VANISH: Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
Study Details
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 |
|---|---|---|
|
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
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 Names:
Drug: Placebo
During Active Run-In, all patients take Valsartan. During maintenance, all patients are randomized to valsartan or placebo
Other Names:
|
| 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 Names:
Drug: Placebo
During Active Run-In, all patients take Valsartan. During maintenance, all patients are randomized to valsartan or placebo
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Composite z-score [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
- z-score serum NTproBNP [2 years]
Z-score for the 2 year change for serum NTproBNP
- z-score high sensitivity cardiac troponin [2 years]
Z-score for the 2 year change for high-sensitivity cardiac troponin
- z-score LV mass [2 years]
Z-score for the 2 year change in LV Mass
- z-score LA volume [2 years]
Z-score for the 2 year change in LA Volume
- z-score LV end diastolic volume [2 years]
Z-score for the 2 year change in LV end diastolic volume
- z-score LV end systolic volume [2 years]
Z-score for the 2 year change in LV end systolic volume
- z-score maximal LV wall thickness [2 years]
Z-score for the 2 year change in Maximal LV wall thickness
- z-score echo E' velocity [2 years]
Z-score for the 2 year change in echo E' velocity
- z-score echo S' velocity [2 years]
Z-score for the 2 year change in echo S' velocity
- Binary indicator of success or failure [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
- Safety of valsartan as assessed by incidence of adverse events [2 years]
Safety of valsartan as assessed by incidence of adverse events
Eligibility Criteria
Criteria
Inclusion Criteria:
- All subjects must have a Pathogenic or Likely Pathogenic HCM Sarcomere Mutation
- 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
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Age 10-25 years
-
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)
-
Able to attend follow-up appointments, complete all study assessments, and provide written informed consent
Subject Exclusion Criteria
-
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.
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Pregnant or breastfeeding females - Females of childbearing potential with no effective contraceptive method (including abstinence)
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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)]
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Obstructive physiology, defined by resting, Valsalva-provoked or exercise-induced gradient >30mmHg within the past 24 months
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Prior septal myectomy or alcohol septal ablation
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Stanford University | Stanford | California | United States | 94305 |
| 2 | University of Colorado | Aurora | Colorado | United States | 80045 |
| 3 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 4 | Johns Hopkins University | Baltimore | Maryland | United States | 21287 |
| 5 | Brigham & Women's Hospital | Boston | Massachusetts | United States | 02115 |
| 6 | Children's Hospital Boston | Boston | Massachusetts | United States | 02115 |
| 7 | University of Michigan | Ann Arbor | Michigan | United States | 48109 |
| 8 | Washington University School Medicine | Saint Louis | Missouri | United States | 63110 |
| 9 | Cinncinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
| 10 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 11 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 12 | University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19104 |
| 13 | Vanderbilt University | Nashville | Tennessee | United States | 37232 |
| 14 | Toronto General Hospital | Toronto | Ontario | Canada | M4W3S5 |
| 15 | 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VANISH
- 5P50HL112349