Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00319982
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Boston Children's Hospital (Other)
• Enrollment: 39
• Locations: 2
• Arms: 2
• Duration (Months): 95
• Patients Per Site: 19.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertrophic Cardiomyopathy	Drug: Diltiazem; Drug: Placebo	Phase 2/Phase 3

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: I- Diltiazem Diltiazem- study medication	Drug: Diltiazem; 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: II- Placebo Placebo Comparator	Drug: Placebo; Placebo comparator (double-blind allocation of study medication)

Outcome Measures

Primary Outcome Measures

1. Increase, Stability of, or Decrease in the Decline of Diastolic Function as Reflected by the Global Early Myocardial Relaxation (E') Velocity [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.

Secondary Outcome Measures

1. Safety and Tolerability of Diltiazem Treatment [Baseline through final study visits]

   Adverse events were compared between participants assigned to diltiazem and those assigned to placebo

2. Impact of Diltiazem on Heart Rate [Baseline and final study visits]

   Change in Value (Difference between Final and Baseline Visits)

3. Left Ventricular Cavity Size [Baseline and final study visits]

   Change in Left Ventricular End-Diastolic Diameter z-score (Final Value - Baseline Value)

4. Development of Left Ventricular Hypertrophy [Baseline through final study visits]

   The number of participants who developed overt left ventricular hypertrophy during the duration of the trial was analyzed

5. Adherence to Study Medication [Duration of the trial]

   Adherence to study medication was assessed by pill count

6. Impact of Diltiazem on Systolic Blood Pressure [Baseline and final study visits]

   Change in Value (Difference between Final and Baseline Visits)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 39 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Preclinical HCM (identified sarcomere mutation with no clinical evidence of left ventricular hypertrophy)

• Able to provide informed consent (or parental consent)

Exclusion Criteria:

• Contraindication to diltiazem administration

• Impaired hepatic or renal function

• Age < 5 years

• Pregnant or breastfeeding women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
2	Children's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital
• National Heart, Lung, and Blood Institute (NHLBI)
• Boston Children's Hospital

Investigators

• Principal Investigator: Carolyn Y Ho, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Fatkin D, McConnell BK, Mudd JO, Semsarian C, Moskowitz IG, Schoen FJ, Giewat M, Seidman CE, Seidman JG. An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. J Clin Invest. 2000 Dec;106(11):1351-9.
• Ho CY, Abbasi SA, Neilan TG, Shah RV, Chen Y, Heydari B, Cirino AL, Lakdawala NK, Orav EJ, González A, López B, Díez J, Jerosch-Herold M, Kwong RY. T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. Circ Cardiovasc Imaging. 2013 May 1;6(3):415-22. doi: 10.1161/CIRCIMAGING.112.000333. Epub 2013 Apr 2.
• Ho CY, Lakdawala NK, Cirino AL, Lipshultz SE, Sparks E, Abbasi SA, Kwong RY, Antman EM, Semsarian C, González A, López B, Diez J, Orav EJ, Colan SD, Seidman CE. Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. JACC Heart Fail. 2015 Feb;3(2):180-8. doi: 10.1016/j.jchf.2014.08.003. Epub 2014 Oct 31.
• Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, Kwong R, González A, Colan SD, Seidman JG, Díez J, Seidman CE. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 2010 Aug 5;363(6):552-63. doi: 10.1056/NEJMoa1002659.
• Ho CY, Seidman CE. A contemporary approach to hypertrophic cardiomyopathy. Circulation. 2006 Jun 20;113(24):e858-62. Review.
• Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, Seidman CE, Solomon SD. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002 Jun 25;105(25):2992-7.
• Lakdawala NK, Thune JJ, Maron BJ, Cirino AL, Havndrup O, Bundgaard H, Christiansen M, Carlsen CM, Dorval JF, Kwong RY, Colan SD, Køber LV, Ho CY. Electrocardiographic features of sarcomere mutation carriers with and without clinically overt hypertrophic cardiomyopathy. Am J Cardiol. 2011 Dec 1;108(11):1606-13. doi: 10.1016/j.amjcard.2011.07.019. Epub 2011 Sep 21.
• Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt JP, McConnell BK, Reiken S, Mende U, Marks AR, Kass DA, Seidman CE, Seidman JG. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Invest. 2002 Apr;109(8):1013-20.
• Valente AM, Lakdawala NK, Powell AJ, Evans SP, Cirino AL, Orav EJ, MacRae CA, Colan SD, Ho CY. Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy. Circ Cardiovasc Genet. 2013 Jun;6(3):230-7. doi: 10.1161/CIRCGENETICS.113.000037. Epub 2013 May 20.

