Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

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.

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.