Clinical trial NCT04219826: Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM
Official title: A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertrophic Cardiomyopathy (HCM)
Keywords: CK-3773274
CK-274
obstructive hypertrophic cardiomyopathy
oHCM
REDWOOD-HCM
non-obstructive hypertrophic cardiomyopathy
nHCM
hypertrophic cardiomyopathy
HCM
aficamten
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
First posted: 2020-01-07
Enrollment: 96
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: This study is being performed to understand the effect of different doses of CK-3773274 on patients with hypertrophic cardiomyopathy (HCM).


Eligibility criteria: Inclusion Criteria

* Males and females between 18 and 85 years of age at screening.
* Body weight is ≥45 kg at screening.
* Diagnosed with HCM per the following criteria:

  * Has left ventricular (LV) hypertrophy with non-dilated LV chamber in the absence of other cardiac disease.
  * Has minimal wall thickness ≥15 mm (minimal wall thickness ≥13 mm is acceptable with a positive family history of HCM or with a known disease-causing gene mutation).
* Adequate acoustic windows for echocardiography.
* For Cohorts 1, 2 and 3 has LVOT-G during screening as follows:

  * Resting gradient ≥50 mmHg OR
  * Resting gradient ≥30 mmHg and \<50 mmHg with post-Valsalva LVOT-G ≥50 mmHg
* For Cohort 4 has resting and post-Valsalva LVOT-G \< 30 mmHg at the time of screening
* For Cohort 4 has elevated NT-proBNP \> 300 pg/mL at the time of screening
* LVEF ≥60% at screening.
* New York Heart Association (NYHA) Class II or III at screening.
* Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been on stable doses for \>4 weeks prior to randomization and anticipate remaining on the same medication regimen during the study.
* For Cohort 3: Patients must be taking disopyramide. Patients should have been on stable disopyramide doses for \>4 weeks prior to screening and anticipate remaining on the same medication regimen during the study.

Exclusion Criteria

* Aortic stenosis or fixed subaortic obstruction.
* Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
* History of LV systolic dysfunction (LVEF \<45%) at any time during their clinical course.
* Documented history of current obstructive coronary artery disease (\>70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction.
* Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the study period (Cohorts 1, 2, and 3 only). Patients having undergone septal reduction therapy \> 12 months prior to screening who remain symptomatic from nHCM, and who meet all other criteria for inclusion, may be enrolled in Cohort 4.
* For Cohorts 1, 2 and 4: Has been treated with disopyramide or antiarrhythmic drugs that have negative inotropic activity within 4 weeks prior to screening. (For Cohort 3, use of disopyramide is required).
* Has any ECG abnormality considered by the investigator to pose a risk to patient safety (eg, second degree atrioventricular block type II).
* Paroxysmal atrial fibrillation or flutter documented during the screening period.
* Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) ≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for \>6 months).
* History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
* Has received prior treatment with CK-3773274 or mavacamten.
* For Cohort 4: has any documented history of LVOT-G ≥ 30 mmHg at rest, with Valsalva, or with exercise (for subjects who have had prior septal reduction therapy, this exclusion criteria only applies to gradients detected following septal reduction therapy).

Primary outcomes:
measure: Incidence of adverse events observed during dosing of CK--3773274 in patients with HCM
timeFrame: 14 weeks
Secondary outcomes:
measure: Incidence of left ventricular ejection fraction (LVEF) < 50% observed during dosing of CK-3773274 in patients with HCM
timeFrame: 14 weeks
measure: Incidence of serious adverse events observed during dosing of CK-3773274 in patients with HCM
timeFrame: 14 weeks
measure: Concentration-response relationship of CK-3773274 on the resting left ventricular outflow tract gradient (LVOT-G) on echocardiogram over 10 weeks of treatment in patients with oHCM (Cohorts 1, 2, 3 only)
timeFrame: 10 weeks
measure: Concentration-response relationship of CK-3773274 on the post-Valsalva left ventricular outflow tract gradient (LVOT-G) on echocardiogram over 10 weeks of treatment in patients with oHCM (Cohorts 1, 2, 3 only)
timeFrame: 10 weeks
measure: Dose response relationship on LVOT-G of CK-3773274 in patients with oHCM at rest (Cohorts 1, 2, 3 only)
timeFrame: 10 weeks
measure: Dose response relationship on LVOT-G of CK-3773274 in patients with oHCM post-Valsalva (Cohorts 1, 2, 3 only)
timeFrame: 10 weeks
measure: Concentration-response relationship of CK-3773274 on left ventricular ejection fraction (LVEF) over 10 weeks of treatment in patients with HCM
timeFrame: Day 1 to End of Study (EOS) (Week 14)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedar-Sinai Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
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: Ann Arbor
country: United States
facility: Michigan Medicine - University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: New York University Langone Health 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: Portland
country: United States
facility: Oregon Health and 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: UMPC Heart and Vascular Institute
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center (Erasmus MC)
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro de Majadahonda
Study officials:
affiliation: Cytokinetics
name: Cytokinetics, MD
role: STUDY_DIRECTOR
References:
citation: Zampieri M, Argiro A, Marchi A, Berteotti M, Targetti M, Fornaro A, Tomberli A, Stefano P, Marchionni N, Olivotto I. Mavacamten, a Novel Therapeutic Strategy for Obstructive Hypertrophic Cardiomyopathy. Curr Cardiol Rep. 2021 Jun 3;23(7):79. doi: 10.1007/s11886-021-01508-0.