Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM (VANISH)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by New England Research Institutes
Sponsor:
Collaborator:
Information provided by (Responsible Party):
New England Research Institutes
ClinicalTrials.gov Identifier:
NCT01912534
First received: June 5, 2013
Last updated: April 16, 2014
Last verified: July 2013
  Purpose

The purpose of this trial is to determine whether treatment with valsartan will have beneficial effect in early hypertrophic cardiomyopathy (HCM) by assessing many domains that reflect myocardial structure, function and biochemistry.


Condition Intervention Phase
Hypertrophic Cardiomyopathy
Drug: Valsartan
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

Resource links provided by NLM:


Further study details as provided by New England Research Institutes:

Primary Outcome Measures:
  • A combined single composite z-score (described below) will serve as primary surrogate endpoint to monitor response to valsartan treatment [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Myocardial injury, hemodynamic stress, collagen metabolism, functional capacity, myocardial fibrosis, cardiac morphology, and cardiac function endpoints will be combined into a single composite z-score.


Secondary Outcome Measures:
  • Impact of valsartan treatment on disease pathology [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Improvement in, stability of, or attenuation of progression in 7 components of primary composite outcomes; left atrial size; assessment of left ventricle (LV) mass by cardiac magnetic resonance imaging(CMR); LV systolic and diastolic function; the degree of interstitial myocardial fibrosis as assessed by novel CMR sequences; additional parameters from metabolic exercise testing and additional serum biomarkers that reflect fibrosis, injury and stress

  • Clinical outcomes and assessment of symptom burden [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Specifically, decline 1 point on NYHA or increase in therapy for HCM; development of arrhythmias; time to development of HCM-related symptoms; development of obstructive physiology; development of a new murmur; activity level as tracked by activity monitor and survey.

  • Incidence of adverse drug reactions, frequency of subject drop-out, and responses to validated quality of life metrics between valsartan and placebo-treated group [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Incidence of adverse drug reactions, frequency of subject drop-out, and responses to validated quality of life metrics between valsartan and placebo-treated group


Estimated Enrollment: 300
Study Start Date: April 2014
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Valsartan

During active run-in, all subjects will be started on valsartan at an initial dose of 40 mg twice daily (20 mg twice daily in children ≤16 years old, or adults with baseline systolic BP<100 mmHg). This initial dose will be received through the mail within 2 weeks of Visit 1 and titration will begin after communication with the study coordinator confirming that trial eligibility criteria were met. Valsartan dose will be titrated at 2-week intervals to a target dose of 320 mg/day in adults; 160 mg/day in children ≥35 kg; 80 mg/day in children <35 kg.

Subjects who tolerate active run-in and titration to target dose of valsartan will then undergo stratified randomization and begin blinded treatment with valsartan or matched placebo on maximal tolerated dose, according to their assigned treatment group. Treatment will continue for 2 years.

Drug: Valsartan
40, 80 and 160 mg tablets of Valsartan
Other Name: Diovan
Drug: Placebo
During Active Run-In, all patients take Valsartan. During maintenance, all patients are randomized to valsartan or placebo
Other Name: Placebo pills manufactured to match Valsartan 160 mg, 80 mg, 40 mg tablets
Placebo Comparator: Placebo

During active run-in, all subjects will be started on valsartan at an initial dose of 40 mg twice daily (20 mg twice daily in children ≤16 years old, or adults with baseline systolic BP<100 mmHg). This initial dose will be received through the mail within 2 weeks of Visit 1 and titration will begin after communication with the study coordinator confirming that trial eligibility criteria were met. Valsartan dose will be titrated at 2-week intervals to a target dose of 320 mg/day in adults; 160 mg/day in children ≥35 kg; 80 mg/day in children <35 kg.

Subjects who tolerate active run-in and titration to target dose of valsartan will then undergo stratified randomization and begin blinded treatment with valsartan or matched placebo on maximal tolerated dose, according to their assigned treatment group. Treatment will continue for 2 years.