• Responsible Party: Carolyn Yung Ho, MD, Associate Physician, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT00319982
• Other Study ID Numbers: 001936; K23HL078901
• First Posted: Apr 27, 2006
• Last Update Posted: Apr 7, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Carolyn Yung Ho, MD, Associate Physician, Brigham and Women's Hospital: Hypertrophic Cardiomyopathy; Left ventricular hypertrophy; Diltiazem
• Additional relevant MeSH terms: Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy; Diltiazem

Study Results

Participant Flow

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.

Arm/Group Title	I- Diltiazem (Active Arm)	II- Placebo
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

Baseline Characteristics

Arm/Group Title	I- Diltiazem	II- Placebo	Total
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 Participants	18	20	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.1 (1.7)	17.3 (2.1)	15.8 (8.6)
Sex: Female, Male (Count of Participants)
Female	11 61.1%	11 55%	22 57.9%
Male	7 38.9%	9 45%	16 42.1%
Region of Enrollment (participants) [Number]
United States	18 100%	19 95%	37 97.4%
Australia	0 0%	1 5%	1 2.6%

Outcome Measures

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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I- Diltiazem	II- Placebo
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)
Measure Participants	18	20
Mean (Standard Error) [cm/sec (difference final-baseline)]	-0.06 (0.27)	-0.21 (0.42)

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
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
Description	Adverse events were compared between participants assigned to diltiazem and those assigned to placebo
Time Frame	Baseline through final study visits

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I- Diltiazem	II- Placebo
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)
Measure Participants	18	20
Number [Participants Reporting Adverse Events]	10 55.6%	12 60%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I- Diltiazem, II- Placebo
	Comments	Adverse Events
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Impact of Diltiazem on Heart Rate
Description	Change in Value (Difference between Final and Baseline Visits)
Time Frame	Baseline and final study visits

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I- Diltiazem	II- Placebo
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)
Measure Participants	18	20
Mean (Standard Error) [beats/minute]	-4.9 (2.2)	2.0 (2.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I- Diltiazem, II- Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
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
Description	Change in Left Ventricular End-Diastolic Diameter z-score (Final Value - Baseline Value)
Time Frame	Baseline and final study visits

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I- Diltiazem	II- Placebo
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)
Measure Participants	18	20
Mean (Standard Error) [z-score units]	0.60 (0.17)	-0.53 (0.16)

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
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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I- Diltiazem	II- Placebo
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)
Measure Participants	18	20
Number [participants]	2 11.1%	2 10%

6. Secondary Outcome

Title	Adherence to Study Medication
Description	Adherence to study medication was assessed by pill count
Time Frame	Duration of the trial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I- Diltiazem	II- Placebo
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)
Measure Participants	18	20
Median (Standard Deviation) [percentage of pills taken]	83 (10.8)	90 (6.6)

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
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Impact of Diltiazem on Systolic Blood Pressure
Description	Change in Value (Difference between Final and Baseline Visits)
Time Frame	Baseline and final study visits

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I- Diltiazem	II- Placebo
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)
Measure Participants	18	20
Mean (Standard Error) [mmHg]	-1.4 (1.7)	2.1 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I- Diltiazem, II- Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
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

Adverse Events

Time Frame	Duration of Trial
Arm/Group Title	I- Diltiazem		II- Placebo
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	I- Diltiazem		II- Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	I- Diltiazem		II- Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/18 (55.6%)		12/20 (60%)
Cardiac disorders
Shortness of Breath	6/18 (33.3%)	9	1/20 (5%)	1
Lightheadeness	3/18 (16.7%)	5	5/20 (25%)	6
Chest Pain	3/18 (16.7%)	3	1/20 (5%)	1
Gastrointestinal disorders
Nausea/GI distress	1/18 (5.6%)	1	4/20 (20%)	4
General disorders
Fatigue	1/18 (5.6%)	1	2/20 (10%)	2
Nervous system disorders
Headache	0/18 (0%)	0	1/20 (5%)	2

Limitations/Caveats

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.

More Information

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.