Evaluation of Mavacamten on Left Ventricular Outflow Tract Obstruction in Adolescents with Symptomatic Obstructive Hypertrophic Cardiomyopathy

The primary objective of this study is to evaluate the effect of **mavacamten** compared to placebo on left ventricular outflow tract (LVOT) obstruction in adolescents with symptomatic obstructive hypertrophic cardiomyopathy (HCM). This is clinically relevant as LVOT obstruction is a key pathophysiological feature of obstructive HCM, contributing to symptoms and adverse outcomes. Addressing this obstruction can potentially improve clinical outcomes and quality of life for affected adolescents.

Secondary objectives include: - Evaluating the effect of mavacamten compared to placebo on other clinically meaningful aspects of the disease, such as symptom status and echocardiographic parameters. - Assessing the safety and tolerability of mavacamten in this population. - Investigating the pharmacokinetics (PK) of mavacamten. - Evaluating the taste and swallowability of mavacamten capsules after first and multiple doses. - Assessing the effect of mavacamten on patient-reported symptoms. These secondary objectives aim to provide a comprehensive understanding of the therapeutic profile of mavacamten in adolescents with symptomatic obstructive HCM.

The clinical trial involves a total of **29 participants** diagnosed with **Symptomatic Obstructive Hypertrophic Cardiomyopathy**. The study population consists of adolescents aged 12 to less than 18 years, including both male and female subjects. Participants were selected based on the presence of left ventricular outflow tract obstruction and associated symptoms. The trial population is considered vulnerable due to the age group involved. No specific lifestyle considerations such as diet or physical activity are highlighted in the available data. The selection criteria ensure that only those with a confirmed diagnosis of hypertrophic cardiomyopathy and symptomatic obstruction are included in the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **mavacamten** in adolescents aged 12 to less than 18 years with **symptomatic obstructive hypertrophic cardiomyopathy**. The primary objective is to assess the effect of mavacamten compared to placebo on left ventricular outflow tract (LVOT) obstruction. The trial is expected to commence recruitment on June 29, 2024, and conclude by June 29, 2029. Participants will be randomly assigned to receive either mavacamten or a placebo, both administered in capsule form orally.

The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis of hypertrophic cardiomyopathy, presence of LVOT obstruction, and symptoms. Following randomization, participants will undergo regular follow-up visits to monitor changes in LVOT gradient, maximal wall thickness, and other secondary endpoints. The primary endpoint is the change from baseline in Valsalva LVOT gradient at Week 28. Secondary endpoints include changes in resting LVOT gradient, post-exercise peak LVOT gradient, and other cardiac function parameters.

The expected duration of participant involvement is approximately 28 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The end-of-study visit will assess the overall impact of the treatment and collect final data on the primary and secondary endpoints. Throughout the trial, safety will be closely monitored, with particular attention to treatment-emergent adverse events and changes in left ventricular ejection fraction. The trial aims to provide comprehensive data on the efficacy and safety of mavacamten in this patient population.

The clinical trial involves the administration of **Mavacamten**, a chemical compound developed by Bristol-Myers Squibb International Corporation. Mavacamten is provided in capsule form and is available in various dosages, including 1 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg per capsule. The medication is administered orally. The maximum daily dose and total dose are set at 9999 mg, with a treatment period also capped at 9999 days, although these are theoretical limits rather than practical dosing guidelines. The primary objective of the trial is to evaluate the effect of Mavacamten on left ventricular outflow tract obstruction in adolescents with symptomatic obstructive hypertrophic cardiomyopathy.

A placebo is also utilized in this study to serve as a comparator treatment. 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 is intended to mimic the active treatment in all aspects except for the active substance, ensuring the study remains double-blind. The placebo is administered orally, following the same schedule as the active treatment to maintain consistency across the study groups.

The efficacy of **Mavacamten** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the Valsalva left ventricular outflow tract (LVOT) gradient at Week 28. This measurement will provide insight into the effect of the treatment on LVOT obstruction in adolescents with symptomatic obstructive hypertrophic cardiomyopathy (HCM).

Secondary endpoints include several parameters measured at Week 28: changes from baseline in resting LVOT gradient, post-exercise peak LVOT gradient, maximal wall thickness, and the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’). Additionally, the trial will evaluate the proportion of participants achieving an increase in peak oxygen uptake test (pVO2), a reduction in maximal LVOT gradient to less than 30 mmHg, and at least one class improvement in New York Heart Association (NYHA) class. Other secondary measures include improvements in mitral regurgitation, changes in QT interval on electrocardiogram, and incidences of left ventricular ejection fraction (LVEF) ≤ 30% and < 50%.

Further assessments will involve the summary of plasma concentrations by visit, Cmax and AUC using a population pharmacokinetic approach, and the evaluation of taste and swallowability using specific scales at Day 1 and Week 11. The change from baseline in the HCMSQ SoB domain at Week 28 will also be analyzed. These efficacy parameters will be collected and analyzed at specified timepoints to determine the overall impact of **Mavacamten** on the targeted condition.