Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

Condition(s) targeted: Hypertrophic Cardiomyopathy

Intervention: Valsartan (Drug); Placebo (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: New England Research Institutes

Official(s) and/or principal investigator(s):
Carolyn Y. Ho, MD, Principal Investigator, Affiliation: Brigham and Women's Hospital

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.

Official title: Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: A combined single composite z-score (described below) will serve as primary surrogate endpoint to monitor response to valsartan treatment

Secondary outcome:

Impact of valsartan treatment on disease pathology

Clinical outcomes and assessment of symptom burden

Incidence of adverse drug reactions, frequency of subject drop-out, and responses to validated quality of life metrics between valsartan and placebo-treated group

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.

Minimum age: 8 Years. Maximum age: 45 Years. Gender(s): Both.

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.

Stanford University, Stanford, California 94305, United States; Recruiting
Euan Ashley, MD, PhD, Phone: 650-498-4900, Email: euan@stanford.edu
Aleksandra Pavlovic, MD, PhD, Phone: 650-736-1147, Email: apavlovi@stanford.edu
Euan Ashley, MD, PhD, Principal Investigator
Matthew Wheeler, MD, PhD, Sub-Investigator

University of Colorado, Aurora, Colorado 80045, United States; Recruiting
Matthew Taylor, MD, PhD, Phone: 303-724-1400, Email: matthew.taylor@ucdenver.edu
Christina Schmitt, Phone: 303-724-2098, Email: Christina.schmitt@ucdenver.edu
Matthew Taylor, MD, PhD, Principal Investigator
Luisa Mestroni, MD, Sub-Investigator

University of Chicago, Chicago, Illinois 60637, United States; Recruiting
Amit Patel, MD, Phone: 773-702-1843, Email: amitpatel@uchicago.edu
Linda Bond, MSN NP-C, Phone: 773-702-2676, Email: lbond@medicine.bsd.uchicago.edu
Amit Patel, MD, Principal Investigator

Johns Hopkins University, Baltimore, Maryland 21287, United States; Recruiting
Anne Murphy, MD, Phone: 410-955-5987, Email: murphy@jhmi.edu
Anne Murphy, MD, Principal Investigator
Ted Abraham, MD, Sub-Investigator

Brigham & Women's Hospital, Boston, Massachusetts 02115, United States; Recruiting
Carolyn Ho, MD, Phone: 617-732-5685, Email: cho@partners.org
Allison Cirino, MS, Phone: 617-732-7921, Email: acirino@partners.org
Carolyn Ho, MD, Principal Investigator
Mark A. Fifer, MD, Sub-Investigator

Children's Hospital Boston, Boston, Massachusetts 02115, United States; Recruiting
Steven Colan, MD, Phone: 617-355-7893, Email: colan@alum.mit.edu
Jane Messere, RN, Phone: 857-218-3628, Email: Jane.Messere@cardio.chboston.org
Steven Colan, MD, Principal Investigator
Renee Margossian, MD, Sub-Investigator

University of Michigan, Ann Arbor, Michigan 48109, United States; Recruiting
Sharlene Day, MD, Phone: 734-615-7917, Email: sday@umich.edu
Linda Baty, RN, BSN, Phone: 734-232-4215, Email: lcbaty@med.umich.edu
Sharlene Day, MD, Principal Investigator
Mark Russell, MD, Sub-Investigator

Washington University School Medicine, St. Louis, Missouri 63110, United States; Recruiting
Charles Canter, MD, Phone: 314-454-6095, Email: canter@kids.wustl.edu
Teresa Roberson, Phone: 314-286-2404, Email: Roberson_T@kids.wustl.edu
Charles Canter, MD, Principal Investigator
Keith Mankovitz, MD, Sub-Investigator
Richard Bach, MD, Sub-Investigator

Cinncinnati Children's Hospital Medical Center, Cinncinati, Ohio 45229, United States; Recruiting
John Lynn Jefferies, MD, Phone: 513-636-3049, Email: John.Jefferies@cchmc.org
Paula Casson, Phone: 513-803-9003, Email: Paula.Casson@cchmc.org
John Lynn Jeffries, MD, Principal Investigator

Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States; Recruiting
Harry Lever, MD, Phone: 216-444-6970, Email: leverh@ccf.org
Rita Brienza, Phone: 216-444-0122, Email: BRIENZR@ccf.org
Harry Lever, MD, Principal Investigator
Kenneth Zahka, MD, Sub-Investigator

Toronto General Hospital, Toronto, Ontario M4W3S5, Canada; Not yet recruiting
Harry Rakowski, MD, Phone: 416-340-4062, Email: harry.rakowski@uhn.ca
Amanda Garrioch, Email: amanda.garrioch@uhn.ca
Harry Rakowski, MD, Principal Investigator

Toronto Sick Kids, Toronto, Ontario M5G1X8, Canada; Recruiting
Lee Benson, MD, Phone: 416-813-6141, Email: lee.benson@sickkids.ca
Sonila Mustafa, RN, Phone: 416-813-7654, Ext: 228418, Email: sonila.mustafa@sickkids.ca
Lee Benson, MD, Principal Investigator

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting
Joseph W Rossano, MD, Phone: 267-425-6116, Email: RossanoJ@email.chop.edu
Katherine M Lupton, MPH, Phone: 267-426-9813, Email: LuptonK@email.chop.edu
Kimberly Lin, MD, Sub-Investigator

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting
Anjali T. Owens, MD, Phone: 215-615-0812, Email: anjali.owens@uphs.upenn.edu
Marisa Konig, Phone: 215-615-3236, Email: Marisa.Konig@uphs.upenn.edu

Vanderbilt University, Nashville, Tennessee 37232, United States; Recruiting
Jason Becker, MD, Phone: 615-936-8297, Email: jason.becker@Vanderbilt.Edu
Cheryl Stewart, RN, Phone: 615-322-1880, Email: cheri.stewart@Vanderbilt.Edu
Thomas DiSalvo, MD, Sub-Investigator
Larry Markham, MD, Sub-Investigator
Jason Becker, MD, Principal Investigator

Starting date: April 2014
Last updated: June 4, 2015