Phase 3 Randomized Double-Blind Study of Aficamten Versus Placebo in Adults with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy

Trial ID: 2023-505797-15-00
Protocol: CY 6033
Sponsor: Cytokinetics Inc.

Trial statistics

science

test molecules

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

Hypertrophic cardiomyopathy

Objectives

The primary objective of this Phase 3, multi-center, randomized, double-blind trial is to evaluate the effect of **aficamten** compared with placebo on participant health status and maximal exercise capacity in adults with symptomatic non-obstructive hypertrophic cardiomyopathy. This objective is clinically relevant as it aims to assess the potential of aficamten to improve exercise tolerance and overall health status, which are critical factors in the management of this condition.

Secondary objectives include:

Evaluating the effect of aficamten compared with placebo on maximal and sub-maximal exercise capacity.
Assessing the impact on the New York Heart Association (NYHA) Functional Classification.
Investigating the effect on a biomarker of cardiac wall stress.
Examining echocardiographic measures of structural remodeling.
Evaluating the effect on cardiovascular events.

These secondary objectives aim to provide a comprehensive understanding of aficamten's potential benefits and its impact on various clinical parameters associated with hypertrophic cardiomyopathy.

Participants

The clinical trial involves a total of **260 participants** diagnosed with **symptomatic non-obstructive hypertrophic cardiomyopathy**. The study population includes both male and female subjects, aged between 18 and 85 years, with a body mass index of less than 40 kg/m². Participants were selected based on specific health criteria, including a diagnosis of non-obstructive hypertrophic cardiomyopathy confirmed by echocardiogram measurements, and classified as New York Heart Association class II or III. The trial population is characterized by a respiratory exchange ratio of at least 1.00 at screening and a predicted peak oxygen uptake of 90% or less for age and sex. Additionally, participants have a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score of 85 or less and an N-terminal prohormone brain natriuretic peptide level meeting specified thresholds. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the effect of aficamten compared with placebo on participant health status and maximal exercise capacity.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy and safety of **Aficamten** compared to placebo in adults with symptomatic non-obstructive hypertrophic cardiomyopathy. The trial will span an estimated duration from April 2024 to April 2027. Participants will be randomly assigned to receive either Aficamten or a placebo, with the primary objective being to assess changes in health status and maximal exercise capacity over a 36-week period.

The trial will commence with an inclusion (screening) visit, where participants will be evaluated against specific inclusion criteria, such as age between 18 and 85 years, a body mass index of less than 40 kg/m², and a confirmed diagnosis of non-obstructive hypertrophic cardiomyopathy. Following successful screening, participants will undergo randomization and begin the treatment phase. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol. These visits will include assessments of the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and peak oxygen uptake (pVO2) as primary endpoints, along with secondary endpoints such as changes in NT-proBNP levels and New York Heart Association (NYHA) Functional Class.

The expected length of participant involvement is approximately 72 weeks, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the overall impact of the treatment. This structured approach ensures a comprehensive evaluation of Aficamten's therapeutic potential in the target population.

Treatment

The clinical trial involves the administration of **Aficamten**, a chemical entity developed by Cytokinetics Inc. Aficamten is provided in the form of a **film-coated tablet** and is intended for oral administration. The maximum daily dose of Aficamten is 20 mg, with a total maximum dose of 9660 mg over a treatment period of up to 72 weeks. The active substance in Aficamten is chemically derived and is identified by the chemical name (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, also known by the sponsor product code CK-3773274. The trial aims to evaluate the efficacy and safety of Aficamten in adults with symptomatic non-obstructive hypertrophic cardiomyopathy.

In addition to Aficamten, the study includes a **placebo** comparator, which is a tablet placebo designed to match the 5 mg Aficamten tablet. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and serves as a control to assess the true efficacy and safety of Aficamten. The administration of the placebo follows the same oral route and dosing schedule as the active treatment to ensure consistency across the study arms.