Drug: Valsartan
40, 80 and 160 mg tablets of Valsartan
Other Name: Diovan
Drug: Placebo
During Active Run-In, all patients take Valsartan. During maintenance, all patients are randomized to valsartan or placebo
Other Name: Placebo pills manufactured to match Valsartan 160 mg, 80 mg, 40 mg tablets

Detailed Description:

This is a multicenter, double-blind, placebo-controlled Phase II, randomized clinical trial to assess the safety and efficacy of valsartan in attenuating disease evolution in early HCM. Sarcomere mutation carriers with asymptomatic or mildly symptomatic overt disease (NYHA class I-II), and mutation carriers without left ventricular hypertrophy (LVH) will be studied.

  Eligibility

Ages Eligible for Study:   8 Years to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All subjects must have a Pathogenic or Likely Pathogenic HCM Sarcomere Mutation
  • The following categories of mutations are considered acceptable for subjects who have previously undergone clinical genetic testing. If results are ambiguous, they will be reviewed by the Clinical Coordinating Center to determine eligibility.

    1. Laboratory for Molecular Medicine (Pathogenic, Likely Pathogenic)
    2. Transgenomics/ PGXHealth (Class I)
    3. GeneDx (Disease causing; Variant; likely disease-causing; Published, disease-causing mutation; Novel, likely disease-causing, mutation)
    4. Correlagen (Associated; Probably Associated

Overt HCM Cohort

  • LV wall thickness ≥12 mm and < 20 mm (in subjects ≥18 years) or z score ≥3 and < 10 as determined by rapid assessment by the echocardiographic core laboratory
  • NYHA functional class I or II; no perceived or only slight limitations in physical activities
  • No resting or provokable LV obstruction (peak gradient ≤ 30 mmHg) on clinically-obtained Exercise Tolerance Test (ETT)-echo within the past 24 months or transthoracic echo with Valsalva maneuver within the past 12 months
  • Age 8-30 years
  • Able to attend follow-up appointments, complete all study assessments, and provide written informed consent

Preclinical HCM Cohort (G+/LVH-)

  • LV Wall Thickness <12 mm (in subjects ≥18 years) or z score <3 (in subjects <18 years), as determined by rapid assessment by the echocardiographic core laboratory
  • Age 10-25 years
  • E' z score ≤ -2 OR ECG abnormalities other than Non-specific ST or T-wave abnormalities (NSSTW) changes (Q waves, T wave inversion, repolarization changes)
  • Able to attend follow-up appointments, complete all study assessments, and provide written informed consent

Subject Exclusion Criteria

  • Contraindication to angiotensin receptor blocker (ARB) administration, including impaired renal function, hyperkalemia (serum K>5.0 mmol/L), prior history of angioedema
  • Medical conditions associated with increased collagen turnover that may confound interpretation of biomarkers of collagen synthesis (liver, pulmonary or renal fibrosis, inflammatory states, cancer, trauma or surgery within 6 months of enrollment)
  • Concomitant or prior use of ARB or ACE-inhibitors
  • Pregnant or breastfeeding females
  • Females of childbearing potential with no effective contraceptive method (including abstinence)
  • Systemic Hypertension (HTN) (Systolic Blood Pressure (SBP) >140 and/or Diastolic Blood Pressure (DBP) >90), or on medical therapy for HTN
  • Obstructive physiology, defined by resting, Valsalva-provoked or exercise-induced gradient >30 mm Hg within the past 24 months
  • Prior septal myectomy or alcohol septal ablation
  • Known, suspected, or symptomatic coronary artery disease or evidence of prior myocardial infarction based on symptoms or cardiac imaging
  • More than mild valvular heart disease or congenital heart disease (allowable conditions include bicuspid aortic valve without stenosis or regurgitation; spontaneously closed ventricular septal defects; patent foramen ovale, small (</=2mm) restrictive ventricular septal defects with normal ventricular size, and other minor defects that are considered allowable after review and consensus by the echo core lab, participating pediatric cardiologists, and overall study PI)
  • Left ventricular ejection fraction (LVEF) <55%
  • Concomitant medical conditions that would preclude performance of or confound interpretation of echocardiography, exercise testing, or CMR (eg, renal insufficiency, lung disease, orthopedic/rheumatologic conditions, implantable cardioverter-defibrillator (ICD) or pacemaker, atrial fibrillation)
  • Prior treatment or hospitalization for symptomatic heart failure
  • Participation in a clinical trial (except observational studies) involving investigational medications within the previous 30 days.
  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: NCT01912534

