A study to evaluate the safety and benefit of Mavacamten (MYK 461) in adults with an inherited heart disease causing thickening of the heart muscle

• Register: EUCTR
• Last refreshed on: 20 July 2020
• Main ID: EUCTR2017-002530-23-DK
• Date of registration: 24/09/2018
• Prospective Registration: Yes
• Primary sponsor: MyoKardia, Inc.
• Public title: A study to evaluate the safety and benefit of Mavacamten (MYK 461) in adults with an inherited heart disease causing thickening of the heart muscle
• Scientific title: A Randomized, Double blind, Placebo controlled Clinical Study to Evaluate Mavacamten (MYK-461) in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy - EXPLORER-HCM
• Date of first enrolment: 19/11/2018
• Target sample size: 220
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002530-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Czech Republic, Denmark, France, Germany, Israel, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trial or Medical Inquiries
• Affiliation: MyoKardia, Inc.

• Name: Clinical Trial or Medical Inquiries
• Affiliation: MyoKardia, Inc.

Key inclusion & exclusion criteria

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 TTE at rest =30 mmHg, determined by echocardiography core laboratory
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)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 187
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 33

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 on 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 ß-blockers and verapamil or a combination of ß-blockers and diltiazem
12.Individuals on ß-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 no

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Hypertrophic Cardiomyopathy
MedDRA version: 20.0 Level: PT Classification code 10020871 Term: Hypertrophic cardiomyopathy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: Mavacamten
Product Code: MYK-461
Pharmaceutical Form: Capsule
INN or Proposed INN: NA
CAS Number: NA
Current Sponsor code: MYK-461
Other descriptive name: MAVACAMTEN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Mavacamten
Product Code: MYK-461
Pharmaceutical Form: Capsule
INN or Proposed INN: NA
CAS Number: NA
Current Sponsor code: MYK-461
Other descriptive name: MAVACAMTEN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Mavacamten
Product Code: MYK-461
Pharmaceutical Form: Capsule
INN or Proposed INN: NA
CAS Number: NA
Current Sponsor code: MYK-461
Other descriptive name: MAVACAMTEN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Mavacamten
Product Code: MYK-461
Pharmaceutical Form: Capsule
INN or Proposed INN: NA
CAS Number: NA
Current Sponsor code: MYK-461
Other descriptive name: MAVACAMTEN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: 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)

Timepoint(s) of evaluation of this end point: Week 30

Secondary Objective: 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

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.

Secondary Outcome(s)

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 (pVO2) as determined by CPET
4. Change from baseline to Week 30 in patient-reported severity of HCM symptoms as assessed by the HCM Symptom Questionnaire score
5. Change from baseline to Week 30 in participant-reported health related quality of life as assessed by the KCCQ score

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

Secondary ID(s)

121904

2017-002530-23-DE

MYK-461-005

NCT03470545

Source(s) of Monetary Support

MyoKardia, Inc.

Ethics review

Status: Approved
Approval date: 14/11/2018
Contact: