A Randomized, Double-blind, Placebo-controlled Clinical Study to Evaluate Mavacamten in Adults with Cardiomyopathy

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

13 Apr 2023 → 21 Oct 2025

Decision date (initial)

2024-05-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

MyoKardia Inc., a wholly owned subsidiary of Bristol Myers Squibb Company

External identifiers

EU CT number

2023-506352-24-00

EudraCT number

2021-005329-26

WHO UTN

U1111-1269-8581

ClinicalTrials.gov

NCT05582395

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Pharmacodynamic, Efficacy, Safety, Dose response, Pharmacokinetic, Pharmacogenetic

1. To assess the efficacy of a 48-week course of mavacamten compared to placebo on patient reported health status (symptoms and physical limitations).
2. To assess the efficacy of a 48-week course of mavacamten compared to placebo on exercise capacity

Secondary objectives 4

1. Evaluate the effects of mavacamten on ventilatory efficiency as measured by the VE/VCO2 slope
2. Evaluate the effects of mavacamten on NYHA classification
3. Evaluate the effects of mavacamten on patient reported shortness of breath
4. Evaluate the effects of mavacamten on cardiac biomarkers of wall stress

Conditions and MedDRA coding

Non-obstructive Hypertrophic Cardiomyopathy

Regulatory references

Scientific advice from competent authorities

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 Myers 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 1

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 % on screening echocardiography measured by Central Echocardiography Laboratory 10. KCCQ-23 CSS Score ≤ 85 at screening

Exclusion criteria 1

1. Medical Conditions - Known infiltrative or storage disorder causing cardiac hypertrophy that mimics nHCM such as amyloidosis, Fabry disease, 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 halflives 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change from baseline in KCCQ CSS at Week 48
2. Change from baseline in pVO2 at Week 48

Secondary endpoints 4

1. Change from baseline in VE/VCO2 slope to Week 48
2. Proportion of participants with at least 1 class of NYHA improvement from baseline to Week 48
3. (3.-4.) 3. Change from baseline in NT-pro BNP to Week 48 4. Change from baseline in cTn-T to Week 48
4. (5.-6.) 5. Change from baseline in HCMSQ-SoB domain to Week 48 6. Time to First MACE-Plus events defined as any CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, hospitalization for arrhythmias or appropriate ICD therapy

Investigational products

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

Test 5

Placebo 1

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 15

Locations

13 EU/EEA countries · 79 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 87 files

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

Application history

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