Efficacy

The efficacy of Aficamten in the treatment of symptomatic non-obstructive hypertrophic cardiomyopathy will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and the change in predicted peak oxygen uptake (pVO2) from baseline to Week 36. These measures will evaluate the impact of Aficamten on participant health status and maximal exercise capacity.

Secondary endpoints will further assess efficacy by examining changes in the composite of two Z-scores of cardiopulmonary exercise testing (CPET) parameters, specifically pVO2 and VE/VCO2 slope, from baseline to Week 36. Additionally, the proportion of participants experiencing at least one class improvement in New York Heart Association (NYHA) Functional Class, changes in N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels, and changes in left atrial volume index (LAVI) from baseline to Week 36 will be evaluated. The time to first event of cardiovascular death, heart transplantation, or other significant cardiac events will also be monitored.

These efficacy parameters will be measured and collected at specified timepoints, with the primary focus on changes observed by Week 36. The use of validated scales and laboratory tests will ensure the accuracy and reliability of the data collected. The trial is designed to provide a comprehensive assessment of Aficamten's efficacy in improving clinical outcomes for patients with symptomatic non-obstructive hypertrophic cardiomyopathy.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Between 18–85 years of age at screening
Body mass index < 40 kg/m2
Diagnosed with nHCM and has a screening echocardiogram with the following: • End-diastolic LV wall thickness: − ≥ 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 AND − Resting LVOT-G < 30 mmHg AND Valsalva LVOT-G < 50 mmHg AND − LVEF ≥ 60% • Participants with a history of intracavitary obstruction are eligible
New York Heart Association (NYHA) class II or III
Respiratory exchange ratio of ≥ 1.00 at screening by CPET and predicted peak oxygen uptake (pVO2) of ≤ 90% for age and sex
KCCQ-CSS score ≤ 85
N-terminal prohormone brain natriuretic peptide (NT-proBNP) of: • ≥ 300 pg/mL or ≥ 900 pg/mL if in atrial fibrillation or atrial flutter OR • For Black participants, ≥ 225 pg/mL or ≥ 675 pg/mL if in atrial fibrillation or atrial flutter
Hemoglobin ≥ 10 g/dL

cancel

Exclusion Criteria

Significant valvular heart disease (per Investigator judgment) • Moderate or severe valvular aortic stenosis or fixed subaortic obstruction • Moderate or severe mitral regurgitation
Received prior treatment with aficamten
Received treatment with mavacamten within 3 months prior to screening (must be discussed with the medical monitor prior to screening)
Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics nHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis)
Known current unrevascularized coronary artery stenosis of ≥ 70% or documented history of Type 1 myocardial infarction.
History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy
Inability to exercise on a treadmill or bicycle (e.g., orthopedic limitations)
Documented room air oxygen saturation reading < 90% at screening or history of significant chronic obstructive pulmonary disease or severe/significant pulmonary hypertension
History of the following events with exercise within 3 months prior to screening • syncope, • symptomatic ventricular arrhythmia, or • sustained ventricular tachyarrhythmia
History of resistant hypertension (persistently elevated blood pressure despite maximal doses of 3 or more classes of medications for hypertension control)
Screening diastolic blood pressure ≥ 100 mmHg
Undergone septal reduction therapy < 6 months prior to screening
Is being considered for or is likely to be considered for heart transplant listing or left ventricular assist device placement during the study period
Paroxysmal or permanent atrial fibrillation is excluded only if: • rhythm restoring treatment (e.g., direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) has been required ≤ 3 months prior to randomization • rate control and anticoagulation have not been achieved for at least 3 months prior to screening

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Recruiting	30 Apr 2024	8
France	Not Recruiting	30 Apr 2024	24
Germany	Not Recruiting	30 Apr 2024	15
Greece	Not Recruiting	30 Apr 2024	12
Hungary	Not Recruiting	30 Apr 2024	7
Iceland	Not Recruiting	30 Apr 2024	3
Italy	Not Recruiting	30 Apr 2024	27
The Netherlands	Not Recruiting	30 Apr 2024	—
Poland	Not Recruiting	30 Apr 2024	24
Portugal	Not Recruiting	30 Apr 2024	15