Ignite Creation Date:
2024-05-05 @ 4:46 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00319982
Status:
COMPLETED
Last Update Posted:
2015-04-07
First Post:
2006-04-27
Brief Title:
Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem
Sponsor:
Brigham and Womens Hospital
Organization:
Brigham and Womens Hospital
Study Overview
Official Title:
Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem
Status:
COMPLETED
Status Verified Date:
2015-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 hearts ability to relax using echocardiography as well as exploratory analyses of a broad range of features reflecting the hearts structure and function
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 hearts ability to relax using echocardiography as well as exploratory analyses of a broad range of features reflecting the hearts 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 GLVH- 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 GLVH- 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 symptomsside 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 GLVH- 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 3648 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 Womens Hospital children age 5-15 years will be enrolled via Childrens Hospital Boston
Major Inclusion Criteria
Preclinical HCM as defined by above GLVH- 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 andor 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 eg 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
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 GLVH- 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 GLVH- 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 symptomsside 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 GLVH- 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 3648 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 Womens Hospital children age 5-15 years will be enrolled via Childrens Hospital Boston
Major Inclusion Criteria
Preclinical HCM as defined by above GLVH- 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 andor 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 eg 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| K23HL078901 | NIH | None | httpsreporternihgovquickSearchK23HL078901 |