NCT03470545: EXPLORER-HCM

Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy

Completed Phase 3 Results posted Last updated 4 October 2021

What this trial tests

Phase 3 trial testing mavacamten in Obstructive Hypertrophic Cardiomyopathy in 251 participants. Completed in 6 May 2020.

Timeline

29 May 2018

Primary endpoint
14 March 2020

6 May 2020

Quick facts

Lead sponsor	MyoKardia, Inc.
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	251
Start date	29 May 2018
Primary completion	14 March 2020
Estimated completion	6 May 2020
Sites	71 locations across Denmark, France, Italy, Netherlands, Belgium, United Kingdom, Germany, Israel

Drugs / interventions tested

• mavacamten (MAVACAMTEN) — full drug profile →
• Placebo

Conditions studied

• Obstructive Hypertrophic Cardiomyopathy — all drugs for Obstructive Hypertrophic Cardiomyopathy →

Sponsor

MyoKardia, Inc. — full company profile →

Who can join

18 and older, any sex, with Obstructive Hypertrophic Cardiomyopathy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Achieving A Clinical Response Primary · 30 weeks

A positive clinical response (value="YES") is defined as having achieved either an improvement of at least 1.5 mL/kg/min in peak oxygen consumption (pVO2) as determined by cardiopulmonary exercise testing (CPET) and a reduction of one or more class in New York Heart Association (NYHA) functional classification (e.g.I, II, III, or IV) -OR- an improvement of 3.0 mL/kg/min or more in pVO2 with no worsening in NYHA Functional Class.

Group	Value	95% CI
Mavacamten (MYK-461)	45
Placebo	22

Changes From Baseline to Week 30 in Post Exercise in LVOT Peak Gradient. Secondary · 30 weeks

The post-exercise LVOT gradient was measured from echocardiograms obtained at baseline and week 30 following a study-specified exercise protocol and read by the Cardiovascular Imaging Core Laboratory (CICL, Boston MA). Change from baseline was determined as per the study statistical analysis plan and compared between treatment arms.

Group	Value	95% CI
Mavacamten (MYK-461)	-47	± 40.3
Placebo	-10	± 29.6

Change From Baseline to Week 30 in pVO2 as Assessed by CPET Secondary · 30 weeks

Cardiopulmonary exercise testing (CPET) was performed at baseline and week 30 following a study-specified protocol and peak oxygen consumption (pVO2) was determined by the Cardiovascular Metabolic Disease Research Institute (CMDRI, Palo Alto, CA). Change from baseline was determined as per the study statistical analysis plan and compared between treatment arms.

Group	Value	95% CI
Mavacamten (MYK-461)	1.4	± 3.12
Placebo	-0.05	± 3.02

Proportion of Participants With at Least 1 Class Improvement in NYHA Functional Class From Baseline to Week 30 Secondary · 30 weeks

New York Heart Association (NYHA) functional classification was determined by the principal investigator at baseline and at specified timepoints in the study. At baseline, all subjects were NYHA Class II or III. For the secondary outcome, NYHA class at Week 30 was compared to baseline and the proportion of subjects with an improvement of at least one class was determined, and the difference between treatment groups was analyzed. The proportion was also multiplied by 100 to provide the result as a percent.

Group	Value	95% CI
Mavacamten (MYK-461)	80
Placebo	40

Change From Baseline to Week 30 in Participant-reported Health-related Quality of Life as Assessed by the KCCQ Score Secondary · 30 weeks

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient reported outcome instrument with minimum score = 0 and maximum score = 100 where higher score indicates better health status. There are no units to the score. The instrument utilizes a recall period of 2 weeks over which patients describe the frequency and severity of their symptoms, their physical and social limitations, and how they perceive their heart failure symptoms to affect their quality of life. The KCCQ clinical summary (KCCQ-CS) score, a prespecified secondary outcome of EXPLORER-HCM, combines the physical limitation a

Group	Value	95% CI
Mavacamten (MYK-461)	13.6	± 14.42
Placebo	4.2	± 13.68

Change From Baseline to Week 30 in Participant-reported Severity of HCM Symptoms as Assessed by the HCMSQ Score Secondary · 30 weeks

The Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) is a patient reported outcome instrument that is a daily self-administered 11-item questionnaire. The HCMSQ assesses the core symptoms of HCM (tiredness/fatigue, heart palpitations, chest pain, dizziness, and shortness of breath). The Shortness of Breath domain score, a pre-specified secondary outcome of EXPLORER-HCM, assesses the frequency and severity of shortness of breath. The minimum score = 0 and maximum score = 18 where lower score indicates better health status. There are no units to the score.

