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

Obstructive Hypertrophic Cardiomyopathy Clinical Trial

— EXPLORER-HCM  

Official title:

A Randomized, Double Blind, Placebo Controlled Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03470545
• Other study ID #: MYK-461-005
• Status: Completed
• Phase: Phase 3
• Start date: May 29, 2018
• Est. completion date: May 6, 2020

Study information

• Verified date: May 2020
• Source: MyoKardia, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 251
• Est. completion date: May 6, 2020
• Est. primary completion date: March 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Age 18 and greater, body weight = 45kg
• Has adequate acoustic windows to enable accurate transthoracic echocardiograms (TTEs)
• Diagnosed with oHCM consistent with current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines

and satisfy both criteria:

• Has documented left ventricular ejection fraction (LVEF) =55%
• NYHA Class II or III
• Has documented oxygen saturation at rest =90% at Screening
• Is able to perform an upright CPET and has a respiratory exchange ratio (RER) =1.0 at Screening per central reading

Key Exclusion Criteria:

• Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy
• History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to Screening
• History of resuscitated sudden cardiac arrest (at any time) or known history of appropriate implantable cardioverter defibrillator (ICD) discharge for life-threatening ventricular arrhythmia within 6 months prior to Screening
• Paroxysmal, intermittent atrial fibrillation with atrial fibrillation present at Screening
• Persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening and/or not adequately rate controlled within 6 months prior to Screening
• Treatment (within 14 days prior to Screening) or planned treatment during the study with disopyramide or ranolazine
• Treatment (within 14 days prior to Screening) or planned treatment during the study with a combination of ß-blockers and calcium channel blockers
• LVOT gradient with Valsalva maneuver <30 mmHg at Screening
• Has been successfully treated with invasive septal reduction (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
• ICD placement within 2 months prior to Screening or planned ICD placement during the study
• Has a history or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion
• Prior treatment with cardiotoxic agents such as doxorubicin or similar

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Hypertrophic
• Hypertrophy
• Obstructive Hypertrophic Cardiomyopathy

Intervention

Drug:
• mavacamten
mavacamten capsules
• Placebo
placebo oral capsule

Locations

Country	Name	City	State
Belgium	Onze-Lieve-Vrouwziekenhuis	Aalst	Oost-Vlaanderen
Belgium	Hôpital Erasme	Brussels
Belgium	UZ Antwerpen	Edegem	Antwerpen
Czechia	Institut Klinicke a Experimentalni Mediciny	Prague
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
Denmark	Aarhus Universitetshospital	Aarhus N
Denmark	Bispebjerg Hospital	København NV
Denmark	Odense Universitetshospital	Odense
France	CHRU Nantes	Nantes	Loire-Atlantique
France	Groupe Hospitalier Pitié Salpétrière	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital de Rangueil	Toulouse
Germany	Kerckhoff-Klinik-Forschungs-GmbH	Bad Nauheim
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Charité Campus Buch - Experimental and Clinical Research Center	Berlin
Germany	Cardiologicum Dresden und Pirna	Dresden
Germany	University Medicine Göttingen	Göttingen	Neidersachsen
Germany	University Clinic Heidelberg - PPDS	Heidelberg
Germany	Universitatsklinikum Schleswig-Holstein	Kiel
Israel	Barzilai Medical Center	Ashkelon
Israel	Hadassah Medical Center PPDS -	Jerusalem
Israel	Rabin Medical Center - PPDS	Petach Tikva
Israel	The Chaim Sheba Medical Center - The Edmond and Lily Safra Children's Hospital	Ramat-Gan
Israel	Kaplan Medical Center	Re?ovot
Israel	ZIV Medical Center	Safed
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv	Tel-Aviv
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Netherlands	Maastricht University Medical Center	Maastricht	Limburg
Netherlands	Erasmus MC	Rotterdam	Zuid-Holland
Poland	Kardio Klinika Brynów	Katowice	Slaskie
Poland	Collegium Medicum Uniwersytetu Jagiellonskiego	Kraków	Malopolskie
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwesytetu Medycznego im. Karola Marcinkowskiego	Poznan
Poland	Instytut Kardiologii im Prymasa Tysiaclecia Kardynala Stefana Wyszynskiego	Warsaw
Portugal	Hospital Garcia de Orta	Almada
Portugal	Hospital da Luz	Lisboa
Spain	Hospital Universitario Virgen de La Arrixaca	El Palmar	Murcia
Spain	Hospital Universitario A Coruña	La Coruña
Spain	Hospital Universitario Puerta de Hierro - Majadahonda	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Virgen Macarena	Sevilla
United Kingdom	University Hospital of Wales	Cardiff	South Glamergon
United Kingdom	St Bartholomew's Hospital	London
United States	University of Michigan	Ann Arbor	Michigan
United States	St. Luke's Cardiology Associates	Bethlehem	Pennsylvania
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke Cardiology at Southpoint	Durham	North Carolina
United States	Spectrum Health	Grand Rapids	Michigan
United States	Houston Methodist Hospital	Houston	Texas
United States	University of Texas Houston Medical School	Houston	Texas
United States	University Of Iowa Hospitals And Clinics	Iowa City	Iowa
United States	Mayo Clinic Jacksonville - PPDS	Jacksonville	Florida
United States	Cedars-Sinai Medical Center (Smidt Heart Institute)	Los Angeles	California
United States	Methodist University Hospital	Memphis	Tennessee
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	NYU Langone Medical Center	New York	New York
United States	University of Pennsylvania (Penn Heart and Vascular Center)	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center Presbyterian	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Intermountain Medical Center	Salt Lake City	Utah
United States	University of Utah	Salt Lake City	Utah
United States	UCSF School of Medicine	San Francisco	California
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	University of Washington Medical Center	Seattle	Washington
United States	Stanford University	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
MyoKardia, Inc.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Achieving A Clinical Response	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.	30 weeks
Secondary	Changes From Baseline to Week 30 in Post Exercise in LVOT Peak Gradient.	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.	30 weeks
Secondary	Change From Baseline to Week 30 in pVO2 as Assessed by CPET	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.	30 weeks
Secondary	Proportion of Participants With at Least 1 Class Improvement in NYHA Functional Class From Baseline to Week 30	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.	30 weeks
Secondary	Change From Baseline to Week 30 in Participant-reported Health-related Quality of Life as Assessed by the KCCQ Score	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 and total symptom scores.	30 weeks
Secondary	Change From Baseline to Week 30 in Participant-reported Severity of HCM Symptoms as Assessed by the HCMSQ Score	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.	30 weeks