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: 16 November 2020
• Main ID: EUCTR2017-002530-23-IT
• Date of registration: 10/11/2020
• Prospective Registration: No
• 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: 11/09/2018
• 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, Czechia, 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 New York Heart Association (NYHA) funtional 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)
111.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 or sustained VT with exercise within 6 months prior to Screening
7.History of resuscitated sudden CA (at any time) or history of appropriate ICD discharge for life-threatening VA within 6 months prior to Screening
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.Has LVOT gradient with Valsalva maneuver <30 mmHg at Screening
TTE
14.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
15.ICD placement within 6 months prior to Screening or planned ICD
placement during study
16.Has QT interval with Fridericia correction (QTcF) >480 ms or other ECG abnormality considered by investigator to pose risk to participant safety (eg, second-degree atrioventricular block type II)
17.Documented OCAD (>70% stenosis in one or more epicardial coronary arteries) or history of MI
18.Moderate or severe (as per investigator's judgment) AVS at
Screening
19.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
20.Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation
21.History of clinically significant malignant disease within 10 years of
Screening:
•Who have been successfully treated for nonmetastatic cutaneous squamous cell or basal cell carcinoma or been adequately treated for cervical carcinoma in situ can be included in the study
•With other malignancies who are cancer free for more than 10 years before Screening can be included in the study
22.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

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

Health Condition(s) or Problem(s) studied

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

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

Intervention(s)

Product Name: Mavacamten
Product Code: MYK-461
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Mavacamten
Current Sponsor code: MYK-461
Other descriptive name: Mavacamten
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Mavacamten
Product Code: MYK-461
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Mavacamten
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, hard
Route of administration of the placebo: Oral use

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

Product Name: Mavacamten
Product Code: MYK-461
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Mavacamten
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, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): •Clinical response defined as achieving (1) an improvement of 1.5 mL/kg/min or more in peak oxygen consumption (pVO2) as determined by CPET, & (2) a reduction of one or more class in NYHA Functional Classification, at the end of Week 30 dosing period

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

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

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)

Secondary Outcome(s)

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 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 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

Secondary ID(s)

2017-002530-23-DE

121904

ISRCTN00000000

MYK-461-005

NCT03470545

Source(s) of Monetary Support

MyoKardia Inc

Ethics review

Status: Approved
Approval date: 11/09/2018
Contact: