| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypertrophic Cardiomyopathy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inherited heart disease causing thickening of the muscle wall of the heart |
|
| 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 | 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 compare the effect of a 30-week course of mavacamten with placebo on clinical response comprising of exercise capacity and clinical symptoms in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) |
|
| E.2.2 | Secondary objectives of the trial |
To compare the effect of a 30-week course of mavacamten with placebo on symptoms and left ventricular outflow tract (LVOT) obstruction as determined by Doppler echocardiography
To compare the effect of a 30-week course of mavacamten with placebo on exercise capacity, clinical symptoms and Patient Reported Outcomes individually
To assess the safety and tolerability of mavacamten
To assess the pharmacokinetic (PK) characteristics of mavacamten
|
|
| 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 |
Substudy is described in main protocol (amendment 3, dated 21 March 2018).
•To assess the effect of mavacamten on cardiac mass and structure as evaluated by cardiac magnetic resonance imaging (CMR)
.At selected sites, participants will have the option to participate in the CMR substudy. Approximately 80 participants will be enrolled (~40 per treatment group). In addition to the main study schedule of procedures, participants will undergo CMR at Day 1 and Week 30. |
|
| E.3 | Principal inclusion criteria |
1.Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines before the first study specific procedure
2.Is at least 18 years old at Screening
3.Body weight is greater than 45 kg at Screening
4.Has adequate acoustic windows to enable accurate TTEs (Refer to Echocardiography Site Instruction Manual)
5.Diagnosed with oHCM consistent with current AACF/AMA and ESC guidelines, ie, satisfy both criteria below (criteria to be documented by the echocardiography core laboratory):
A.Has unexplained left ventricular (LV) hypertrophy with nondilated ventricular chambers in the absence of other cardiac (eg, hypertension, aortic stenosis) or systemic disease and with maximal LV wall thickness ≥15 mm (or ≥13 mm with positive family history of hypertrophic cardiomyopathy [HCM]), as determined by core lab interpretation and B.Has LVOT peak gradient ≥50 mmHg during Screening as assessed by echocardiography at rest, after Valsalva maneuver, or postexercise
(confirmed by echocardiography core laboratory interpretation)
6.Has documented left ventricular ejection fraction (LVEF) ≥55% by echocardiography core laboratory read of Screening TTE at rest 7. Has LVOT gradient with Valsalva maneuver at Screening TTE of ≥30
mmHg, determined by echocardiography core laboratory 8.Has (NYHA) functional Class II or III symptoms at Screening 9.Has documented oxygen saturation at rest ≥90% at Screening
10.Is able to perform an upright 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 only if it is determined by the central CPET laboratory that peak exercise has been achieved in the subject (the only permitted reasons for subpeak performance are [1] a decrease in systolic blood pressure or [2] severe angina as described in the CPET Laboratory Manual)
11.Female participants must not be pregnant or lactating and, if sexually active, must use one of the following highly effective birth control methods from the Screening visit through 3 months after the last dose of investigational medicinal product (IMP).
• combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation or progestogenonly hormonal contraception associated with inhibition of ovulation by oral, implantable, or injectable route of administration
•intrauterine device (IUD)
•intrauterine hormone-releasing system (IUS)
•bilateral tubal occlusion
•Female is surgically sterile for 6 months or postmenopausal for 1 year. Permanent
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or documented bilateral tubal occlusion at least 6 months prior to Screening. Females are considered
postmenopausal if they have had amenorrhea for at least 1 year or more following
cessation of all exogenous hormonal treatments and follicle stimulating hormone levels are in the postmenopausal range.
