Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem

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. The genetic etiology of HCM is autosomal dominant mutations in contractile
proteins—genes encoding the elements of the sarcomere apparatus. 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 demonstrate 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, attenuates the degree of hypertrophic remodeling and diminishes the
phenotypic manifestations of sarcomere mutations. 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.

A small number of previous studies have been performed on individuals with sarcomere gene
mutations at different stages in the development of an overt phenotype of hypertrophic
cardiomyopathy. Subjects with gene mutations but no 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 gene mutations have evidence of abnormal diastolic function by TDI as
demonstrated by a 13-19% reduction in early myocardial relaxation velocities (Ea), as
compared to healthy controls.

Since LVH develops in a time-dependent manner, genetic diagnosis provides a mechanism for
early identification of individuals at risk for developing HCM, prior to the expression of
typical 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 objective of this proposal is to evaluate the efficacy of diltiazem administration in
attenuating the natural history of HCM, focusing on tolerability and effects on diastolic
function. The primary 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 in the diltiazem group compared to
the placebo group 2 years after randomization. Treatment effects on multiple related
parameters including changes in LV dimensions and mass, development of overt LVH,
development of MRI evidence of fibrosis, and levels of serum biomarkers will be analyzed in
an exploratory manner. 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 single center, placebo-controlled, randomized double-blind Phase
III clinical trial.

Eligible G+/LVH- subjects will undergo baseline studies (physical examination,
echocardiography, cardiac MRI, 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 13 and older will be enrolled at Brigham and Women's
Hospital; children age 5-12 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 Ea velocity compared to
baseline (Ea velocities improve, remain stable, or decline less in the treated group) 2
years following initiation of treatment

SECONDARY ENDPOINTS:

- Improvement of Ea velocities at 3, 6, and 18 months, annually and at study end

- Stability of Ea velocities at earlier time points annually and at study end

- Attenuation of the decline of Ea velocities at earlier timepoints, annually and at
study end

- Delayed or Attenuated development of left ventricular hypertrophy

- Improvement in, stability of, or attenuation of increase in serum biomarkers (ANP, BNP,
ST2, PIIINP, PINP) at 3, 6, and 18 months, annually and at study end

- Improvement in, stability of or attenuation of increase in MRI evidence of myocardial
fibrosis

- Safety: no excess of all cause death, CV death (including sudden death), heart failure
requiring medication or hospitalization

- Tolerability: no excess need to reduce or withdraw study medication