Locations
United States, California
Stanford University Not yet recruiting
Stanford, California, United States, 94305
Contact: Euan Ashley, MD, PhD    650-498-4900    euan@stanford.edu   
Principal Investigator: Euan Ashley, MD, PhD         
United States, Colorado
University of Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Matthew Taylor, MD, PhD    303-724-1400    matthew.taylor@ucdenver.edu   
Principal Investigator: Matthew Taylor, MD, PhD         
Sub-Investigator: Luisa Mestroni, MD         
United States, Illinois
University of Chicago Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Elizabeth McNally, MD    773-702-2672    emcnally@uchicago.edu   
Principal Investigator: Elizabeth McNally, MD         
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Anne Murphy, MD    410-955-5987    murphy@jhmi.edu   
Principal Investigator: Anne Murphy, MD         
Sub-Investigator: Ted Abraham, MD         
United States, Massachusetts
Brigham & Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Carolyn Ho, MD    617-732-5685    cho@partners.org   
Principal Investigator: Carolyn Ho, MD         
Sub-Investigator: Mark A. Fifer, MD         
Children's Hospital Boston Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Steven Colan, MD    617-355-7893    colan@alum.mit.edu   
Principal Investigator: Steven Colan, MD         
Sub-Investigator: Renee Margosian, MD         
United States, Michigan
University of Michigan Not yet recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Sharlene Day, MD    734-615-7917    sday@umich.edu   
Principal Investigator: Sharlene Day, MD         
Sub-Investigator: Mark Russell, MD         
United States, Missouri
Washington University School Medicine Not yet recruiting
St. Louis, Missouri, United States, 63110
Contact: Charles Canter, MD    314-454-6095    canter@kids.wustl.edu   
Principal Investigator: Charles Canter, MD         
Sub-Investigator: Keith Mankovitz, MD         
United States, Ohio
Cinncinnati Children's Hospital Medical Center Recruiting
Cinncinati, Ohio, United States, 45229
Contact: Jeffrey Towbin, MD    513-636-3049    jeffrey.towbin@cchmc.org   
Principal Investigator: Jeffrey Towbin, MD         
Sub-Investigator: John Lynn Jeffries, MD         
Cleveland Clinic Foundation Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Harry Lever, MD    216-444-6970    leverh@ccf.org   
Principal Investigator: Harry Lever, MD         
Sub-Investigator: Kenneth Zahka, MD         
United States, Tennessee
Vanderbilt University Not yet recruiting
Nashville, Tennessee, United States, 37232
Contact: Thomas DiSalvo, MD    615-322-2318    thomas.g.disalvo@vanderbilt.edu   
Principal Investigator: Thomas DiSalvo, MD         
Sub-Investigator: Jason Becker, MD         
Sub-Investigator: Larry Markham, MD         
Canada, Ontario
Toronto Sick Kids Not yet recruiting
Toronto, Ontario, Canada, M5G1X8
Contact: Lee Benson, MD    416-813-6141    lee.benson@sickkids.ca   
Principal Investigator: Lee Benson, MD         
Toronto General Hospital Not yet recruiting
Toronto, Ontario, Canada, M4W3S5
Contact: Harry Rakowski, MD    416-340-4062    harry.rakowski@uhn.ca   
Principal Investigator: Harry Rakowski, MD         
Sponsors and Collaborators
New England Research Institutes
Investigators
Principal Investigator: Carolyn Y. Ho, MD Brigham and Women's Hospital
  More Information

No publications provided

Responsible Party: New England Research Institutes
ClinicalTrials.gov Identifier: NCT01912534     History of Changes
Other Study ID Numbers: VANISH, 5P50HL112349
Study First Received: June 5, 2013
Last Updated: April 16, 2014
Health Authority: United States: Federal Government

Keywords provided by New England Research Institutes:
Sarcomere Mutations

Additional relevant MeSH terms:
Cardiomyopathy, Hypertrophic
Cardiomyopathies
Hypertrophy
Heart Diseases
Cardiovascular Diseases
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases
Pathological Conditions, Anatomical
Valsartan
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 24, 2014