Phase 3 Randomized Double-Blind Study of Aficamten vs. Metoprolol Succinate in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy

The primary objective of this study is to evaluate the effect of **aficamten** compared with **metoprolol** on exercise capacity in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). This is clinically relevant as improving exercise capacity can significantly enhance the quality of life and functional status of individuals with oHCM, a condition characterized by left ventricular outflow obstruction and impaired cardiac function.

Secondary objectives include:

• Evaluating the effect of aficamten compared with metoprolol on the New York Heart Association (NYHA) Functional Classification, which assesses the severity of heart failure symptoms.
• Assessing the impact on participant health status, providing insights into overall well-being and symptom burden.
• Investigating the effect on structural remodeling, which may indicate changes in cardiac structure and function.
• Measuring the levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP), a biomarker associated with heart failure severity.
• Evaluating the effect on post-Valsalva left ventricular outflow tract gradients (LVOT-G), which are indicative of the degree of obstruction in the heart.

The clinical trial involves a total of **117 participants** diagnosed with **Symptomatic Obstructive Hypertrophic Cardiomyopathy** (oHCM). The study population includes both male and female subjects, aged between 18 to 85 years. Participants were selected based on specific criteria, including a body mass index of less than 35 kg/m² and a diagnosis of oHCM confirmed by cardiac magnetic resonance imaging or echocardiography. The trial population is characterized by a non-dilated left ventricular chamber and a left ventricular wall thickness of at least 15 mm in one or more myocardial segments, or at least 13 mm with a known disease-causing gene mutation or positive family history of hypertrophic cardiomyopathy. Participants must have a Kansas City Cardiomyopathy Questionnaire (KCCQ) score of 90 or less and a hemoglobin level of at least 10 g/dL at screening. The study includes individuals who have previously been exposed to mavacamten, provided they have discontinued its use for at least eight weeks. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The population includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's effects across diverse demographics.

The clinical trial is a **Phase 3**, multi-center, randomized, double-blind study designed to evaluate the efficacy and safety of **Aficamten** compared to **Metoprolol** in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). The trial aims to assess the effect of Aficamten on exercise capacity, with the primary endpoint being the change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET) from baseline to Week 24. Secondary endpoints include improvements in NYHA Functional Class, changes in the Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS), left ventricular mass index (LVMI), left atrial volume index (LAVI), NT-proBNP levels, and post-Valsalva LVOT-G from baseline to Week 24.

The trial is expected to last until October 2025, with participant recruitment starting in October 2023. Participants will be involved for a maximum of 24 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, baseline assessments, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to collect final data. Participants must be between 18 to 85 years old, have a body mass index (BMI) of less than 35 kg/m², and meet specific diagnostic criteria for oHCM. Conditions for early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety.

The trial involves the administration of Aficamten and Metoprolol, with the latter being provided as Metoprololsuccinat STADA® 47.5 mg prolonged-release tablets. Aficamten is administered as a film-coated tablet. Both medications are taken orally. A placebo is also used to maintain the double-blind nature of the study. The trial is not classified as a low-intervention study, and it adheres to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Aficamten**, a film-coated tablet containing the active substance aficamten, chemically known as (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 20 mg, with a total maximum dose of 3360 mg over a treatment period of 24 weeks. The product is manufactured by Cytokinetics Inc.

**Metoprololsuccinat STADA® 47.5 mg Retardtabletten** is used as a comparator in the trial. It is a prolonged-release tablet containing the active substance metoprolol tartrate. The route of administration is oral, with a maximum daily dose of 200 mg and a total maximum dose of 33600 mg over a 24-week treatment period. The product is manufactured by STADAPHARM GMBH.

**Dobutamine Hydrochloride** is used as an auxiliary treatment in the trial. It is administered via infusion, with no specified maximum daily or total dose, and is used for a maximum treatment period of 1 day. The pharmaceutical form is coded as PHF633, and the active substance is of chemical origin.

The trial also includes two placebo treatments: **Placebo (Metoprolol succinate)** and **Placebo (Aficamten)**. Both are used to maintain the double-blind nature of the study. The pharmaceutical form and route of administration for these placebos are not specified.

The efficacy of the investigational treatment in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the change in peak oxygen uptake (**pVO2**) measured by cardiopulmonary exercise testing (CPET) from baseline to Week 24. This parameter is crucial for evaluating the effect of the treatment on exercise capacity in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM).

Secondary endpoints include several measures to provide a comprehensive assessment of efficacy. These are:

• Proportion of participants with at least one class improvement in the New York Heart Association (NYHA) Functional Class from baseline to Week 24.
• Change in the Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS) from baseline to Week 24.
• Change in left ventricular mass index (LVMI) and left atrial volume index (LAVI) from baseline to Week 24.
• Change from baseline values in NT-proBNP from baseline to Week 24.
• Change in post-Valsalva left ventricular outflow tract gradient (LVOT-G) from baseline to Week 24.

These endpoints will be measured and collected at specified timepoints, with the primary endpoint being assessed at Week 24. The use of validated scales and laboratory tests will ensure the reliability and accuracy of the data collected. The analysis of these efficacy parameters will provide insights into the potential benefits of the treatment compared to the control group, contributing to the overall evaluation of the treatment's efficacy in the target population.