A Long-term Safety Extension Study of Mavacamten (MYK-461) in Adults with Hypertrophic Cardiomyopathy Who Have Completed the MAVERICKHCM (MYK-461-006) or EXPLORER-HCM (MYK-461-005) Trials (MAVA-LTE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Myokardia Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

5 Sep 2019 → 17 Jan 2026

Decision date (initial)

2023-10-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Myokardia, Inc, A Wholly Owned Susidiary of Bristol Myers Squibb Company

External identifiers

EU CT number

2022-502858-14-00

EudraCT number

2018-004039-64

ClinicalTrials.gov

NCT03723655

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Dose response, Pharmacokinetic, Efficacy

To assess the long-term safety and tolerability of mavacamten in participants with hypertrophic cardiomyopathy (HCM) previously enrolled in 1 of 2 placebo-controlled trials: MAVERICK-HCM (MYK-461-006) for non-obstructive HCM (nHCM) and EXPLORER-HCM (MYK-461-005) for obstructive HCM (oHCM)
Sub-Study Main Objective: To assess the long-term effects of mavacamten on cardiac mass and structure as evaluated by cardiac magnetic resonance imaging (CMR)

Secondary objectives 2

1. To assess the long-term effects of mavacamten on symptoms and ECHO measures of cardiac function
2. To assess left ventricular outflow tract (LVOT) obstruction, as determined by Doppler echocardiography, in the EXPLORER-LTE cohort

Conditions and MedDRA coding

Hypertrophic cardiomyopathy

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

BMS will provide access to individual anonymized participant data upon request from qualified researchers, and subject to certain criteria. Additional information regarding Bristol Myer Squibb's data sharing policy and process can be found at: https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Has completed the Parent Study through to the EOS Visit within 90 days of signing consent. (Participants who are beyond the 90-day window from the EOS Visit may be included in this study pending MyoKardia Medical Monitor approval). Participants who prematurely discontinued from the Parent Study or the MAVA-LTE Study may be considered for inclusion.
2. Is able to understand and comply with the study procedures, understand the risks involved in the study, and provide informed consent according to federal, local, and institutional guidelines before the first study-specific procedure
3. Body weight is greater than 45 kg at the Screening Visit or Day 1 (Day 1 weight must be verified prior to dosing)
4. Has adequate acoustic windows to enable accurate TTEs (refer to the Echocardiography Site Instruction Manual)
5. Has documented LVEF ≥ 50% by echocardiography core laboratory read of screening TTE at rest
6. Has safety laboratory parameters within normal limits (according to the central laboratory reference range); however, a participant with safety laboratory parameters outside normal limits may be included if he or she meets all of the following criteria: • The safety laboratory parameter outside normal limits is considered by the Investigator to be clinically unimportant • If there is an alanine aminotransferase or aspartate aminotransferase result, the value must be < 3 × the upper limit of the laboratory reference range • The body size–adjusted estimated glomerular filtration rate is ≥ 30 mL/min/1.73 m2
7. 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 4 months after the last dose of investigational medicinal product (IMP) • combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation or progestogen-only 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. In addition to the above contraceptive requirements for female participants, male partners must also use a contraceptive (eg, barrier, condom, or vasectomy)
8. Sub-Study Inclusion Criteria: Each participant must meet the inclusion/exclusion criteria and be enrolled in the MYK-461-007 Study. Participants from the MAVERICK-HCM Study may participate in the CMR substudy. Participants from the EXPLORER-HCM Study must have already participated in the CMR substudy.

Exclusion criteria 16

1. Has persistent or permanent atrial fibrillation, not on anticoagulation for at least 4 weeks prior, and/or is not adequately rate-controlled (Note: participants with persistent or permanent atrial fibrillation who are anticoagulated and adequately rate-controlled are allowed)
2. Has any ECG abnormality considered by the Investigator to pose a risk to participant safety (eg, second-degree atrioventricular block type II)
3. Has documented obstructive coronary artery disease (> 70% stenosis in one or more epicardial coronary arteries) or history of myocardial infarction
4. Has known moderate or severe (as per Investigator’s judgment) aortic valve stenosis at Screening Visit
5. Has hypersensitivity to any of the components of the mavacamten formulation
6. Has participated in a clinical trial in which the participant received any investigational drug (or is currently using an investigational device) within 30 days prior to Screening, or at least 5 times the respective elimination half-life (whichever is longer), except for participation in MAVERICK-HCM or EXPLORER-HCM. Prior participation in a non-interventional observational study is allowed.
7. Has a history of syncope or a history of sustained ventricular tachyarrhythmia with exercise between Parent Study EOS Visit and Screening Visit.
8. Has a history of resuscitated sudden cardiac arrest or known history of appropriate implantable cardioverter-defibrillator (ICD) discharge for lifethreatening ventricular arrhythmia between Parent Study EOS Visit and Screening Visit. (Note: history of anti-tachycardia pacing is allowed)
9. Sub-Study Exclusion Criteria: An ICD or pacemaker. Starting with Protocol Amendment 4, participants must not have a device that is incompatible with MRI.  Atrial fibrillation at the time of scheduled day of CMR (Note: See Appendix 5 for Germany-specific requirements, starting with Amendment 3.2 G).
10. Currently treated with disopyramide or ranolazine (within 14 days prior to Screening Visit) or treatment with disopyramide or ranolazine is planned during the study
11. Currently treated or planned treatment during the study with a combination of beta blocker and verapamil or a combination of beta blocker and diltiazem
12. Has any 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 and safety assessments in the study
13. History of clinically significant malignant disease that developed since enrollment in the Parent Study  Participants who have been successfully treated for nonmetastatic cutaneous squamous cell or basal cell carcinoma or have been adequately treated for cervical carcinoma in situ or breast ductal carcinoma in situ can be included in the study
14. Is unable to comply with the study requirements, including the number of required visits to the clinical site
15. Is employed by or is a relative of someone employed by MyoKardia, the Investigator, or his/her staff or family
16. Is currently taking, or has taken within 14 days of Screening, a prohibited medication such as a cytochrome P450 (CYP) 2C19 inhibitor (eg, omeprazole), a strong CYP 3A4 inhibitor, or St. John’s Wort (see APPENDIX 2 for more details). (Note: See Appendix 5 for Germany-specific requirements).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 9

1. Incidence of major adverse cardiac events (death, stroke, acute myocardial infarction)
2. Incidence of hospitalizations (both cardiovascular [CV] and non-CV)
3. Incidence of heart failure (HF) events (includes HF hospitalizations and urgent emergency room/outpatient visits for HF)
4. Incidence of atrial fibrillation/flutter (new from Screening Visit)
5. Incidence of ICD discharges and resuscitated cardiac arrest
6. Incidence of ventricular tachyarrhythmias (includes ventricular tachycardia or ventricular fibrillation)
7. Incidence of any AE potentially linked to QT prolongation (Torsade de pointes, CV or sudden death, sustained ventricular tachycardia, ventricular fibrillation and flutter, syncope, and seizures)
8. Frequency and severity of treatment-emergent AEs, treatment-emergent serious AEs, and laboratory abnormalities (including trends in NT-proBNP)
9. For Participants from EXPLORER-HCM Change from Week 24 in left ventricular (LV) mass index For Participants from MAVERICK-HCM Change from baseline in LV mass index

Secondary endpoints 5

1. Change from baseline in ECHO parameters of systolic function (eg, LVEF) and diastolic function (eg, peak velocity of early diastolic septal and lateral mitral annular motion [eꞌ], ratio of peak velocity of early diastolic transmitral flow [E] to eꞌ [E/eꞌ], ratio of E to peak velocity of late transmitral flow [A] [E/A], pulmonary artery systolic pressure, or left atrium size) over time.
2. Change from baseline in resting and post-Valsalva LVOT gradient (EXPLORER-HCM participants only)
3. Change from baseline in New York Heart Association functional class over time
4. Change from baseline in NT-proBNP over time
5. Frequency of cardiac transplantation

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Myokardia Inc.

Sponsor organisation

Myokardia Inc.

Address

1000 Sierra Point Parkway

City

Brisbane

Postcode

94005-1804

Country

United States

Scientific contact point

Organisation

Myokardia Inc.

Contact name

GSM-CT

Public contact point

Organisation

Myokardia Inc.

Contact name

GSM-CT

Third parties 14

Locations

10 EU/EEA countries · 30 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications