Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (SEQUOIA-HCM)
- Conditions
- Obstructive Hypertrophic Cardiomyopathy (oHCM)
- Interventions
- Drug: Aficamten (5 mg, 10 mg, 15 mg, and 20 mg)Drug: Placebo to match aficamten
- Registration Number
- NCT05186818
- Lead Sponsor
- Cytokinetics
- Brief Summary
The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction.
- Detailed Description
CY 6031 was a Phase 3, randomized, placebo-controlled, double-blind, multi-center trial in participants with symptomatic oHCM. Eligible participants were randomized in a 1:1 ratio to receive aficamten or placebo. Randomization was stratified by use of beta-blockers (yes or no) and cardiopulmonary exercise testing (CPET) exercise modality (treadmill or bicycle). Enrollment limits were applied as follows: participants taking beta-blockers were capped at approximately 70% of total enrollment; participants taking disopyramide were capped at approximately 10% of total enrollment; participants with persistent atrial fibrillation (AF) at screening were capped at approximately 15% of total enrollment; and participants using the bicycle CPET exercise modality were capped at approximately 50% of total enrollment.
Investigational product (IP) was administered orally once daily (QD) with or without food for 24 weeks. During the initial 6 weeks of the treatment period, IP doses were individually titrated at Weeks 2, 4, and 6 based on echocardiography-guided criteria. Dose escalation at Weeks 2, 4, and 6 occurred only if a participant had a Valsalva LVOT-G ≥ 30 mmHg and a biplane left ventricular ejection fraction (LVEF) ≥ 55%. Echocardiograms were performed at each subsequent visit during the trial, and the IP dose was down-titrated if the LVEF was \< 50%. The primary endpoint of peak oxygen uptake (pVO2) was measured by CPET at screening and at the end of treatment (Week 24). A participant's background HCM therapy was individually optimized according to local practice prior to enrollment in the study.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 282
-
Males and females between 18 and 85 years of age, inclusive, at screening.
-
Body mass index <35 kg/m2.
-
Diagnosed with HCM per the following criteria:
-
Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and
-
Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of:
- ≥15 mm in one or more myocardial segments OR
- ≥13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM
-
-
Has resting LVOT-G ≥30 mmHg and post-Valsalva LVOT G ≥50 mmHg during screening as determined by the echocardiography core laboratory.
-
LVEF ≥60% at screening as determined by the echocardiography core laboratory.
-
NYHA Functional Class II or III at screening.
-
Hemoglobin ≥10g/dL at screening.
-
Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening CPET per the core laboratory.
-
Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker.
Key
-
Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
-
Significant valvular heart disease (per investigator judgment).
- Moderate-severe valvular aortic stenosis.
- Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve.
-
History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during their clinical course.
-
Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations).
-
Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.
-
Documented paroxysmal atrial fibrillation during the screening period.
-
Paroxysmal or permanent atrial fibrillation is only excluded IF:
- rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) has been required ≤6 months prior to screening.
- rate control and anticoagulation have not been achieved for at least 6 months prior to screening.
-
History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
-
Has received prior treatment with CK-3773274 or mavacamten.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Aficamten up to 20 mg Aficamten (5 mg, 10 mg, 15 mg, and 20 mg) Participants received 5 mg, 10 mg, 15 mg, or 20 mg of aficamten; dose levels were guided by echocardiography assessments. Treatment was administered for up to 24 weeks. Placebo to match aficamten Placebo to match aficamten Participants received placebo for up to 24 weeks.
- Primary Outcome Measures
Name Time Method Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET) Baseline to Week 24 Effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM
- Secondary Outcome Measures
Name Time Method Proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) Functional Class Baseline to Week 12 and Week 24 Effect of CK-3773274 on NYHA Functional Classification
Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) Baseline to Week 12 and Week 24 Effect of CK-3773274 on patient health status
Change in post-Valsalva left ventricular outflow tract gradients (LVOT-G) Baseline to Week 12 and Week 24 Effect of CK-3773274 on post-Valsalva LVOT-G
Proportion of patients with post-Valsalva LVOT G <30 mmHg Baseline to Week 12 and Week 24 Effect of CK-3773274 on post-Valsalva LVOT-G
Change in total workload during CPET Baseline to Week 24 Effect of CK-3773274 on exercise capacity
Duration of eligibility for septal reduction therapy (SRT) Baseline to Week 24 Effect of CK-3773274 on duration of eligibility for septal reduction therapy
Trial Locations
- Locations (113)
Cedars-Sinai Medical Center - Smidt Heart Institute Clinic
🇺🇸Los Angeles, California, United States
MedStar Medical Group Cardiology at Union Memorial
🇺🇸Baltimore, Maryland, United States
Medstar Franklin Square Medical Center
🇺🇸Baltimore, Maryland, United States
The University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Amsterdam UMC, location AMC
🇳🇱Amsterdam, Netherlands
Mayo Clinic Florida
🇺🇸Jacksonville, Florida, United States
Alaska Heart and Vascular Institute
🇺🇸Anchorage, Alaska, United States
Piedmont Fayette Hospital
🇺🇸Fayetteville, Georgia, United States
Emory Clinic
🇺🇸Atlanta, Georgia, United States
Holy Cross Hospital / Cardiology Associates
🇺🇸Fort Lauderdale, Florida, United States
Sanger Heart and Vascular Institute - HCM Clinic
🇺🇸Charlotte, North Carolina, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Spectrum Health Medical Group Cardiovascular Medicine
🇺🇸Grand Rapids, Michigan, United States
NYU Langone Health
🇺🇸New York, New York, United States
Duke Health Center Arringdon
🇺🇸Morrisville, North Carolina, United States
The Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Interni klinika kardiologie a angiologie
🇨🇿Praha, Czechia
UPMC Presbyterian
🇺🇸Pittsburgh, Pennsylvania, United States
University of Washington Medical
🇺🇸Seattle, Washington, United States
Hospital da Luz
🇵🇹Lisboa, Portugal
CHU du Haut Lveque Cardiologie
🇫🇷Pessac, France
Ascension St. John Clinical Research Institute
🇺🇸Tulsa, Oklahoma, United States
Stern Cardiovascular Foundation, Inc
🇺🇸Germantown, Tennessee, United States
Charite-Universitaetsmedizin Berlin Campus Virchow-Klinikum (CVK) Medizinische Klinik mit Schwerpunkt Kardiologie
🇩🇪Berlin, Germany
University of Virginia Health System University Hospital
🇺🇸Charlottesville, Virginia, United States
CHU de Nantes
🇫🇷Nantes, France
CHU de Bordeaux Hopital Cardiologique Haut-Leveque
🇫🇷Pessac, France
Hopital Lariboisiere, Service de Cardiologie
🇫🇷Paris, France
Universitaetsklinikum Heidelberg
🇩🇪Heidelberg, Germany
M Health Fairview University of Minnesota Medical Center - East Bank
🇺🇸Minneapolis, Minnesota, United States
Houston Methodist Hospital
🇺🇸Houston, Texas, United States
Aalborg University Hospital, Department of Cardiology
🇩🇰Aalborg, Denmark
Department of Cardiology Aarhus University Hospital
🇩🇰Aarhus, Denmark
Copenhagen University Hospital
🇩🇰Copenhagen, Denmark
Queen Elizabeth Hospital Birmingham University Hospitals Birmingham NHS Foundation Trust
🇬🇧Edgbaston, Birmingham, United Kingdom
Beijing Chao-Yang Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Nanfang Hospital Southern Medical University
🇨🇳Guanzhou, Guangdong, China
Peking University Third Hospital
🇨🇳Beijing, Beijing, China
Xiangya Hospital of the Central South University
🇨🇳Changsha, Hunan, China
The First Affiliated Hospital of Xi'an Jiaotong University
🇨🇳Xi'an, Shanxi, China
Fondazione toscana Gabriele Monesterio per la ricarca medica Dipartimento Cardiotoracico UOC Cardiologia e Medicina Cardiovasculare Ospedale San Cataldo
🇮🇹Pisa, Italy
Universitaetsklinikum Jena Klinik fuer Innere Medizin 1
🇩🇪Jena, Germany
Hjertecentret (The Heart Center)
🇩🇰Copenhagen, Denmark
UC San Diego Health - Sulpizio Cardiovascular Center
🇺🇸La Jolla, California, United States
Stanford University Hospital
🇺🇸Stanford, California, United States
