Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 211
- 试验地点
- 15
- 主要终点
- Composite z-score
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 8 Years 至 45 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
- •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
- •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.
- •Pregnant or breastfeeding females - Females of childbearing potential with no effective contraceptive method (including abstinence)
- •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)]
- •Obstructive physiology, defined by resting, Valsalva-provoked or exercise-induced gradient >30mmHg within the past 24 months
- •Prior septal myectomy or alcohol septal ablation
- •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.
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Placebo (Drug)
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.
干预措施: Valsartan (Drug)
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.
干预措施: Valsartan (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Composite z-score
时间窗: 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
次要结局
- z-score LV mass(2 years)
- z-score LA volume(2 years)
- z-score LV end diastolic volume(2 years)
- z-score serum NTproBNP(2 years)
- z-score high sensitivity cardiac troponin(2 years)
- z-score LV end systolic volume(2 years)
- z-score maximal LV wall thickness(2 years)
- z-score echo E' velocity(2 years)
- z-score echo S' velocity(2 years)
- Binary indicator of success or failure(2 years)