Evaluation of Mavacamten in Adults with Symptomatic Non-obstructive Hypertrophic Cardiomyopathy: A Randomized, Double-blind, Placebo-controlled Study

The primary objective of this study is to assess the efficacy of a 48-week course of **mavacamten** compared to placebo on patient-reported health status, specifically focusing on symptoms and physical limitations, as well as on exercise capacity in adults with symptomatic non-obstructive hypertrophic cardiomyopathy. This is clinically relevant as it aims to determine the potential of mavacamten to improve quality of life and functional capacity in patients suffering from this condition, which is characterized by thickened heart muscle that can lead to heart failure and other complications.

Secondary objectives include evaluating the effects of mavacamten on:

• Ventilatory efficiency as measured by the VE/VCO2 slope.
• New York Heart Association (NYHA) classification.
• Patient-reported shortness of breath.
• Cardiac biomarkers of wall stress.

The clinical trial involves a total of **196 participants** diagnosed with **Non-obstructive Hypertrophic Cardiomyopathy**. The study population includes both male and female subjects, aged 18 years and older, with no upper age limit specified. Participants were selected based on specific criteria, including a diagnosis consistent with guidelines from the American College of Cardiology Foundation, American Heart Association, and European Society of Cardiology. The trial includes individuals who are classified as New York Heart Association Class II or III, with a left ventricular ejection fraction of 60% or higher. Participants must have a peak left ventricular outflow tract pressure gradient of less than 30 mmHg at rest and less than 50 mmHg with provocation. The study population is required to have an oxygen saturation at rest greater than 90% and be capable of performing an upright cardiopulmonary stress test. Both genders are included, with female participants adhering to highly effective contraceptive methods unless they have documented proof of not being of childbearing potential. The trial does not require additional contraceptive measures for male participants. The study also considers vulnerable populations, ensuring comprehensive representation. Lifestyle factors such as diet and physical activity are not explicitly detailed in the trial data provided.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **mavacamten** in adults with symptomatic **non-obstructive hypertrophic cardiomyopathy**. The trial aims to assess the impact of a 48-week course of mavacamten compared to placebo on patient-reported health status, including symptoms and physical limitations, as well as exercise capacity. The study is expected to conclude by July 2029, with recruitment having commenced in April 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and specific clinical parameters. Following successful screening, participants will be randomized to receive either mavacamten or a placebo, administered orally in capsule form. The trial includes multiple follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. These visits will involve assessments such as echocardiography, cardiopulmonary exercise testing, and evaluation of New York Heart Association (NYHA) class. The end-of-study visit will occur at the conclusion of the 48-week treatment period, where final assessments will be conducted to evaluate changes from baseline in key endpoints.

Participant involvement is expected to last approximately 48 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. The primary endpoints include changes from baseline in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS) and peak oxygen consumption (pVO2) at Week 48. Secondary endpoints encompass changes in ventilatory efficiency, NYHA class improvement, and biomarkers such as NT-proBNP and cardiac troponin-T. The trial is conducted under the sponsorship of Bristol-Myers Squibb International Corporation, with mavacamten being the investigational product under evaluation.

The clinical trial involves the administration of **Mavacamten**, an investigational medication, in the form of oral capsules. Mavacamten is chemically synthesized and is provided by Bristol-Myers Squibb International Corporation. The pharmaceutical form of Mavacamten is a capsule, and it is administered orally. The specific dosage, frequency, and treatment duration are determined by the study protocol, with a maximum daily dose and total dose amount set at 9999 mg. The active substance in Mavacamten is identified as MYK-461, with synonyms including 6-{[(1S)-1-phenylethyl]amino}-3-(propan-2-yl)-1,2,3,4 tetrahydropyrimidine-2,4-dione and SAR439152. The sponsor product code for Mavacamten is BMS-986427/MYK-461.

In addition to the experimental treatment, a placebo is utilized in the study. The placebo is designed to match the Mavacamten capsules in appearance and is provided in size 2 gelatin capsules, each containing 120 mg of an excipient blend. The placebo serves as a control to evaluate the efficacy of Mavacamten in the study. The placebo is also administered orally, following the same schedule as the active treatment to ensure blinding and consistency in the trial.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial aims to assess the efficacy of Mavacamten over a 48-week period in adults with symptomatic nonobstructive hypertrophic cardiomyopathy, with a focus on patient-reported health status and exercise capacity. The study is conducted under a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the results.

The efficacy of **Mavacamten** in the treatment of symptomatic nonobstructive hypertrophic cardiomyopathy will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoints for evaluating efficacy include the change from baseline in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS) and the change in peak oxygen consumption (pVO2) at Week 48. Secondary endpoints will assess additional parameters such as the change from baseline in the ventilatory efficiency (VE/VCO2 slope), the proportion of participants with at least one class improvement in the New York Heart Association (NYHA) classification, and changes in biomarkers such as NT-proBNP and cardiac troponin T (cTn-T) at Week 48. Other secondary endpoints include the change in the Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath (HCMSQ-SoB) domain and the time to first major adverse cardiovascular events (MACE-Plus).

Measurements will be collected at baseline and at the 48-week mark using validated scales and laboratory tests. The KCCQ CSS and HCMSQ-SoB domain will be assessed through patient-reported outcomes, while pVO2 and VE/VCO2 slope will be measured using cardiopulmonary exercise testing. Biomarker levels, including NT-proBNP and cTn-T, will be determined through laboratory analysis. The NYHA classification will be evaluated by clinical assessment. The trial is designed to provide comprehensive data on the efficacy of **Mavacamten** over a 48-week treatment period, with the primary and secondary endpoints offering a robust framework for assessing the therapeutic impact on both symptoms and physical limitations associated with the condition.