SCOUT-HCM (NCT06253221) is a phase 3, randomized, placebo-controlled, double-blind, parallel-group, multicenter, international study in symptomatic adolescent patients with obstructive HCM. The target sample size is 40 participants recruited from sites in Australia, Canada, France, Germany, Italy, Spain, the Republic of Ireland, the UK, and the US. An independent Data Monitoring Committee will be responsible for safeguarding the interests of the study participants by reviewing efficacy and safety data throughout the study. Input into the study design from patients and their guardians was obtained through interviews and a patient advisory board.

Key inclusion and exclusion criteria are detailed in Table 1 . Participants must be ≥12 years and <18 years of age at the time of informed consent/assent. Other key inclusion criteria include a diagnosis of HCM, a Valsalva LVOT gradient of ≥30 mmHg and a maximal measured LVOT gradient of ≥50 mmHg (at rest, after Valsalva maneuver, or postexercise), a left ventricular ejection fraction (LVEF) of ≥60% at rest, and NYHA functional class II–III symptoms. Key exclusion criteria include diagnosis of HCM “phenocopies” (diseases resulting in ventricular hypertrophy not related to sarcomere dysfunction), evidence of resting LVEF <50% in the previous 6 months, planned escalation in HCM therapy or upcoming major cardiac intervention, concomitant treatment with moderate or strong cytochrome P450 2C19 (CYP2C19) inhibitors or strong cytochrome P450 3A4 inhibitors, or pregnancy. The full list of inclusion and exclusion criteria are presented in Supplementary Table I .

Participants will be permitted to continue their existing HCM therapy (eg, beta-blockers, non-dihydropyridine calcium channel blockers, disopyramide, or combinations thereof) for the duration of the study.

The study will consist of 5 periods: screening; a double-blind, placebo-controlled period; an active-treatment period; a long-term extension (LTE) period; and a follow-up period ( Figure 1 ).

Study design. Participants will initiate mavacamten treatment at 2.5 mg or 5 mg depending on body weight at visit (2.5 mg, 35 kg to <45 kg; 5 mg, ≥45 kg). Participants in Europe who are CYP2C19 poor metabolizers will initiate mavacamten treatment at a 2.5 mg dose irrespective of body weight at baseline. Mavacamten dose will be titrated to 1, 2.5, 5, 10, or 15 mg based on echocardiographic assessment of Valsalva LVOT gradient and LVEF. Among patients who continue receiving treatment in the LTE period, the EOS visit will occur 8 weeks or 18 weeks (CYP2C19 poor metabolizers only) after the last dose of study intervention. ^a Participants completing the active-treatment period may continue to the LTE period for ≤144 weeks (approximately 2.8 years). ^b Participants will continue to receive the same dose when entering the LTE period. Dose modifications may occur during the LTE period. CYP2C19, cytochrome P450 2C19; EOS, end-of-study; HCM, hypertrophic cardiomyopathy; LTE, long-term extension; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; R, randomization.

Participants will be screened for eligibility and will receive a baseline evaluation at the sites. Screening procedures include physical examination, vital signs, 12-lead electrocardiogram monitoring, resting, Valsalva, and post-exercise transthoracic echocardiographic assessments, laboratory tests, and CYP2C19 genotyping. Participants will perform the Valsalva maneuver by bearing down and holding a forceful expiration against a closed nose and mouth. The Valsalva LVOT gradient will be captured on the echocardiogram after the participant bears down for 3 to 4 seconds. Consistent with the increasing usage of goal-directed Valsalva (GDV), sites will be given GDV kits which can be used by participants entering the study. To avoid participants changing techniques in the middle of the study, those who do not use GDV kits at screening will not use it during the study. Conversely, participants who use GDV kits at screening will use it throughout the study. Participants who use GDV kits will be instructed to develop ≥40 mmHg of pressure during the Valsalva maneuver at screening. The use of GDV kits and the pressure developed by each participant will be recorded. Participants will be instructed to target the same level of pressure at subsequent visits.

Following a screening period of ≤5 weeks, eligible participants will be centrally randomized 1:1 using interactive response technology to receive oral mavacamten or placebo once daily for 28 weeks. Randomization will be stratified by age (≥12 years to <15 years, ≥15 years to <18 years) and by beta-blocker use (yes, no). At week 28, patients randomized to placebo will cross over to receive mavacamten for 28 weeks (the active-treatment period). Sites and patients will remain blinded to original treatment assignment and dose throughout the active-treatment period. Furthermore, sites will be masked to echocardiogram data throughout the placebo-controlled and active-treatment periods to ensure treatment assignment blinding; however, each site will have a non-study physician who will be unmasked to echocardiogram results for the purpose of safety monitoring. To collect additional efficacy and safety data, participants who complete the placebo-controlled and active-treatment periods (from baseline to week 56) will continue to receive mavacamten in the open-label LTE period for an additional 144 weeks (approximately 2.8 years). Among patients who continue to receive treatment in the LTE period, the end of study (EOS) visit will occur 8 weeks or 18 weeks (CYP2C19 poor metabolizers only) after the last dose of study intervention. Among participants who discontinue study intervention prematurely, the EOS visit will occur at either week 56 or 8 weeks (18 weeks for CYP2C19 poor metabolizers) after the last dose of study intervention, whichever occurs latest. Therefore, the maximum duration of the study is 223 weeks from the date of consent to the EOS visit.

Participants randomized to mavacamten will initiate once-daily treatment at a starting dose of 2.5 mg if body weight at baseline is between 35 kg and <45 kg, or 5 mg if body weight at baseline is ≥45 kg. For participants randomized to placebo who enter the active-treatment period and initiate mavacamten at week 28, the same criteria will be used based on body weight at week 28. Participants in Europe who are CYP2C19 poor metabolizers will initiate mavacamten treatment at a 2.5 mg dose irrespective of body weight at baseline, consistent with the mavacamten EU and UK summary of product characteristics for adult patients.

Core laboratory echocardiographic assessment of Valsalva LVOT gradient and LVEF measured at the visit before the titration step will inform mavacamten stepwise dose down- or up-titration from the 2.5 mg or 5 mg starting doses to one of the following available doses: 1, 2.5, 5, 10, or 15 mg. Owing to European regulatory requirements, the maximum available dose for participants in Europe who are CYP2C19 poor metabolizers will be 5 mg. For participants in Australia, Canada, and the US, the maximum available dose will be 15 mg irrespective of CYP2C19 metabolizer phenotype. In the double-blind, placebo-controlled period, potential down-titration steps will occur at weeks 5 and 9, while potential up-titration steps will occur at weeks 12 and 24. In the active-treatment period, potential down-titration steps will occur at weeks 33 and 37 (limited to those randomized to placebo and crossed over to mavacamten at week 28) and potential up-titration steps will occur at weeks 40 and 52 (limited to those not already receiving the maximum dose of 15 mg). The goal of dose titration is to achieve the lowest tolerated dose necessary for each participant to achieve a maximal Valsalva LVOT gradient of <30 mmHg while maintaining an LVEF of ≥50%. Therefore, the dose will only be up-titrated if a participant’s Valsalva LVOT gradient is ≥30 mmHg and their LVEF is ≥55%. If Valsalva LVOT gradient reduces to <20 mmHg in the first 8 weeks after study drug initiation, the dose will be down-titrated by 1 dose level. If LVEF is <50% at any time during the study period (read by the core laboratory in the first 56 weeks and by the site laboratory in the LTE period), study drug will be interrupted for ≥4 to 6 weeks. If LVEF recovers to ≥55% during follow-up, study drug can be resumed at 1 dose level lower (or at 1 mg for those who were receiving a 1 mg dose). If a site non-study physician confirms an LVEF <50% in the first 56 weeks, the study drug will be temporarily interrupted until the core laboratory determination is received. An alert will be sent to the site from the interactive response technology system to indicate if the participant should formally interrupt treatment (core laboratory LVEF <50%). Study drug will be permanently discontinued if a participant has 2 consecutive LVEF readings <50% while receiving study drug 1 mg, or if the site or core laboratory-read LVEF is ≤30% at any dose or visit.

Efficacy, safety, and PK parameters will be measured from baseline through week 200 (end of treatment). A schedule of measurements in SCOUT-HCM is detailed in Supplementary Table II .

The primary endpoint is the change from baseline to week 28 in Valsalva LVOT gradient ( Table 2 ). The secondary endpoints related to mavacamten efficacy, safety, taste and swallowability, and PK are detailed in Table 2 . Secondary safety endpoints that will be assessed during the study period include the incidence of adverse events, serious adverse events, and LVEF measurements <50% and ≤30%. Exploratory endpoints related to mavacamten efficacy are detailed in Table 3 .

Table 2

Study primary and secondary endpoints

Category	Endpoint
Primary endpoint
Efficacy	Change from baseline to week 28 in Valsalva LVOT gradient *
Secondary endpoints
Efficacy	Change from baseline to week 28 in:
	• resting LVOT gradient *
	• post-exercise peak LVOT gradient *
	• maximal left ventricular wall thickness *
	• E/e’ (septal, lateral, average) *
	• HCMSQ SoB domain score
	Proportion of participants:
	• achieving an increase from baseline to week 28 in pVO 2
	• achieving a reduction from baseline to week 28 in maximal LVOT gradient to <30 mmHg
	• with ≥1 class improvement in NYHA functional class from baseline to week 28
	• with ≥1 grade improvement in mitral regurgitation from baseline to week 28
Safety	Incidence of TEAEs and TESAEs †
	Change from baseline to week 28 in QT interval on ECG
	Incidence of LVEF <50%*
	Incidence of LVEF ≤30%*
Taste and swallowability	Proportion of participants who evaluate taste and swallowability as neutral or better by using taste and swallowability scales on day 1 and at week 11
PK	Summary of plasma concentrations by visit (C trough and post-dose)
	C max and AUC

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