Symptomatic heart failure
• Sick sinus syndrome
• Concomitant treatment with verapamil and/or beta-blockers
• Concomitant treatment with cyclosporine or FK506
• Impaired hepatic or renal function
• Age <5 years
• Pregnant or breastfeeding women

PRIMARY AND SECONDARY ENDPOINTS

PRIMARY ENDPOINT:

Improvement in diastolic function as reflected by the averaged E' velocity compared to baseline (E' velocities improve, remain stable, or decline less in the treated group) 2 years following initiation of treatment.

As a pilot study, numerous other parameters reflecting myocardial structure and function will also be explored.

SECONDARY ENDPOINTS:

• Development of left ventricular hypertrophy

• Improvement in, stability of, or attenuation of increase in serum biomarkers (e.g., BNP, ST2, PICP, PIIINP, PINP) at 3, 6, and 18 months, annually and at study end

• Improvement in, stability of or attenuation of increase in CMR evidence of myocardial fibrosis

  - Impact on left ventricular morphology, remodeling, and cavity size

• Safety: no excess of all cause death, CV death (including sudden death), heart failure requiring medication or hospitalization; No excess of adverse events

• Tolerability: no excess need to reduce or withdraw study medication; no significant difference in adherence to study medication

Inclusion Criteria:

• Preclinical HCM (identified sarcomere mutation with no clinical evidence of left ventricular hypertrophy)
• Able to provide informed consent (or parental consent)

Exclusion Criteria:

• Contraindication to diltiazem administration
• Impaired hepatic or renal function
• Age < 5 years
• Pregnant or breastfeeding women

Participants enrolled through Brigham and Women's Hospital (Boston, MA), Boston Children's Hospital, and Royal Prince Alfred Hospital (Sydney, Australia) were randomized 1:1 to diltiazem or placebo. Participants were 5-39 years old, carried the sarcomere mutation presumed to cause HCM in the family, and had normal LV wall thickness by echo.

Duration of Trial

Small number of participants and short follow-up duration. Currently available tools to monitor treatment response/ phenotypic progression are may lack adequate resolution. The penetrance of sarcomere mutations is variable and may not be complete.