| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypertrophic cardiomyopathy |
| Hypertrofisk kardiomyopati |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hypertrophic cardiomyopathy |
| Hypertrofisk kardiomyopati |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020204 |
| E.1.2 | Term | HOCM Hypertrophic obstructive cardiomyopathy |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effect of Valsartan in young patients in an early stage of hypertrophic cardiomyopathy. |
| At undersøge effekten af Valsartan hos unge patienter i et tidlig stadium af hypertrofisk kardiomyopati. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the safety of Valsartan in young patients in an early stage of hypertrophic cardiomyopathy. |
| At undersøge om Valsartan er sikkert hos unge patienter i et tidlig stadium af hypertrofisk kardiomyopati. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
5.2 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 or testing was performed at a lab other than those listed below, they will be reviewed by the Clinical Coordinating Center to determine eligibility.
i. Laboratory for Molecular Medicine
1. Pathogenic
2. Likely Pathogenic
ii. Transgenomics/ PGXHealth
1. Class I
iii. GeneDx
1. Disease causing
2. Variant, likely disease-causing
3. Published, disease-causing mutation
4. Novel, likely disease-causing, mutation
iv. Correlagen
1. Associated
2. Probably Associated
2. Group 1 Cohort
a. LV wall thickness ≥12 mm and ≤25 mm or z score ≥3 and ≤18 as determined by rapid assessment by the echocardiographic core laboratory
b. NYHA functional class I or II; no perceived or only slight limitations in physical activities
c. No resting or provokable LV obstruction (peak gradient ≤ 30 mmHg) on clinically-obtained ETT-echo within the past 24 months or transthoracic echo with Valsalva maneuver within the past 12 months
d. Age 8-45 years
3. Group 2 Cohort (G+/LVH-)
a. LV Wall Thickness <12 mm and z score <3, as determined by rapid assessment by the echocardiographic core laboratory
b. Age 10-25 years
c. 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
|
Inklusionskriterier
Alle forsøgspersoner skal have en genfejl der er blevet klassificeret som sygdomsfremkallende eller formentlig sygdomsfremkallende for HCM.
1) Gruppe 1
a) Maksimal tykkelse af hjertets væg ≥12 mm og ≤25 mm eller z score ≥3 og ≤18 bedømt af Core lab ud fra ekkokardiografi.
b) NYHA klasse I eller II; ingen eller kun få begrænsninger ved fysisk aktivitet.
c) Ingen udløbsgradient (modstand mod at blodet løber forbi hjertemuskelfortykkelsen og ud i hovedpulsåren). Ekkokardiografisk målt gradient skal foreligge og have været ≤ 30 mmHg under stress (indenfor sidste 24 måneder) eller under Valsalva manøvre (indenfor 12 måneder).
d) Alder 8-45 år.
2) Gruppe 2
a) Maksimal tykkelse af hjertets væg <12 mm og z score <3 bedømt af Core lab ud fra ekkokardiografi.
b) Alder 10-25 år.
c) E’ z score ≤ -1.5 eller abnormt EKG (andet end non-specifikke ST-ændringer; f.eks. Q-takker, T-taks inversion eller repolariserings abnormaliteter).
3) Kunne medvirke til opfølgende besøg, alle undersøgelser samt give samtykke.
|
|
| E.4 | Principal exclusion criteria |
5.3 Subject Exclusion Criteria
1. Contraindication to 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, Aliskren, 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
5. Females of childbearing potential with no effective contraceptive method (including abstinence)
6. 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)
7. Obstructive physiology, defined by resting, Valsalva-provoked or exercise-induced gradient >30mmHg within the past 24 months
8. Prior septal myectomy or alcohol septal ablation
9. Known, suspected, or symptomatic coronary artery disease or evidence of prior myocardial infarction based on symptoms or cardiac imaging
10. 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.
11. LVEF <55%
12. 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)
13. Secondary prevention implantable cardioverter-defibrillator device (ICD; primary prevention ICDs without a history of appropriate therapy, including shock or ATP, are allowable).
14. Prior treatment or hospitalization for symptomatic heart failure
15. Participation in a clinical trial (except observational studies) involving investigational medications within the previous 30 days.
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Eksklusionskriterier
1) Kontraindikation til valsartan inklusive hyperkaliæmi, nedsat nyrefunktion, tidligere angioødem.
2) Sygdomme der er associeret med en øget kollagen omsætning og som kan lede til forvirring ved fortolkning af de biomarkører der er involverede i kollagen syntese (lever, lunge eller nyre fibrose, inflammatoriske sygdomme, cancer, trauma eller operation indenfor de seneste 6 måneder)
3) Behandling indenfor de seneste 2 uger med en medicin der hæmmer renin-angiotensin-systemet
4) Graviditet eller amning
5) Intet brug af sikker prævention (se neden for detalier*)
6) Systolisk blodtryk >160 eller diastolisk blodtryk> 90 hos voksne eller tilsvarende hos børn (Systolisk blodtryk >99th or diastolisk blodtryk>95th percentilen for køn, alder og højde baseret på the American Academy of Pediatrics normalværdier).
7) Udløbsgradient >30 mmHg i hvile, under Valsalva manøvre eller ved stress ekkokardiografi indenfor 24 måneder.
8) Tidligere myektomi eller alkohol ablation
9) Kendt eller mistænkt, tidligere eller nuværende sygdom i kranspulsårerne.
10) Mere end mild hjerteklapssygdom eller medfødt hjertesygdom udfra detaljerede kriterier i protokollen.
11) Nedsat pumpefunktion af hjertet (LVEF <55%)
12) Komorbiditet som kan medføre nedsat arbejdskapacitet eller som kan forstyrre fortolkningen af undersøgelserne (f.eks. nyresvigt, lungesygdom, sygdomme i bevægeapparatet, atrieflimmer).
13) Sekundær profylaktisk ICD (Primær prævention ICD uden tidligere shock eller ATP er tilladt).
14) Tidligere behandling eller indlæggelse pga. symptomgivende hjertesvigt.
15) Deltagelse indenfor de sidste 30 dage i et klinisk studie der involverer afprøvning af medicin.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| We hypothesize that administration of the ARB, valsartan, compared to placebo, will demonstrate treatment efficacy across multiple domains of cardiac structure/ function and clinical outcomes. Average z scores will be calculated for key components of the primary outcome. The primary endpoint will compare the composite total z score across all domains for sarcomere mutation carriers with at least borderline left ventricular hypertrophy (designated Group 1) treated with valsartan compared to placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| We will more broadly characterize the impact of valsartan treatment on disease pathology, and identify variables that may influence both treatment response and disease progression. We will assess the impact of valsartan therapy on the important but relatively rare cohort of preclinical HCM (designated Group 2). These analyses will provide a crucial foundation for future studies to test novel strategies of disease prevention. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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