Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

NCT01912534 | Completed Phase 2 DMC

• 2 other identifiers: VANISH5P50HL112349
• Study Type: interventional
• Target: 211
• Locations: 2 countries
• Sites: 15

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.

Conditions

Hypertrophic Cardiomyopathy

Keywords

Sarcomere Mutations

Outcome Measures

Primary Outcomes (1)

• Composite z-score

  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

  2 years

Secondary Outcomes (10)

• z-score serum NTproBNP

  2 years

• z-score high sensitivity cardiac troponin

  2 years

• z-score LV mass

  2 years

• z-score LA volume

  2 years

• z-score LV end diastolic volume

  2 years

Other Outcomes (1)

• Safety of valsartan as assessed by incidence of adverse events

  2 years

Study Arms (2)

Valsartan

ACTIVE COMPARATOR

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; Drug: Placebo

Placebo

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

Valsartan DRUG

40, 80 and 160 mg tablets of Valsartan

Also known as: Diovan

Placebo; Valsartan

Placebo DRUG

During Active Run-In, all patients take Valsartan. During maintenance, all patients are randomized to valsartan or placebo

Also known as: Matching Placebo pills

Placebo; Valsartan

Eligibility Criteria

• Age: 8 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• \. 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)
• LV wall thickness ≥12 mm and ≤25 mm or z score ≥3 and ≤18 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 8-45 years
• Able to attend follow-up appointments, complete all study assessments, and provide written informed consent
• Group 2 (Preclinical HCM Cohort (G+/LVH-))
• LV Wall Thickness \<12 mm and z score \<3 , as determined by rapid assessment by the echocardiographic core laboratory
• Age 10-25 years

You may not qualify if:

• 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 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.
• Pregnant or breastfeeding females - Females of childbearing potential with no effective contraceptive method (including abstinence)
• Uncontrolled systemic HTN \[persistent SBP\>160 and/or DBP\>90 in adult or equivalent in children (e.g., SBP\>99th or DBP\>95th percentile for sex, age, and height centile based on the American Academy of Pediatrics normal values)\]
• Obstructive physiology, defined by resting, Valsalva-provoked or exercise-induced gradient \>30mmHg 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 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.
• Left ventricular ejection fraction (LVEF) \<55%
• 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)
• Secondary prevention implantable cardioverter-defibrillator device (ICD; primary prevention ICDs without a history of appropriate therapy, including shock or ATP, are allowable).
• Prior treatment or hospitalization for symptomatic heart failure
• Participation in a clinical trial (except observational studies) involving investigational medications within the previous 30 days.

Sponsors & Collaborators

• Carelon Research: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (15)

Stanford University

Stanford, California, 94305, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Washington University School Medicine

St Louis, Missouri, 63110, United States

Location

Cinncinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Toronto General Hospital

Toronto, Ontario, M4W3S5, Canada

Location

Toronto Sick Kids

Toronto, Ontario, M5G1X8, Canada

Location

Related Publications (7)

• Topriceanu CC, Vissing CR, Axelsson Raja A, Day SM, Russell MW, Zahka K, Pereira AC, Colan SD, Murphy AM, Canter C, Bach RG, Wheeler MT, Rossano JW, Owens AT, Mestroni L, Taylor MRG, Moon JC, Captur G, Patel AR, Wilmot I, Soslow JH, Becker JR, Seidman CE, Lakdawala NK, Bundgaard H, Tahir UA, Ho CY. Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Clinical Trial. Circ Heart Fail. 2025 Jun;18(6):e012393. doi: 10.1161/CIRCHEARTFAILURE.124.012393. Epub 2025 May 9.

  PMID: 40340372 DERIVED

• Ostrominski JW, Claggett BL, Jerosch-Herold M, Raja AA, Day SM, Russell MW, Zahka K, Pereira AC, Colan SD, Murphy AM, Canter C, Bach RG, Wheeler MT, Rossano JW, Owens AT, Mestroni L, Taylor MRG, Patel AR, Wilmot I, Soslow JH, Becker JR, Lakdawala NK, Bundgaard H, Vargas JD, Ho CY; Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Investigators. Valsartan and Cardiac Remodeling in Early-Stage Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial Cardiac Magnetic Resonance Substudy. JAMA Cardiol. 2025 Jun 1;10(6):617-623. doi: 10.1001/jamacardio.2024.5677.

  PMID: 40042824 DERIVED

• Ireland CG, Burstein DS, Day SM, Axelsson Raja A, Russell MW, Zahka KG, Pereira A, Canter CE, Bach RG, Wheeler MT, Rossano JW, Owens AT, Bundgaard H, Mestroni L, Taylor MRG, Patel AR, Wilmot I, Soslow JH, Becker JR, Giverts I, Orav EJ, Claggett B, Lin KY, Ho CY. Quality of Life and Exercise Capacity in Early Stage and Subclinical Hypertrophic Cardiomyopathy: A Secondary Analysis of the VANISH Trial. Circ Heart Fail. 2024 Aug;17(8):e011663. doi: 10.1161/CIRCHEARTFAILURE.124.011663. Epub 2024 Aug 1.

  PMID: 39087355 DERIVED

• Vissing CR, Axelsson Raja A, Day SM, Russell MW, Zahka K, Lever HM, Pereira AC, Colan SD, Margossian R, Murphy AM, Canter C, Bach RG, Wheeler MT, Rossano JW, Owens AT, Benson L, Mestroni L, Taylor MRG, Patel AR, Wilmot I, Thrush P, Soslow JH, Becker JR, Seidman CE, Lakdawala NK, Cirino AL, McMurray JJV, MacRae CA, Solomon SD, Bundgaard H, Orav EJ, Ho CY; Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Investigators. Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial. JAMA Cardiol. 2023 Nov 1;8(11):1083-1088. doi: 10.1001/jamacardio.2023.2808.

  PMID: 37672268 DERIVED

• 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.

  PMID: 34556856 DERIVED

• 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.

  PMID: 31813281 DERIVED

• 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.

  PMID: 28912187 DERIVED

MeSH Terms

Conditions

Cardiomyopathy, Hypertrophic

Interventions

Valsartan

Condition Hierarchy (Ancestors)

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Study Officials

• Carolyn Y. Ho, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2013
• First Posted: July 31, 2013
• Study Start: March 1, 2014
• Primary Completion: July 1, 2019
• Study Completion: July 1, 2019
• Last Updated: January 11, 2021

Record last verified: 2020-04

Locations

CA (2); US (13)