Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

Hypertrophic Cardiomyopathy Clinical Trial

— VANISH  

Official title:

Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01912534
• Other study ID #: VANISH
• Secondary ID: 5P50HL112349
• Status: Completed
• Phase: Phase 2
• Start date: March 2014
• Est. completion date: July 2019

Study information

• Verified date: April 2020
• Source: HealthCore-NERI
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 211
• Est. completion date: July 2019
• Est. primary completion date: July 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Hypertrophic
• Hypertrophic Cardiomyopathy

Intervention

Drug:
• Valsartan
40, 80 and 160 mg tablets of Valsartan
• Placebo
During Active Run-In, all patients take Valsartan. During maintenance, all patients are randomized to valsartan or placebo

Locations

Country	Name	City	State
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Toronto Sick Kids	Toronto	Ontario
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Children's Hospital Boston	Boston	Massachusetts
United States	University of Chicago	Chicago	Illinois
United States	Cinncinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Vanderbilt University	Nashville	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Washington University School Medicine	Saint Louis	Missouri
United States	Stanford University	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
HealthCore-NERI	National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety of valsartan as assessed by incidence of adverse events	Safety of valsartan as assessed by incidence of adverse events	2 years
Primary	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	z-score serum NTproBNP	Z-score for the 2 year change for serum NTproBNP	2 years
Secondary	z-score high sensitivity cardiac troponin	Z-score for the 2 year change for high-sensitivity cardiac troponin	2 years
Secondary	z-score LV mass	Z-score for the 2 year change in LV Mass	2 years
Secondary	z-score LA volume	Z-score for the 2 year change in LA Volume	2 years
Secondary	z-score LV end diastolic volume	Z-score for the 2 year change in LV end diastolic volume	2 years
Secondary	z-score LV end systolic volume	Z-score for the 2 year change in LV end systolic volume	2 years
Secondary	z-score maximal LV wall thickness	Z-score for the 2 year change in Maximal LV wall thickness	2 years
Secondary	z-score echo E' velocity	Z-score for the 2 year change in echo E' velocity	2 years
Secondary	z-score echo S' velocity	Z-score for the 2 year change in echo S' velocity	2 years
Secondary	Binary indicator of success or failure	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	2 years