MedStar Washington Hospital Center
🇺🇸Washington, District of Columbia, United States
Lahey Hospital & Medical Center
🇺🇸Burlington, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
Mount Sinai Hospital
🇺🇸New York, New York, United States
Columbia University Medical Center/NY Presbyterian Hospital
🇺🇸New York, New York, United States
Hospital of the University of Pennsylvania (University of Pennsylvania School of Medicine)
🇺🇸Philadelphia, Pennsylvania, United States
Beijing Anzhen Hospital
🇨🇳Beijing, Beijing, China
The First Affiliated Hospital of Zhengzhou University
🇨🇳Zhengzhou, Henan, China
Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology
🇨🇳Wuhan, Hubei, China
Charles University
🇨🇿Praha, Czechia
The First Hospital of Jinlin University
🇨🇳Changchun, Jinlin, China
Hopital Universitaire de Rangueil (CHU de Toulouse) Service de Cardiologie
🇫🇷Toulouse, Cedex, France
CHU de Marseille - Hopital de la Timone Service de cardiologie
🇫🇷Marseille, France
CHU Pitie-Salpetriere, Centre de reference maladies cardiaques hereditaires ou rares
🇫🇷Paris, France
Universitaetsmedizin Goettingen
🇩🇪Gottingen, Germany
Hôpital Européen Georges Pompidou
🇫🇷Paris, France
Universitaetsklinikum Essen Westdeutsches Herz-Gefaesszentrum
🇩🇪Essen, Germany
Kerckhoff-Klinik GmbH Abteilung Administration Forschung und Lehre
🇩🇪Bad Nauheim, Germany
Universitätsklinikum Würzburg
🇩🇪Würzburg, Germany
Unniversitaetsklinikum Magdeburg Klinik fur Kardiologie und Anglologie
🇩🇪Magdeburg, Germany
Klinikumder Georg-August-Universitaet
🇩🇪Göttingen, Germany
The Barzilai University Medical Center
🇮🇱Ashkelon, Israel
The Olga & Lev Leviev Heart Center The Chaim Sheba Medical Center
🇮🇱Ramat Gan, Tel Hasomer, Israel
Semmelweis Egyetem Varosmajori Sziv es Ergyogyasazati Klinika
🇭🇺Budapest, Hungary
Hadassah Medical Center- Ein Kerem
🇮🇱Jerusalem, Israel
Ziv Medical Center
🇮🇱Zefat, Israel
Kaplan Medical Center
🇮🇱Reẖovot, Israel
UOC Cardiologica Azienda Ospedaliera Spedali Civili di Brescia
🇮🇹Brescia, Italy
Azienda Ospedaliero Universitaria Careggi Dipartimento Cardiotoracovascolare - Cardiomiopatie Unit
🇮🇹Florence, Italy
Dipartimento di Medicina Clinica e Molecolare Universita Sapienza di Roma Unita di Terapia Intensiva Cardiologica Azienda Ospedaliero Universitaria Sant'Andrea
🇮🇹Roma, Italy
Erasmus Medical Center
🇳🇱Rotterdam, Netherlands
Centro Hospitalar Do Baixo Vouga, EPE AV ARTUR RAVARA
🇵🇹Aveiro, Portugal
Narodowy Instytut Kardiologii Stefana Kardynała Wyszynskiego- Panstwowy Instytut Badawczy
🇵🇱Warsaw, Mazowieckie, Poland
University Hospital Maastricht
🇳🇱Maastricht, Netherlands
Complejo Hospitalario Universitario
🇪🇸A Coruña, La Coruna, Spain
Hospital Universitario Puerta de Hierro
🇪🇸Madrid, Majadahonda, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Clinico Universitario Virgen de la Arrixaca
🇪🇸Murcia, Spain
Hospital Universitario Son Llatzer Secretaria de Cardiologia
🇪🇸Palma, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Queen Elizabeth University Hospital - HWS Greater Glasgow and Clyde
🇬🇧Glasgow, United Kingdom
Liverpool Heart and Chest Hospital - Liverpool Heart and Chest Hospital NHS Foundation Trust- HWS Greater Glasgow and Clyde
🇬🇧Liverpool, United Kingdom
Radcliffe Department of Medicine
🇬🇧Oxford, United Kingdom
Westchester Medical Center
🇺🇸Valhalla, New York, United States
Oxford Centre for Clinical Magnetic Resonance Research
🇬🇧Oxford, United Kingdom
University of Iowa
🇺🇸Iowa City, Iowa, United States
Sanger Heart and Vascular Institute
🇺🇸Charlotte, North Carolina, United States
Hospital Universitario Virgen Macarena-merge
🇪🇸Sevilla, Spain
St George's University Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Barts Health NS Trust
🇬🇧London, United Kingdom
Michigan Medicine
🇺🇸Ann Arbor, Michigan, United States
Henry Ford Medical Center
🇺🇸Detroit, Michigan, United States
Kardio Brynow S.C
🇵🇱Katowice, Poland
Krakowskie Centrum
🇵🇱Kraków, Poland
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
Yale School of Medicine
🇺🇸New Haven, Connecticut, United States
Saint Luke's Hospital of Kansas City
🇺🇸Kansas City, Missouri, United States
Yale University School of Medicine
🇺🇸New Haven, Connecticut, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
University of Utah Hospital
🇺🇸Salt Lake City, Utah, United States
Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
Royal Brompton Hospital
🇬🇧London, United Kingdom