| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Symptomatic Nonobstructive Hypertrophic Cardiomyopathy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Symptomatic hardening of the left ventricle. |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10049813 |
| E.1.2 | Term | Non-obstructive cardiomyopathy |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020871 |
| E.1.2 | Term | Hypertrophic cardiomyopathy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 efficacy of a 48-week course of
mavacamten compared to placebo on patient reported health status
To assess the efficacy of a 48-week course of
mavacamten compared to placebo on exercise
capacity |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the effects of mavacamten on exercise capacity as measured by VE/VCO2 slope
Evaluate the effects of mavacamten on NYHA classification
Evaluate the effects of mavacamten on the composite of NYHA and pVO2
Evaluate the effects of mavacamten on cardiac biomarkers
Evaluate the effects of mavacamten on patient reported shortness of breath
Evaluate the effects of mavacamten on composite of cardiovascular events
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Cardiac magnetic resonance (CMR) imaging sub-study (80 participants)
•Primary endpoint: change in measures of LV mass index
•Exploratory endpoints: changes in myocardial fibrosis
•CMR will be done at randomization and at week 48, and Week 96 or 48 weeks after the last blinded visit for participants randomized to mavacamten in Part A.
Incidence of cardiac arrhythmias sub-study
•Sub-study endpoint: Incidence of AF, ventricular tachycardia, ventricular fibrillation, and conduction abnormalities including heart block from baseline to 52 weeks
•A wearable electrocardiogram (ECG) monitor will be applied 10 times during the study as per the Schedule of Activities
•All participants are encouraged to participate where feasible and regulatory laws allow |
|
| E.3 | Principal inclusion criteria |
1. Participants must be at least 18 years old or local age of majority at the time of signing the informed consent
2. Female participants must adhere to highly effective contraceptive methods or have documented proof that they are not of childbearing potential
3. No additional contraceptive measures are required to be used for male participants
4. Diagnosis of HCM consistent with current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines.
5. Peak LVOT pressure gradient < 30 mmHg at rest and < 50 mmHg with provocation (Valsalva maneuver and stress echocardiography)
6. CPET: Documented oxygen saturation at rest >90% at Screening. Able to perform an upright cardiopulmonary stress test (CPET) and has a respiratory exchange ratio (RER) ≥ 1.0 at Screening per central reading. If the RER is between 0.91 and 1.0, the participant may be enrolled if the central CPET laboratory determines that peak exercise has been achieved. Participants with subpeak performance may not be enrolled as described in the CPET Laboratory Manual.
7. New York Heart Association (NYHA) Class II or III
8. NT-proBNP≥200 pg/mL or BNP≥70 pg/mL
9. LVEF ≥60 % as determined by the echocardiography central laboratory
10. KCCQ-23 CSS Score ≤ 85 at screening
|
|
| E.4 | Principal exclusion criteria |
Medical Conditions
- Known infiltrative or storage disorder causing cardiac hypertrophy that mimics nHCM such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy
Note: Investigators should not screen participants who have comprehensive Echo features suggestive of amyloidosis, including
abnormal global longitudinal strain in the setting of an appropriate clinical picture which could include low voltage on ECG and severely
elevated NT-proBNP or BNP
- History of unexplained syncope within 6 months prior to screening
- History of sustained ventricular tachyarrhythmia (> 30 seconds) within 6 months prior to Screening
- Paroxysmal or persistent (non-permanent) AF detected at the time of screening. Permanent AF is allowed if the participant is anticoagulated and the investigator considers the heart rate adequately controlled
- CV diseases or treatments that in the opinion of the investigator increase the unpredictability of or change the participants’ clinical course.
- Acute heart failure from 4 weeks prior to screening up to randomization
- Coronary artery disease requiring intervention, including myocardial infarction (increase in cardiac enzymes in combination with symptoms of ischemia or new ischemic ECG changes), coronary artery bypass graft surgery, or other major CV surgery, stroke, or transient ischemic attack in the past 90 days
- Women who are breastfeeding or pregnant.
Prior/Concomitant Therapy
- Any adjustments of beta-blockers, verapamil, or diltiazem within 2 weeks prior to Screening and up to the day of randomization
- Concomitant use of strong inhibitors of cytochrome P450 (CYP) 2C19
Note: Use should be discontinued for a minimum of 5 elimination half-lives prior to first dose of study intervention.
Other Exclusion Criteria
- Any other serious condition that in the opinion of the investigator could prevent participation in the study and follow-up, including active
infection with COVID-19 from 4 weeks prior to screening up to randomization
- Completed a study with an investigational device < 30 days prior to screening or an investigational drug < 5 half-lives prior to screening
- Participants who have completed a study with mavacamten or aficamten
- Enrolled in another study and receiving any investigational treatment (device or drug) other than the study intervention given in this study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change from baseline in KCCQ CSS
2. Change from baseline in pVO2
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Change from baseline in VE/VCO2 slope
2. Proportion of participants with at least 1 class of NYHA improvement from baseline
3. Change from baseline in NT-pro BNP
4. Change from baseline in cTn-T
5. Change from baseline in HCMSQ-SoB domain
6. Time to First MACE-Plus events defined as any CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, or hospitalization for arrhythmias
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 48
2. Week 48
3. Week 48
4. Week 48
5. Week 48
6. From the study drug initiation to occurrence of the first MACE-Plus or when the last subject reaches Week 48 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 89 |
| 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 |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
