Trial record 7 of 23 for:    Cardiomyopathy | Open Studies | NIH, U.S. Fed

Hypertrophic Regression With N-Acetylcysteine in HCM (HALT)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2012 by The University of Texas Health Science Center, Houston
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Ali. J. Marian, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier:
NCT01537926
First received: February 15, 2012
Last updated: February 17, 2012
Last verified: February 2012
  Purpose

The purpose of the sudy is to conduct a small study to gather the preliminary data for future lage scale clinical studies that will be designed test the potential beneficial efffect of over-the counter study anti-oxidant drug called N-acetylcysteine (NAC) in patients with a heart muscle condition called Hypertrophic Cardiomyopathy (HCM). The present study is a pilot feasibility study, the investigators want to find out whether the investigators can recruit and retain patients with HCM in the study and whether these patients can tolerate this drug and can stay on one year. Likewise, the investigators want to find out any potential side effects that this drug might have and estimate whether ii has any beneficial effects.


Condition Intervention Phase
Hypertrophic Cardiomyopathy
Drug: N-acetylcysteine (NAC)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Feasibility Study With N-acetylcystein (NAC) in Patients With HCM Caused by Sarcomere Proteins Mutations

Resource links provided by NLM:


Further study details as provided by The University of Texas Health Science Center, Houston:

Primary Outcome Measures:
  • Recruitment rate [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]

    We will determine the estimates and 95% confidence intervals (CIs) of

    • The recruitment and accrual rates
    • Patient compliance rate with the two escalating doses of NAC and placebo
    • Patients developing side effects
    • Drop outs (and those who do not complete the studies) including percentage of patients unable to complete study due to implantation of a pacemaker or ICD
    • Patients who complete the intended 12 months treatment with NAC and placebo.
    • Baseline estimates and effect size of NAC on indices of cardiac hypertrophy mainly LVM indexed to body surface area (LVMI).


Secondary Outcome Measures:
  • indices of cardiac mass and function [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
    Changes in LV maximum and mean wall thicknesses; LVED volume (EDDV), LV end systolic volume (ESV), circumferential LV strain, LVEF, peak filling rate (PFR), peak ejection rate (PER) and time to PER; and macroscopic interstitial myocardial fibrosis, as defined by delayed MRI following gadolinium contrast administration.


Estimated Enrollment: 75
Study Start Date: January 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NAC for patients with HCM Drug: N-acetylcysteine (NAC)
NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.
Placebo Comparator: Control Arm Drug: N-acetylcysteine (NAC)
NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.

Detailed Description:

The primary objective is to perform a pilot study in patients with hypertrophic cardiomyopathy (HCM) and mutations in genes encoding sarcomere proteins to assess safety and gather the pre-requisite data for subsequent robust randomized placebo-controlled efficacy studies with N-acetylcysteine (NAC). We will gather data on the recruitment, accrual, retention, and compliance rates of HCM patients randomized to treatment with a placebo or two escalating doses of NAC. Likewise, we will determine any potential side effects and estimate the effect size of NAC on indices of cardiac hypertrophy.

HCM, the main focus of our research during the past two decades, is the most common cause of sudden cardiac death (SCD) in the young and an important cause of morbidity in the elderly. Despite its clinical impact, there is no effective pharmacological therapy for HCM. None of the current pharmacological therapies reverses or attenuates cardiac hypertrophy or reduces the risk of SCD in adults. Cardiac hypertrophy, the quintessential clinical feature of human HCM, is a major determinant of morbidity and the risk of SCD. Regression of cardiac hypertrophy is expected to improve morbidity and decrease the risk of SCD in HCM, as observed upon regression of load-dependent cardiac hypertrophy.

