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

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	Phase
Hypertrophic Cardiomyopathy	Drug: Valsartan; Drug: Placebo	Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	211 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
Study Start Date :	April 2014
Estimated Primary Completion Date :	November 2018
Estimated Study Completion Date :	July 2019

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Valsartan; 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: Matching Placebo pills
Placebo Comparator: Placebo; 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: Matching Placebo pills

Outcome Measures

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Primary Outcome Measures :

1. A combined single composite z-score (described below) will serve as primary surrogate endpoint to monitor response to valsartan treatment [ Time Frame: 2 years ]
   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 :

1. Impact of valsartan treatment on disease pathology [ Time Frame: 2 years ]
   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
2. Clinical outcomes and assessment of symptom burden [ Time Frame: 2 years ]
   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.
3. 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 ]
   Incidence of adverse drug reactions, frequency of subject drop-out, and responses to validated quality of life metrics between valsartan and placebo-treated group

Eligibility Criteria

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Ages Eligible for Study:	8 Years to 45 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. All subjects must have a Pathogenic or Likely Pathogenic HCM Sarcomere Mutation

a. 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.

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

Group 1 (Overt HCM Cohort)

1. LV wall thickness ≥12 mm and ≤25 mm or z score ≥3 and ≤18 as determined by rapid assessment by the echocardiographic core laboratory
2. NYHA functional class I or II; no perceived or only slight limitations in physical activities
3. 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
4. Age 8-45 years
5. Able to attend follow-up appointments, complete all study assessments, and provide written informed consent

Group 2 (Preclinical HCM Cohort (G+/LVH-))

1. LV Wall Thickness <12 mm and z score <3 , as determined by rapid assessment by the echocardiographic core laboratory
2. Age 10-25 years
3. E' z score ≤ -1.5 OR ECG abnormalities other than NSSTW changes (Q waves, T wave inversion, repolarization changes) OR LV wall thickness z-score 1.5-2.9 combined with LV thickness to dimension ratio ≥0.19 (as determined by rapid assessment by the echocardiographic core laboratory)
4. Able to attend follow-up appointments, complete all study assessments, and provide written informed consent

Subject Exclusion Criteria

1. Contraindication to angiotensin receptor blocker (ARB) administration, including impaired renal function, hyperkalemia (serum K>5.0 mmol/L), prior history of angioedema
2. 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)
3. Concomitant use of Spironolactone, Lithium, or Aliskiren, ARB or ACE-inhibitors. If these drugs are in active use but not necessary for medical care, they may be discontinued and baseline studies can be performed after a 2-week washout period.
4. Pregnant or breastfeeding females - Females of childbearing potential with no effective contraceptive method (including abstinence)
5. Uncontrolled systemic HTN [persistent SBP>160 and/or DBP>90 in adult or equivalent in children (e.g., SBP>99th or DBP>95th percentile for sex, age, and height centile based on the American Academy of Pediatrics normal values)]
6. Obstructive physiology, defined by resting, Valsalva-provoked or exercise-induced gradient >30mmHg within the past 24 months
7. Prior septal myectomy or alcohol septal ablation
8. Known, suspected, or symptomatic coronary artery disease or evidence of prior myocardial infarction based on symptoms or cardiac imaging
9. More than mild valvular heart disease or clinically significant congenital heart disease. Allowable conditions include bicuspid aortic valve without clinically significant stenosis or regurgitation; spontaneously closed ventricular septal defects; patent foramen ovale, small (≤ 2 mm) restrictive ventricular septal defects with normal ventricular size, and other minor defects that are considered allowable after [review and consensus by participating pediatric cardiologists, overall study PI and] adjudication by the echocardiographic core laboratory.
10. Left ventricular ejection fraction (LVEF) <55%
11. Concomitant medical conditions that would preclude performance of or confound interpretation of echocardiography, exercise testing, or CMR (e.g., renal insufficiency, lung disease, orthopedic/rheumatologic conditions, atrial fibrillation)
12. Secondary prevention implantable cardioverter-defibrillator device (ICD; primary prevention ICDs without a history of appropriate therapy, including shock or ATP, are allowable).
13. Prior treatment or hospitalization for symptomatic heart failure
14. Participation in a clinical trial (except observational studies) involving investigational medications within the previous 30 days.

Contacts and Locations

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Locations

United States, California
Stanford University
Stanford, California, United States, 94305
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02115
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Washington University School Medicine
Saint Louis, Missouri, United States, 63110
United States, Ohio
Cinncinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada, M4W3S5
Toronto Sick Kids
Toronto, Ontario, Canada, M5G1X8

Sponsors and Collaborators

New England Research Institutes

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

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

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lee TM, Hsu DT, Kantor P, Towbin JA, Ware SM, Colan SD, Chung WK, Jefferies JL, Rossano JW, Castleberry CD, Addonizio LJ, Lal AK, Lamour JM, Miller EM, Thrush PT, Czachor JD, Razoky H, Hill A, Lipshultz SE. Pediatric Cardiomyopathies. Circ Res. 2017 Sep 15;121(7):855-873. doi: 10.1161/CIRCRESAHA.116.309386. Review.

Responsible Party:	New England Research Institutes
ClinicalTrials.gov Identifier:	NCT01912534 History of Changes
Other Study ID Numbers:	VANISH; 5P50HL112349 ( U.S. NIH Grant/Contract )
First Posted:	July 31, 2013
Last Update Posted:	February 5, 2018
Last Verified:	May 2017

Keywords provided by New England Research Institutes:

Sarcomere Mutations

Additional relevant MeSH terms:

Cardiomyopathies; Hypertrophy; Cardiomyopathy, Hypertrophic; Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Stenosis, Subvalvular	Aortic Valve Stenosis; Heart Valve Diseases; Valsartan; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action