Male partners must also use a contraceptive (eg, barrier, condom or vasectomy) |
|
| E.4 | Principal exclusion criteria |
1.Previously participated in a clinical study with mavacamten
2.Hypersensitivity to any of the components of the mavacamten
formulation
3.Participated in a clinical trial in which the participant received any
investigational drug (or is currently using an investigational device)
within 30 days of Screening, or at least 5x the respective elimination half life (whichever is longer) 4.Infiltrative or storage disorder causing CH that mimics oHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LVH
5.Medical condition that precludes upright exercise stress testing
6.History of syncope within 6 months prior to Screening or history of
sustained ventricular tachyarrhythmia with exercise within 6 months
prior to Screening
7.History of resuscitated sudden CA (at any time) or history of
appropriate ICD discharge/shock for life-threatening VA within 6 months prior to Screening (Note: history of anti-tachycardia pacing (ATP) within 6 months or ever is allowed)
8.Has paroxysmal, intermittent AF with AF present per the investigator's evaluation of the participant's ECG at time of Screening
9.Has persistent/permanent AF not on anticoagulation for at least 4
weeks to Screening &/or not adequately rate controlled within 6 months prior to Screening
10.Current treatment (within 14 days to Screening) or planned
treatment during the study with disopyramide or ranolazine
11.Current treatment (within 14 days prior to Screening) or planned
treatment during the study with a combination of β-blockers and
verapamil or a combination of β-blockers and diltiazem
12.Individuals on β-blockers, verapamil, or diltiazem, any dose
adjustment of that medication <14 days to Screening or any anticipated change in treatment regimen using these medications during the study
13.(Note: Prev. #13 was removed entirely) Successfully treated with ISR (surgical myectomy or percutaneous alcohol septal ablation [ASA])
within 6 months prior to Screening or plans to have either of these
treatments during the study
14.ICD placement or pulse generator change within 2 months prior to
Screening or planned new ICD placement during study (pulse generator changes, if needed during the study, are allowed)
15.Has QT interval with Fridericia correction (QTcF) >500 ms at
screening or other ECG abnormality considered by investigator to pose
risk to participant safety (eg, second-degree atrioventricular block type II)
16.Documented OCAD (>70% stenosis in one or more epicardial
coronary arteries) or history of MI
17.Moderate or severe (as per investigator's judgment) AVS at
Screening
18.Acute or serious comorbid condition (eg, major infection or
hematologic, renal, metabolic, gastrointestinal, or endocrine
dysfunction) that, in the judgment of the investigator, could lead to
premature termination of study participation or interfere with the
measurement or interpretation of the efficacy & safety assessments in
the study
19.Has pulmonary disease that limits exercise capacity or systemic
arterial oxygen saturation
20.History of malignant disease within 10 years of Screening: see
details in protocol
21.Has safety laboratory parameters (chemistry, hematology,
coagulation, & urinalysis) outside normal limits (according to the central
laboratory reference range) at Screening as assessed by the central
laboratory; however, participant with safety laboratory parameters
outside normal limits may be included if he or she meets all of the
following criteria:
•Safety laboratory parameter outside normal limits is considered by the investigator to be clinically not significant
•If there is an alanine aminotransferase or aspartate aminotransferase
result, the value must be <3 × the upper limit of the laboratory
reference range
•Body size–adjusted estimated glomerular filtration rate is ≥30
mL/min/1.73 m2
22.Positive serologic test at Screening for infection with human
immunodeficiency virus, hepatitis C virus, or hepatitis B virus
23.History or evidence of any clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to
participant safety or interfere with the study evaluation, procedures, or completion
24.Currently taking, or has taken within 14 days prior to Screening, a
prohibited medication, such as a cytochrome P450 (CYP) 2C19 inhibitor (eg, omeprazole or esomeprazole), a strong CYP 3A4 inhibitor, or St. John's Wort. Alternatives, such as pantoprazole, are allowed and may be discussed with the medical monitor.
25.Prior treatment with cardiotoxic agents such as doxorubicin or
similar.
26.Unable to comply with the study requirements, including the number of required visits to the clinical site
27.First degree relative of personnel directly affiliated with the study at the clinical study site, any study vendor, or the study Sponsor |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical response defined as achieving: 1) An improvement of at least 1.5
mL/kg/min in peak oxygen consumption (pVO2) as determined by CPET
and a reduction of one or more class in NYHA Functional Classification or
2) an improvement of 3.0 mL/kg/min or more in pVO2 with no worsening in NYHA Functional Class. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Change from baseline to Week 30 in post-exercise LVOT peak gradient
2. proportion of participants with at least 1 class improvement in NYHA functional class from baseline to Week 30
3. Change from baseline to Week 30 in peak oxygen consumption (pVO2) as determined by CPET
4. Change from baseline to week 30 in participant-reported health related quality of life as assessed by the KCCQ score
5. Change from baseline to Week 30 in patient-reported severity of HCM symptoms as assessed by the HCM Symptom Questionnaire score
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 30
2. Week 30
3. Week 30
4. Week 30
5. Week 30
6. Week 30 |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Belgium |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| United Kingdom |
| United States |
|
| 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 | |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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