NCT00319982

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
39

participants targeted

Target at P25-P50 for phase_2

Timeline
Completed

Started Jan 2006

Longer than P75 for phase_2

Geographic Reach
1 country

2 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

January 1, 2006

Completed
4 months until next milestone

First Submitted

Initial submission to the registry

April 27, 2006

Completed
Same day until next milestone

First Posted

Study publicly available on registry

April 27, 2006

Completed
6.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2012

Completed
1 year until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2013

Completed
1.3 years until next milestone

Results Posted

Study results publicly available

April 7, 2015

Completed
Last Updated

April 7, 2015

Status Verified

March 1, 2015

Enrollment Period

6.9 years

First QC Date

April 27, 2006

Results QC Date

January 26, 2015

Last Update Submit

March 24, 2015

Conditions

Hypertrophic Cardiomyopathy

Keywords

Hypertrophic CardiomyopathyLeft ventricular hypertrophyDiltiazem

Outcome Measures

Primary Outcomes (1)

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

    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.

    Baseline and final study visits

Secondary Outcomes (6)

  • Safety and Tolerability of Diltiazem Treatment

    Baseline through final study visits

  • Impact of Diltiazem on Heart Rate

    Baseline and final study visits

  • Left Ventricular Cavity Size

    Baseline and final study visits

  • Development of Left Ventricular Hypertrophy

    Baseline through final study visits

  • Adherence to Study Medication

    Duration of the trial

  • +1 more secondary outcomes

Study Arms (2)

I- Diltiazem

EXPERIMENTAL

Diltiazem- study medication

Drug: Diltiazem

II- Placebo

PLACEBO COMPARATOR

Placebo Comparator

Drug: Placebo

Interventions

DiltiazemDRUG

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

I- Diltiazem
PlaceboDRUG

Placebo comparator (double-blind allocation of study medication)

II- Placebo

Eligibility Criteria

Age5 Years - 39 Years
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64)

You may qualify if:

  • Preclinical HCM (identified sarcomere mutation with no clinical evidence of left ventricular hypertrophy)
  • Able to provide informed consent (or parental consent)

You may not qualify if:

  • Contraindication to diltiazem administration
  • Impaired hepatic or renal function
  • Age \< 5 years
  • Pregnant or breastfeeding women

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (10)

  • 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. doi: 10.1172/JCI11093.

    PMID: 11104788BACKGROUND

  • 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. doi: 10.1172/JCI14677.

    PMID: 11956238BACKGROUND

  • 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. doi: 10.1161/01.cir.0000019070.70491.6d.

    PMID: 12081993BACKGROUND

  • Ho CY, Seidman CE. A contemporary approach to hypertrophic cardiomyopathy. Circulation. 2006 Jun 20;113(24):e858-62. doi: 10.1161/CIRCULATIONAHA.105.591982. No abstract available.

    PMID: 16785342BACKGROUND

  • Ho CY, Lakdawala NK, Cirino AL, Lipshultz SE, Sparks E, Abbasi SA, Kwong RY, Antman EM, Semsarian C, Gonzalez A, Lopez 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.

    PMID: 25543971BACKGROUND

  • Ho CY, Lopez B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, Kwong R, Gonzalez A, Colan SD, Seidman JG, Diez 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.

    PMID: 20818890BACKGROUND

  • Ho CY, Abbasi SA, Neilan TG, Shah RV, Chen Y, Heydari B, Cirino AL, Lakdawala NK, Orav EJ, Gonzalez A, Lopez B, Diez 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.

    PMID: 23549607BACKGROUND

  • 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.

    PMID: 23690394BACKGROUND

  • Lakdawala NK, Thune JJ, Maron BJ, Cirino AL, Havndrup O, Bundgaard H, Christiansen M, Carlsen CM, Dorval JF, Kwong RY, Colan SD, Kober 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.

    PMID: 21943931BACKGROUND

  • Ho CY, Cirino AL, Lakdawala NK, Groarke J, Valente AM, Semsarian C, Colan SD, Orav EJ. Evolution of hypertrophic cardiomyopathy in sarcomere mutation carriers. Heart. 2016 Nov 15;102(22):1805-1812. doi: 10.1136/heartjnl-2016-310015. Epub 2016 Sep 2.

    PMID: 27590665DERIVED

MeSH Terms

Conditions

Cardiomyopathy, HypertrophicHypertrophy, Left Ventricular

Interventions

Diltiazem

Condition Hierarchy (Ancestors)

CardiomyopathiesHeart DiseasesCardiovascular DiseasesAortic Stenosis, SubvalvularAortic Valve StenosisAortic Valve DiseaseHeart Valve DiseasesCardiomegalyHypertrophyPathological Conditions, AnatomicalPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

BenzazepinesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-RingHeterocyclic Compounds

Limitations and 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.

Results Point of Contact

Title
Carolyn Ho, MD
Organization
Brigham and Women's Hospital
cho@partners.org
617-732-5685

Study Officials

  • Carolyn Y Ho, MD

    Brigham and Women's Hospital

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Associate Physician

Study Record Dates

First Submitted

April 27, 2006

First Posted

April 27, 2006

Study Start

January 1, 2006

Primary Completion

December 1, 2012

Study Completion

December 1, 2013

Last Updated

April 7, 2015

Results First Posted

April 7, 2015

Record last verified: 2015-03

Locations

US(2)