Clinical trial NCT05186818: Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (SEQUOIA-HCM)
Official title: A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obstructive Hypertrophic Cardiomyopathy (oHCM)
Keywords: Obstructive Hypertrophic Cardiomyopathy
oHCM
CK-3773274
CK-274
Aficamten
SEQUOIA-HCM
CY 6031
SEQUOIA
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
Collaborators: name: Corxel Pharmaceuticals
First posted: 2022-01-11
Enrollment: 282
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Key Inclusion Criteria:

* 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 Exclusion Criteria:

* 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.

Primary outcomes:
measure: Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET)
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS)
timeFrame: Baseline to Week 12 and Week 24
measure: Proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) Functional Class
timeFrame: Baseline to Week 12 and Week 24
measure: Change in post-Valsalva left ventricular outflow tract gradients (LVOT-G)
timeFrame: Baseline to Week 12 and Week 24
measure: Proportion of patients with post-Valsalva LVOT G <30 mmHg
timeFrame: Baseline to Week 12 and Week 24
measure: Change in total workload during CPET
timeFrame: Baseline to Week 24
measure: Duration of eligibility for septal reduction therapy (SRT)
timeFrame: Baseline to Week 24
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Alaska Heart and Vascular Institute
state: Alaska
city: La Jolla
country: United States
facility: UC San Diego Health - Sulpizio Cardiovascular Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center - Smidt Heart Institute Clinic
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Hospital
state: California
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital / Cardiology Associates
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Emory Clinic
state: Georgia
city: Fayetteville
country: United States
facility: Piedmont Fayette Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: MedStar Medical Group Cardiology at Union Memorial
state: Maryland
city: Baltimore
country: United States
facility: Medstar Franklin Square Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Hospital & Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: Michigan Medicine
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Medical Center
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Medical Group Cardiovascular Medicine
state: Michigan
city: Minneapolis
country: United States
facility: M Health Fairview University of Minnesota Medical Center - East Bank
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center/NY Presbyterian Hospital
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Charlotte
country: United States
facility: Sanger Heart and Vascular Institute
state: North Carolina
city: Charlotte
country: United States
facility: Sanger Heart and Vascular Institute - HCM Clinic
state: North Carolina
city: Morrisville
country: United States
facility: Duke Health Center Arringdon
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Tulsa
country: United States
facility: Ascension St. John Clinical Research Institute
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania (University of Pennsylvania School of Medicine)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian
state: Pennsylvania
city: Germantown
country: United States
facility: Stern Cardiovascular Foundation, Inc
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System University Hospital
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical
state: Washington
city: Milwaukee
country: United States
facility: Froedtert Hospital
state: Wisconsin
city: Beijing
country: China
facility: Beijing Chao-Yang Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Beijing Anzhen Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University Third Hospital
state: Beijing
city: Guanzhou
country: China
facility: Nanfang Hospital Southern Medical University
state: Guangdong
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Wuhan
country: China
facility: Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital of the Central South University
state: Hunan
city: Changchun
country: China
facility: The First Hospital of Jinlin University
state: Jinlin
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
state: Shanxi
city: Praha
country: Czechia
facility: Charles University
city: Praha
country: Czechia
facility: Interni klinika kardiologie a angiologie
city: Aalborg
country: Denmark
facility: Aalborg University Hospital, Department of Cardiology
city: Aarhus
country: Denmark
facility: Department of Cardiology Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Hjertecentret (The Heart Center)
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital
city: Toulouse
country: France
facility: Hopital Universitaire de Rangueil (CHU de Toulouse) Service de Cardiologie
state: Cedex
city: Marseille
country: France
facility: CHU de Marseille - Hopital de la Timone Service de cardiologie
city: Nantes Cedex
country: France
facility: CHU de Nantes
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hopital Lariboisiere, Service de Cardiologie
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: CHU Pitie-Salpetriere, Centre de reference maladies cardiaques hereditaires ou rares
city: Pessac
country: France
facility: CHU de Bordeaux Hopital Cardiologique Haut-Leveque
city: Pessac
country: France
facility: CHU du Haut Lveque Cardiologie
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik GmbH Abteilung Administration Forschung und Lehre
city: Berlin
country: Germany
facility: Charite-Universitaetsmedizin Berlin Campus Virchow-Klinikum (CVK) Medizinische Klinik mit Schwerpunkt Kardiologie
city: Essen
country: Germany
facility: Universitaetsklinikum Essen Westdeutsches Herz-Gefaesszentrum
city: Gottingen
country: Germany
facility: Universitaetsmedizin Goettingen
city: Göttingen
country: Germany
facility: Klinikumder Georg-August-Universitaet
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitaetsklinikum Jena Klinik fuer Innere Medizin 1
city: Magdeburg
country: Germany
facility: Unniversitaetsklinikum Magdeburg Klinik fur Kardiologie und Anglologie
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Varosmajori Sziv es Ergyogyasazati Klinika
city: Ramat Gan
country: Israel
facility: The Olga & Lev Leviev Heart Center The Chaim Sheba Medical Center
state: Tel Hasomer
city: Ashkelon
country: Israel
facility: The Barzilai University Medical Center
city: Ashkelon
country: Israel
facility: The Barzilai University Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center- Ein Kerem
city: Reẖovot
country: Israel
facility: Kaplan Medical Center
city: Zefat
country: Israel
facility: Ziv Medical Center
city: Brescia
country: Italy
facility: UOC Cardiologica Azienda Ospedaliera Spedali Civili di Brescia
city: Florence
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi Dipartimento Cardiotoracovascolare - Cardiomiopatie Unit
city: Pisa
country: Italy
facility: Fondazione toscana Gabriele Monesterio per la ricarca medica Dipartimento Cardiotoracico UOC Cardiologia e Medicina Cardiovasculare Ospedale San Cataldo
city: Roma
country: Italy
facility: Dipartimento di Medicina Clinica e Molecolare Universita Sapienza di Roma Unita di Terapia Intensiva Cardiologica Azienda Ospedaliero Universitaria Sant'Andrea
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
city: Maastricht
country: Netherlands
facility: University Hospital Maastricht
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Warsaw
country: Poland
facility: Narodowy Instytut Kardiologii Stefana Kardynała Wyszynskiego- Panstwowy Instytut Badawczy
state: Mazowieckie
city: Katowice
country: Poland
facility: Kardio Brynow S.C
city: Kraków
country: Poland
facility: Krakowskie Centrum
city: Aveiro
country: Portugal
facility: Centro Hospitalar Do Baixo Vouga, EPE AV ARTUR RAVARA
city: Lisboa
country: Portugal
facility: Hospital da Luz
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario
state: La Coruna
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Majadahonda
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Murcia
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arrixaca
city: Palma
country: Spain
facility: Hospital Universitario Son Llatzer Secretaria de Cardiologia
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena-merge
city: Edgbaston
country: United Kingdom
facility: Queen Elizabeth Hospital Birmingham University Hospitals Birmingham NHS Foundation Trust
state: Birmingham
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital - HWS Greater Glasgow and Clyde
city: Liverpool
country: United Kingdom
facility: Liverpool Heart and Chest Hospital - Liverpool Heart and Chest Hospital NHS Foundation Trust- HWS Greater Glasgow and Clyde
city: London
country: United Kingdom
facility: Barts Health NS Trust
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Brompton Hospital
city: Oxford
country: United Kingdom
facility: Oxford Centre for Clinical Magnetic Resonance Research
city: Oxford
country: United Kingdom
facility: Radcliffe Department of Medicine
Study officials:
affiliation: Cytokinetics
name: Cytokinetics MD
role: STUDY_DIRECTOR
References: