Clinical trial NCT03470545: Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
Official title: A Randomized, Double Blind, Placebo Controlled Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obstructive Hypertrophic Cardiomyopathy
Keywords: Symptomatic, left ventricular outflow tract gradient
Lead sponsor: MyoKardia, Inc.
Sponsor class: INDUSTRY
First posted: 2018-03-20
Enrollment: 251
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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 β-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

Primary outcomes:
measure: Percentage of Participants Achieving A Clinical Response
timeFrame: 30 weeks
Secondary outcomes:
measure: Changes From Baseline to Week 30 in Post Exercise in LVOT Peak Gradient.
timeFrame: 30 weeks
measure: Change From Baseline to Week 30 in pVO2 as Assessed by CPET
timeFrame: 30 weeks
measure: Proportion of Participants With at Least 1 Class Improvement in NYHA Functional Class From Baseline to Week 30
timeFrame: 30 weeks
measure: Change From Baseline to Week 30 in Participant-reported Health-related Quality of Life as Assessed by the KCCQ Score
timeFrame: 30 weeks
measure: Change From Baseline to Week 30 in Participant-reported Severity of HCM Symptoms as Assessed by the HCMSQ Score
timeFrame: 30 weeks
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center (Smidt Heart Institute)
state: California
city: San Francisco
country: United States
facility: UCSF School of Medicine
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville - PPDS
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University Of Iowa Hospitals And Clinics
state: Iowa
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke Cardiology at Southpoint
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Bethlehem
country: United States
facility: St. Luke's Cardiology Associates
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania (Penn Heart and Vascular Center)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center Presbyterian
state: Pennsylvania
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas Houston Medical School
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerpen
city: Aalst
country: Belgium
facility: Onze-Lieve-Vrouwziekenhuis
state: Oost-Vlaanderen
city: Brussels
country: Belgium
facility: Hôpital Erasme
city: Prague
country: Czechia
facility: Institut Klinicke a Experimentalni Mediciny
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital
city: København NV
country: Denmark
facility: Bispebjerg Hospital
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Nantes
country: France
facility: CHRU Nantes
state: Loire-Atlantique
city: Paris
country: France
facility: Groupe Hospitalier Pitié Salpétrière
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Toulouse
country: France
facility: Hôpital de Rangueil
city: Göttingen
country: Germany
facility: University Medicine Göttingen
state: Neidersachsen
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik-Forschungs-GmbH
city: Berlin
country: Germany
facility: Charité Campus Buch - Experimental and Clinical Research Center
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Dresden
country: Germany
facility: Cardiologicum Dresden und Pirna
city: Heidelberg
country: Germany
facility: University Clinic Heidelberg - PPDS
city: Kiel
country: Germany
facility: Universitatsklinikum Schleswig-Holstein
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
state: Tel-Aviv
city: Ashkelon
country: Israel
facility: Barzilai Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center PPDS -
city: Petach Tikva
country: Israel
facility: Rabin Medical Center - PPDS
city: Ramat-Gan
country: Israel
facility: The Chaim Sheba Medical Center - The Edmond and Lily Safra Children's Hospital
city: Reẖovot
country: Israel
facility: Kaplan Medical Center
city: Safed
country: Israel
facility: ZIV Medical Center
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
state: Limburg
city: Rotterdam
country: Netherlands
facility: Erasmus MC
state: Zuid-Holland
city: Kraków
country: Poland
facility: Collegium Medicum Uniwersytetu Jagiellonskiego
state: Malopolskie
city: Katowice
country: Poland
facility: Kardio Klinika Brynów
state: Slaskie
city: Poznań
country: Poland
facility: Szpital Kliniczny Przemienienia Panskiego Uniwesytetu Medycznego im. Karola Marcinkowskiego
city: Warsaw
country: Poland
facility: Instytut Kardiologii im Prymasa Tysiaclecia Kardynala Stefana Wyszynskiego
city: Almada
country: Portugal
facility: Hospital Garcia de Orta
city: Lisboa
country: Portugal
facility: Hospital da Luz
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de La Arrixaca
state: Murcia
city: La Coruña
country: Spain
facility: Hospital Universitario A Coruña
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro - Majadahonda
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: South Glamergon
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
Study officials:
affiliation: MyoKardia, Inc.
name: Medical Information Team
role: STUDY_DIRECTOR
References:
citation: Nassif M, Fine JT, Dolan C, Reaney M, Addepalli P, Allen VD, Sehnert AJ, Gosch K, Spertus JA. Validation of the Kansas City Cardiomyopathy Questionnaire in Symptomatic Obstructive Hypertrophic Cardiomyopathy. JACC Heart Fail. 2022 Aug;10(8):531-539. doi: 10.1016/j.jchf.2022.03.002. Epub 2022 May 4.
citation: Reaney M, Addepalli P, Allen V, Spertus JA, Dolan C, Sehnert AJ, Fine JT. Longitudinal Psychometric Analysis of the Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) Using Outcomes from the Phase III EXPLORER-HCM Trial. Pharmacoecon Open. 2022 Jul;6(4):575-586. doi: 10.1007/s41669-022-00340-8. Epub 2022 Jun 20.
citation: Hegde SM, Lester SJ, Solomon SD, Michels M, Elliott PM, Nagueh SF, Choudhury L, Zemanek D, Zwas DR, Jacoby D, Wang A, Ho CY, Li W, Sehnert AJ, Olivotto I, Abraham TP. Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2021 Dec 21;78(25):2518-2532. doi: 10.1016/j.jacc.2021.09.1381.
citation: Xie J, Wang Y, Xu Y, Fine JT, Lam J, Garrison LP. Assessing health-related quality-of-life in patients with symptomatic obstructive hypertrophic cardiomyopathy: EQ-5D-based utilities in the EXPLORER-HCM trial. J Med Econ. 2022 Jan-Dec;25(1):51-58. doi: 10.1080/13696998.2021.2011301.
citation: Burstein Waldman C, Owens A. A plain language summary of the EXPLORER-HCM study: mavacamten for obstructive hypertrophic cardiomyopathy. Future Cardiol. 2021 Oct;17(7):1269-1275. doi: 10.2217/fca-2021-0044. Epub 2021 May 21.
citation: Spertus JA, Fine JT, Elliott P, Ho CY, Olivotto I, Saberi S, Li W, Dolan C, Reaney M, Sehnert AJ, Jacoby D. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021 Jun 26;397(10293):2467-2475. doi: 10.1016/S0140-6736(21)00763-7. Epub 2021 May 15.
citation: Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, Kubanek M, Wojakowski W, Jensen MK, Gimeno-Blanes J, Afshar K, Myers J, Hegde SM, Solomon SD, Sehnert AJ, Zhang D, Li W, Bhattacharya M, Edelberg JM, Waldman CB, Lester SJ, Wang A, Ho CY, Jacoby D; EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Sep 12;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X. Epub 2020 Aug 29.
citation: Ho CY, Olivotto I, Jacoby D, Lester SJ, Roe M, Wang A, Waldman CB, Zhang D, Sehnert AJ, Heitner SB. Study Design and Rationale of EXPLORER-HCM: Evaluation of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy. Circ Heart Fail. 2020 Jun;13(6):e006853. doi: 10.1161/CIRCHEARTFAILURE.120.006853. Epub 2020 Jun 5.