Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem
This is a pilot clinical study 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.
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem|
- Improvement, stability of, or decrease in the decline of diastolic function as reflected by the averaged early myocardial relaxation (Ea) velocity compared to baseline [ Time Frame: 6, and 18 months, annually and at study end ] [ Designated as safety issue: No ]
- Improvement of Ea velocities [ Time Frame: 6, and 18 months, annually and at study end ] [ Designated as safety issue: No ]
- Stability of Ea velocities [ Time Frame: 6, and 18 months, annually and at study end ] [ Designated as safety issue: No ]
- Attenuation of the decline of Ea velocities [ Time Frame: 6, and 18 months, annually and at study end ] [ Designated as safety issue: No ]
- Delayed or Attenuated development of left ventricular hypertrophy [ Time Frame: 6, and 18 months, annually and at study end ] [ Designated as safety issue: No ]
- Improvement in, stability of, or attenuation of increase in serum biomarkers (ANP, BNP, and markers of mechanical stress and collagen turnover) [ Time Frame: Annual visits ] [ Designated as safety issue: No ]
- Improvement in, stability of or attenuation of increase in MRI evidence of myocardial fibrosis [ Time Frame: Study end ] [ Designated as safety issue: No ]
- Safety: no excess of all cause death, CV death (including sudden death), heart failure requiring medication or hospitalization [ Time Frame: Biannually ] [ Designated as safety issue: Yes ]
- Tolerability: no excess need to reduce or withdraw study medication [ Time Frame: Biannually ] [ Designated as safety issue: No ]
|Study Start Date:||January 2006|
|Estimated Study Completion Date:||December 2013|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period
Placebo Comparator: II
Placebo comparator (double-blind allocation of study medication)
Hide Detailed Description
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.
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
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
- 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
|United States, Massachusetts|
|Brigham and Women's Hospital|
|Boston, Massachusetts, United States, 02115|
|Boston, Massachusetts, United States, 02115|
|Principal Investigator:||Carolyn Y Ho, MD||Brigham and Women's Hospital|