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Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem

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ClinicalTrials.gov Identifier: NCT00319982
Recruitment Status : Completed
First Posted : April 27, 2006
Results First Posted : April 7, 2015
Last Update Posted : April 7, 2015
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Boston Children’s Hospital
Information provided by (Responsible Party):
Carolyn Yung Ho, MD, Brigham and Women's Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hypertrophic Cardiomyopathy
Interventions Drug: Diltiazem
Drug: Placebo
Enrollment 39
Recruitment Details Participants were recruited from the HCM clinics at Brigham and Women’s Hospital (Boston, MA), Boston Children’s Hospital (Boston, MA), and Royal Prince Alfred Hospital (Sydney, Australia). Participants were recruited from 2006 through 2010.
Pre-assignment Details  
Arm/Group Title I- Diltiazem (Active Arm) II- Placebo
Hide Arm/Group Description Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Period Title: Overall Study
Started 19 20
Completed 18 20
Not Completed 1 0
Reason Not Completed
Withdrawal by Subject             1             0
Arm/Group Title I- Diltiazem II- Placebo Total
Hide Arm/Group Description Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Total of all reporting groups
Overall Number of Baseline Participants 18 20 38
Hide Baseline Analysis Population Description
Participants enrolled through Brigham and Women’s Hospital (Boston, MA), Boston Children’s Hospital, and Royal Prince Alfred Hospital (Sydney, Australia) were randomized 1:1 to diltiazem or placebo. Participants were 5-39 years old, carried the sarcomere mutation presumed to cause HCM in the family, and had normal LV wall thickness by echo.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants 20 participants 38 participants
14.1  (1.7) 17.3  (2.1) 15.8  (8.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 20 participants 38 participants
Female
11
  61.1%
11
  55.0%
22
  57.9%
Male
7
  38.9%
9
  45.0%
16
  42.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 18 participants 20 participants 38 participants
United States 18 19 37
Australia 0 1 1
1.Primary Outcome
Title Increase, Stability of, or Decrease in the Decline of Diastolic Function as Reflected by the Global Early Myocardial Relaxation (E') Velocity
Hide Description 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.
Time Frame Baseline and final study visits
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description:
Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Overall Number of Participants Analyzed 18 20
Mean (Standard Error)
Unit of Measure: cm/sec (difference final-baseline)
-0.06  (0.27) -0.21  (0.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection I- Diltiazem, II- Placebo
Comments Change in E' Velocity comparing baseline and final study visits
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.75
Comments Adjusted for age, sex, genotype, family relations, and baseline value. p<0.05 considered statistically significant.
Method Generalized estimating equation
Comments Generalized estimating equation approach accounting for an exchangeable correlation structure within families
2.Secondary Outcome
Title Safety and Tolerability of Diltiazem Treatment
Hide Description Adverse events were compared between participants assigned to diltiazem and those assigned to placebo
Time Frame Baseline through final study visits
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description:
Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Overall Number of Participants Analyzed 18 20
Measure Type: Number
Unit of Measure: Participants Reporting Adverse Events
10 12
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection I- Diltiazem, II- Placebo
Comments Adverse Events
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.99
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
3.Secondary Outcome
Title Impact of Diltiazem on Heart Rate
Hide Description Change in Value (Difference between Final and Baseline Visits)
Time Frame Baseline and final study visits
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description:
Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Overall Number of Participants Analyzed 18 20
Mean (Standard Error)
Unit of Measure: beats/minute
-4.9  (2.2) 2.0  (2.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection I- Diltiazem, II- Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.06
Comments Adjusted for age, sex, genotype, family relations, and baseline value. p<0.05 considered statistically significant.
Method Generalized Estimating Equation
Comments Generalized estimating equation approach accounting for an exchangeable correlation structure within families
4.Secondary Outcome
Title Left Ventricular Cavity Size
Hide Description Change in Left Ventricular End-Diastolic Diameter z-score (Final Value - Baseline Value)
Time Frame Baseline and final study visits
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description:
Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Overall Number of Participants Analyzed 18 20
Mean (Standard Error)
Unit of Measure: z-score units
0.60  (0.17) -0.53  (0.16)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection I- Diltiazem, II- Placebo
Comments Change in LV End-Diastolic Diameter z-score from baseline to final visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Adjusted for age, sex, genotype, family relations, and baseline value
Method Generalized Estimating Equation
Comments Generalized estimating equation approach accounting for an exchangeable correlation structure within families
5.Secondary Outcome
Title Development of Left Ventricular Hypertrophy
Hide Description The number of participants who developed overt left ventricular hypertrophy during the duration of the trial was analyzed
Time Frame Baseline through final study visits
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description:
Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Overall Number of Participants Analyzed 18 20
Measure Type: Number
Unit of Measure: participants
2 2
6.Secondary Outcome
Title Adherence to Study Medication
Hide Description Adherence to study medication was assessed by pill count
Time Frame Duration of the trial
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description:
Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Overall Number of Participants Analyzed 18 20
Median (Standard Deviation)
Unit of Measure: percentage of pills taken
83  (10.8) 90  (6.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection I- Diltiazem, II- Placebo
Comments Percentage adherent to study medication
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.08
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
7.Secondary Outcome
Title Impact of Diltiazem on Systolic Blood Pressure
Hide Description Change in Value (Difference between Final and Baseline Visits)
Time Frame Baseline and final study visits
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description:
Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

Overall Number of Participants Analyzed 18 20
Mean (Standard Error)
Unit of Measure: mmHg
-1.4  (1.7) 2.1  (1.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection I- Diltiazem, II- Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.15
Comments Adjusted for age, sex, genotype, family relations, and baseline value
Method Generalized estimating equation
Comments Generalized estimating equation approach accounting for an exchangeable correlation structure within families
Time Frame Duration of Trial
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title I- Diltiazem II- Placebo
Hide Arm/Group Description Diltiazem: Titrated to a target dose of 360 mg daily (sustained release formulation) for the duration of the study period

Placebo Comparator

Placebo: Placebo comparator (double-blind allocation of study medication)

All-Cause Mortality
I- Diltiazem II- Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
I- Diltiazem II- Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/18 (0.00%)      0/20 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
I- Diltiazem II- Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/18 (55.56%)      12/20 (60.00%)    
Cardiac disorders     
Shortness of Breath   6/18 (33.33%)  9 1/20 (5.00%)  1
Lightheadeness   3/18 (16.67%)  5 5/20 (25.00%)  6
Chest Pain *  3/18 (16.67%)  3 1/20 (5.00%)  1
Gastrointestinal disorders     
Nausea/GI distress   1/18 (5.56%)  1 4/20 (20.00%)  4
General disorders     
Fatigue   1/18 (5.56%)  1 2/20 (10.00%)  2
Nervous system disorders     
Headache *  0/18 (0.00%)  0 1/20 (5.00%)  2
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
Small number of participants and short follow-up duration. Currently available tools to monitor treatment response/ phenotypic progression are may lack adequate resolution. The penetrance of sarcomere mutations is variable and may not be complete.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Carolyn Ho, MD
Organization: Brigham and Women's Hospital
Phone: 617-732-5685
Publications:
Responsible Party: Carolyn Yung Ho, MD, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00319982     History of Changes
Other Study ID Numbers: 001936
K23HL078901 ( U.S. NIH Grant/Contract )
First Submitted: April 27, 2006
First Posted: April 27, 2006
Results First Submitted: January 26, 2015
Results First Posted: April 7, 2015
Last Update Posted: April 7, 2015