Group	Value	95% CI
Mavacamten (MYK-461)	-2.8	± 2.68
Placebo	-0.9	± 2.41

Adverse events — posted to ClinicalTrials.gov

Time frame: Treatment-Emergent Adverse Events (TEAEs) were summarized for the on-treatment period (Day 1 to Week 30) and for the treatment-emergent period (Day 1 to Week 38).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Mavacamten (MYK-461)

Serious: 14/123 (11%)

Deaths: 0/123

Placebo

Serious: 12/128 (9%)

Deaths: 1/128

Serious adverse events (29 terms)

Reaction	System	Mavacamten (MYK-461)	Placebo
Atrial Fibrillation	Cardiac disorders	—	—
Syncope	Nervous system disorders	—	—
Stress cardiomyopathy	Cardiac disorders	—	—
Urinary Tract Infection	Infections and infestations	—	—
Atrioventricular block complete	Cardiac disorders	—	—
Cardiac Failure	Cardiac disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Cardiogenic shock	Cardiac disorders	—	—
Pericardial effusion	Cardiac disorders	—	—
Systolic dysfunction	Cardiac disorders	—	—
Ventricular tachycardia	Cardiac disorders	—	—
Atrial septal defect	Congenital, familial and genetic disorders	—	—
Abdominal Pain	Gastrointestinal disorders	—	—
Sudden Death	General disorders	—	—
Bacterial colitis	Infections and infestations	—	—
Diverticulitis	Infections and infestations	—	—
Gastroenteritis viral	Infections and infestations	—	—
Infection	Infections and infestations	—	—
Contusion	Injury, poisoning and procedural complications	—	—
Forearm Fracture	Injury, poisoning and procedural complications	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	—	—
SLE	Musculoskeletal and connective tissue disorders	—	—
Cholesteatoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—

Other adverse events (15 terms — click to expand)

Reaction	System	Mavacamten (MYK-461)	Placebo
Dizziness	Nervous system disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Headache	Nervous system disorders	—	—
Atrial Fibrillation	Cardiac disorders	—	—
Palpitations	Cardiac disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Angina pectoris	Cardiac disorders	—	—
Syncope	Nervous system disorders	—	—
Fatigue	General disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Gastroesophageal reflux disease	Gastrointestinal disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—

Most-reported serious reactions: Atrial Fibrillation, Syncope, Stress cardiomyopathy, Urinary Tract Infection, Atrioventricular block complete, Cardiac Failure, Cardiac failure congestive, Cardiogenic shock.

Data from ClinicalTrials.gov NCT03470545 adverse events section.

Sponsor's own description

This is a multicenter, international, double-blind study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM). Approximately 220 participants will be randomized to receive placebo or mavacamten.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.
   Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, et al · · 2020 · cited 832× · PMID 32871100 · DOI 10.1016/s0140-6736(20)31792-x
2. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
   Spertus JA, Fine JT, Elliott P, Ho CY, et al · · 2021 · cited 166× · PMID 34004177 · DOI 10.1016/s0140-6736(21)00763-7
3. Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy.
   Hegde SM, Lester SJ, Solomon SD, Michels M, et al · · 2021 · cited 141× · PMID 34915982 · DOI 10.1016/j.jacc.2021.09.1381
4. Effect of Mavacamten on Chinese Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy: The EXPLORER-CN Randomized Clinical Trial.
   Tian Z, Li L, Li X, Wang J, et al · · 2023 · cited 83× · PMID 37639259 · DOI 10.1001/jamacardio.2023.3030
5. Update on heart failure management and future directions.
   Choi HM, Park MS, Youn JC. · · 2019 · cited 76× · PMID 30612416 · DOI 10.3904/kjim.2018.428
6. Study Design and Rationale of EXPLORER-HCM: Evaluation of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy.
   Ho CY, Olivotto I, Jacoby D, Lester SJ, et al · · 2020 · cited 74× · PMID 32498620 · DOI 10.1161/circheartfailure.120.006853
7. Mavacamten: First Approval.
   Keam SJ. · · 2022 · cited 69× · PMID 35802255 · DOI 10.1007/s40265-022-01739-7
8. Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort.
   Rader F, Oręziak A, Choudhury L, Saberi S, et al · · 2024 · cited 67× · PMID 38176782 · DOI 10.1016/j.jchf.2023.09.028