Clinical trial NCT01912534: Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
Official title: Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertrophic Cardiomyopathy
Keywords: Sarcomere Mutations
Lead sponsor: Carelon Research
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2013-07-31
Enrollment: 211
Sex: ALL
Minimum age (years): 8
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: Composite z-score
timeFrame: 2 years
Secondary outcomes:
measure: z-score serum NTproBNP
timeFrame: 2 years
measure: z-score high sensitivity cardiac troponin
timeFrame: 2 years
measure: z-score LV mass
timeFrame: 2 years
measure: z-score LA volume
timeFrame: 2 years
measure: z-score LV end diastolic volume
timeFrame: 2 years
measure: z-score LV end systolic volume
timeFrame: 2 years
measure: z-score maximal LV wall thickness
timeFrame: 2 years
measure: z-score echo E' velocity
timeFrame: 2 years
measure: z-score echo S' velocity
timeFrame: 2 years
measure: Binary indicator of success or failure
timeFrame: 2 years
Other outcomes:
measure: Safety of valsartan as assessed by incidence of adverse events
timeFrame: 2 years
Locations:
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School Medicine
state: Missouri
city: Cincinnati
country: United States
facility: Cinncinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Sick Kids
state: Ontario
Study officials:
affiliation: Brigham and Women's Hospital
name: Carolyn Y. Ho, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.