Clinical Trial: Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem

Brief 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 Summary:

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 a
Sponsor: Brigham and Women's Hospital

Current Primary Outcome: Increase, Stability of, or Decrease in the Decline of Diastolic Function as Reflected by the Global Early Myocardial Relaxation (E') Velocity [ Time Frame: Baseline and final study visits ]

The change in E' velocity (difference between final value - baseline value) was compared between participants who received diltiazem and those who received placebo to gauge treatment response. Please note that the total duration on treatment varied between study subjects to maximize time on treatment for the trial. Specifically, subjects that enrolled earliest had the longest duration of treatment; those who enrolled latest had the shortest duration of treatment with a minimum treatment duration of 1 year. All analyses examine the final study visit on treatment to the baseline visit.


Original Primary Outcome: Improvement in diastolic function as reflected by the averaged Ea velocity compared to baseline

Current Secondary Outcome:

  • Safety and Tolerability of Diltiazem Treatment [ Time Frame: Baseline through final study visits ]
    Adverse events were compared between participants assigned to diltiazem and those assigned to placebo
  • Impact of Diltiazem on Heart Rate [ Time Frame: Baseline and final study visits ]
    Change in Value (Difference between Final and Baseline Visits)
  • Left Ventricular Cavity Size [ Time Frame: Baseline and final study visits ]
    Change in Left Ventricular End-Diastolic Diameter z-score (Final Value - Baseline Value)
  • Development of Left Ventricular Hypertrophy [ Time Frame: Baseline through final study visits ]
    The number of participants who developed overt left ventricular hypertrophy during the duration of the trial was analyzed
  • Adherence to Study Medication [ Time Frame: Duration of the trial ]
    Adherence to study medication was assessed by pill count
  • Impact of Diltiazem on Systolic Blood Pressure [ Time Frame: Baseline and final study visits ]
    Change in Value (Difference between Final and Baseline Visits)


Original Secondary Outcome:

  • 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, ?P1P)
  • 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


Information By: Brigham and Women's Hospital

Dates:
Date Received: April 27, 2006
Date Started: January 2006
Date Completion:
Last Updated: March 24, 2015
Last Verified: March 2015