Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem
Condition: Hypertrophic Cardiomyopathy
MeSH terms: Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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
    

Intervention name(s): Diltiazem; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Sustained release formulation titrated to a target dose of 360 mg daily, or a maximum of 5 mg/kg/day in pediatric subjects for the duration of the study period; Placebo comparator (double-blind allocation of study medication)
Intervention MeSH terms: Diltiazem
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hypertrophic Cardiomyopathy; Left ventricular hypertrophy; Diltiazem