We have generated transgenic rabbit and mouse models of HCM and shown that cardiac hypertrophy and fibrosis could be reversed through genetic or pharmacological interventions. Results with NAC, a precursor to glutathione; the largest intracellular thiol pool against oxidative stress, were most promising. In three independent studies in two different transgenic models of HCM (rabbits and mouse), treatment with NAC completely reversed cardiac hypertrophy and fibrosis and improved indices of diastolic function. The ultimate goal of every physician-scientist is to apply the bench discoveries at the bedside. We propose to test our findings in the animal models in humans with HCM caused by sarcomere protein mutations. The use of NAC is also supported by data showing increased oxidative stress in human HCM. Moreover, NAC has been used extensively in humans and has a well-established safety profile. Resources including patients with sarcomere protein mutations are available to successfully complete a randomized placebo-controlled (N=25) pilot study to test two escalating doses of NAC (N=50), administered for one year. We will determine recruitment, accrual, retention and compliance rates; tolerability, safety and side effects; and estimate the effect size of NAC on the indices of cardiac hypertrophy, as determined by serial cardiac magnetic resonance imaging (MRI) at the baseline and after one year of treatment. Only HCM patients with sarcomere proteins mutations will be included to exclude phenocopy. The Core centers will interpret the phenotypic data to assure homogeneity. Data Coordinating Center will assist in the research design, planning and conduct of the study and analysis of the data. The findings will set the stage for large-scale robust randomized placebo-control efficacy studies.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with primary cardiac hypertrophy, non-dilated LV cavity and preserved LV systolic function, hence, the diagnosis of HCM, who have at least an LV end diastolic (LVSD) wall thickness of at least 15 mm on a 2D echocardiogram and
  • Known to have mutations in genes encoding sarcomeric proteins

Exclusion Criteria:

  • Hypersensitivity to NAC
  • Individuals younger than 18 years old (in the pilot study)
  • Phenocopy conditions, diagnosed clinically or genetically
  • Patients who have undergone transcatheter (alcohol) septal ablation within 6 months.
  • Individuals (typically family members) with causal mutations but an LVSD wall thickness of <15 mm
  • Patients with concomitant diseases such as:

    • Significant coronary artery disease >70% luminal diameter stenosis in ny of the major coronary arteries (if known);
    • Valvular heart diseases (more than mild aortic stenosis and mitral regurgitation, the latter judged to be due to primary mitral valve abnormalities);
    • Uncontrolled hypertension, defined as systolic blood pressure of

      • 140 mmHg and diastolic blood pressure of ≥90 mmHg on medication, mean of three measurements at rest);
    • Other significant medical problems, such as moderate to severe chronic renal failure (GFR<45 ml/min/1.73m2), advanced liver disease, cancer, or other disabling conditions
  • Pregnant women, nursing mothers and those who plan pregnancy during the study period
  • Those with active asthma (albeit the concern is relevant to nebulizer form but not oral formulations)
  • Cardiac contra-indications for MRI: Patients with devices such as permanent pacemakers, advanced AV block or severe bradycardia requiring permanent pacemaker implantation and those with ICD or serious ventricular arrhythmias requiring ICD will be excluded. Patients likely to receive pacemakers or ICDs within next 6 months also will be excluded.
  • Other contra-indications to MRI
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01537926

Contacts
Contact: Yanli Tan, BSN 713-500-2310 Yanli.Tan@uth.tmc.edu
Contact: Evelyn Capadocia 713-500-2345 Evelyn.Capadocia@uth.tmc.edu

Locations
United States, Texas
UTHSC Recruiting
Houston, Texas, United States, 77030
Contact: Yanli Tan, BSN    713-500-2310    Yanli@uth.tmc.edu   
Contact: Evelyn Capadocia    713-500-2345    Evelyn.capadocia@uth.tmc.edu   
Principal Investigator: Ali J. Marian, MD         
Sub-Investigator: Mohammad Hossein Rahbar, MD         
Sponsors and Collaborators
The University of Texas Health Science Center, Houston
Investigators
Principal Investigator: Ali J. Marian, MD The University of Texas Health Science Center, Houston
  More Information

No publications provided

Responsible Party: Ali. J. Marian, Professor , Cardiovascular Genetics, IMM, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier: NCT01537926     History of Changes
Other Study ID Numbers: HALT-HCM
Study First Received: February 15, 2012
Last Updated: February 17, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by The University of Texas Health Science Center, Houston:
HALT
HCM

Additional relevant MeSH terms:
Cardiomyopathies
Cardiomyopathy, Hypertrophic
Hypertrophy
Heart Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on September 30, 2014