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

• ClinicalTrials.gov Identifier: NCT01912534
• Recruitment Status: Completed
• First Posted: July 31, 2013
• Last Update Posted: January 11, 2021
• Sponsor: HealthCore-NERI
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): HealthCore-NERI

Study Description

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

• 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
• Actual Study Start Date: March 2014
• Actual Primary Completion Date: July 2019
• Actual Study Completion Date: July 2019

Arms and Interventions

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

Primary Outcome Measures :

1. Composite z-score [ Time Frame: 2 years ]
   Composite z-score which is the average of 9 change-scores of: serum NTproBNP, serum high-sensitivity cardiac troponin, left ventricular (LV) mass, left atrial (LA) volume, LV end diastolic volume, LV end systolic volume, maximal LV wall thickness, echo E' velocity, echo S' velocity

Secondary Outcome Measures :

1. z-score serum NTproBNP [ Time Frame: 2 years ]
   Z-score for the 2 year change for serum NTproBNP
2. z-score high sensitivity cardiac troponin [ Time Frame: 2 years ]
   Z-score for the 2 year change for high-sensitivity cardiac troponin
3. z-score LV mass [ Time Frame: 2 years ]
   Z-score for the 2 year change in LV Mass
4. z-score LA volume [ Time Frame: 2 years ]
   Z-score for the 2 year change in LA Volume
5. z-score LV end diastolic volume [ Time Frame: 2 years ]
   Z-score for the 2 year change in LV end diastolic volume
6. z-score LV end systolic volume [ Time Frame: 2 years ]
   Z-score for the 2 year change in LV end systolic volume
7. z-score maximal LV wall thickness [ Time Frame: 2 years ]
   Z-score for the 2 year change in Maximal LV wall thickness
8. z-score echo E' velocity [ Time Frame: 2 years ]
   Z-score for the 2 year change in echo E' velocity
9. z-score echo S' velocity [ Time Frame: 2 years ]
   Z-score for the 2 year change in echo S' velocity
10. Binary indicator of success or failure [ Time Frame: 2 years ]
    Success defined as an improvement at 2 years in any of the following: serum NTproBNP, serum high-sensitivity troponin, LV Mass, LA Volume, LV end diastolic volume, LV end systolic volume, Maximal LV wall thickness, echo E' velocity, or echo S' velocity

Other Outcome Measures:

1. Safety of valsartan as assessed by incidence of adverse events [ Time Frame: 2 years ]
   Safety of valsartan as assessed by incidence of adverse events

Eligibility Criteria

• 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

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

HealthCore-NERI

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

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

More Information

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

Ho CY, Day SM, Axelsson A, Russell MW, Zahka K, Lever HM, Pereira AC, Colan SD, Margossian R, Murphy AM, Canter C, Bach RG, Wheeler MT, Rossano JW, Owens AT, Bundgaard H, Benson L, Mestroni L, Taylor MRG, Patel AR, Wilmot I, Thrush P, Vargas JD, Soslow JH, Becker JR, Seidman CE, Lakdawala NK, Cirino AL; VANISH Investigators, Burns KM, McMurray JJV, MacRae CA, Solomon SD, Orav EJ, Braunwald E. Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial. Nat Med. 2021 Oct;27(10):1818-1824. doi: 10.1038/s41591-021-01505-4. Epub 2021 Sep 23.

Axelsson Raja A, Shi L, Day SM, Russell M, Zahka K, Lever H, Colan SD, Margossian R, Hall EK, Becker J, Jefferies JL, Patel AR, Choudhury L, Murphy AM, Canter C, Bach R, Taylor M, Mestroni L, Wheeler MT, Benson L, Owens AT, Rossano J, Lin KY, Pahl E, Pereira AC, Bundgaard H, Lewis GD, Vargas JD, Cirino AL, McMurray JJV, MacRae CA, Solomon SD, Orav EJ, Braunwald E, Ho CY. Baseline Characteristics of the VANISH Cohort. Circ Heart Fail. 2019 Dec;12(12):e006231. doi: 10.1161/CIRCHEARTFAILURE.119.006231. Epub 2019 Dec 9.

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: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT01912534
• Other Study ID Numbers: VANISH; 5P50HL112349 ( U.S. NIH Grant/Contract )
• First Posted: July 31, 2013
• Last Update Posted: January 11, 2021
• Last Verified: April 2020

Keywords provided by HealthCore-NERI:

Sarcomere Mutations

Additional relevant MeSH terms:

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