Prospective evaluation of real-world safety, symptoms improvement and adherence to mavacamten among Iranian patients with hypertrophic obstructive cardiomyopathy (PERSIA-HOCM): protocol of a multicentre observational study

Abstract

Introduction

Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder affecting approximately 1 in 200 to 1 in 500 adults, with nearly 70% exhibiting the obstructive phenotype Hypertrophic Obstructive Cardiomyopathy (HOCM). Randomised trials have demonstrated the efficacy of mavacamten, a first-in-class cardiac myosin inhibitor which significantly reduced outflow tract gradients and improved symptoms, exercise capacity and quality of life in the HOCM cases. Despite these findings, prospective real-world data on its safety and effectiveness remain limited, particularly in non-Western populations and further evidence from routine clinical practice is needed.

Methods and analysis

PERSIA-HOCM is a prospective, multicentre, observational study to be conducted at 19 cardiovascular referral centres in Iran. Adults aged 18 years or older with symptomatic obstructive HCM, defined as New York Heart Association (NYHA) class II to IV and a left ventricular outflow tract (LVOT) gradient of at least 50 mm Hg at rest or with provocation, who are prescribed mavacamten, will be enrolled. Key exclusions include left ventricular ejection fraction below 55%, non-obstructive phenotype and lack of consent. Participants will be followed for 1 year at 4-week intervals. Data collection will include symptoms, NYHA class, vital signs, echocardiographic parameters (including outflow gradients and ejection fraction), mavacamten dosing and adjustments and concomitant therapies. Echocardiography will be performed at weeks 4, 8, 12 and 24. Safety will be assessed using a predefined adverse event framework that includes mortality, hospitalisations and major clinical events. At weeks 12 and 48, cardiac troponin, N-terminal pro B-type natriuretic peptide and quality of life will be assessed. Primary endpoints will be safety, change in the NYHA class, resting and provoked LVOT gradient, quality of life, cardiac biomarkers and left ventricular ejection fraction. Secondary endpoints will include cardiac magnetic resonance imaging parameters for cardiac fibrosis, peak oxygen intake and genotype-based outcome. Analyses will be performed using R V.4.5.1, employing descriptive statistics, paired sample t tests and McNemar’s test.

Ethics and dissemination

Ethical approval was obtained from the Research Ethics Committee of Rajaie Cardiovascular, Medical and Research Institute/Iran National Committee for Ethics in Biomedical Research (Code: IR.RHC.REC.1404.210). Written informed consent will be required and filled by the patients. Considering full data confidentiality, analysis reports will be public every 6 months. Findings will be disseminated through peer-reviewed publications and scientific conferences.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The present study is a prospective, real-world study conducted across 19 referral cardiovascular centres with the longest follow-up period (52 weeks) compared with similar studies.

• Standardised case report form and standard operating procedure, supervised by a Data Quality and Validation Committee, ensure consistent and reliable data collection.

• Planned clinical and echocardiographic follow-ups (for 1 year post-initiation) enable close monitoring of left ventricular outflow tract gradients, left ventricular ejection fraction and treatment adherence.

• The observational, non-randomised design limits causal inference and remains susceptible to residual confounding and selection bias.

• Multicentre echocardiographic assessments without a central core laboratory, together with feasibility-based recruitment, may introduce measurement variability and limit statistical power.

Introduction

Hypertrophic cardiomyopathy (HCM) is a dominantly inherited condition that affects the heart, and its overall incidence in the general population is estimated at around 1 in 500 persons.^{1 2} The disease is characterised by an idiopathic thickening of the left ventricle that leads to functional abnormality. In almost two-thirds of the cases, this results in the obstructive form of the disease,^{3 4} characterised by increased intra-cavity pressures, mitral regurgitation, impaired diastolic function and ultimately causing symptoms like exertion-induced breathlessness, syncope, decreased exercise tolerance, symptoms of heart failure, atrial fibrillation and, in some cases, sudden cardiac death.^{5 6} The substantial symptom burden significantly compromises quality of life and necessitates timely diagnosis and appropriate management.

Current pharmacological therapy for symptomatic HOCM primarily includes beta blockers (BBs), non-dihydropyridine calcium channel blockers and disopyramide.² Although these agents may alleviate symptoms, they do not directly target the underlying sarcomeric hypercontractility responsible for left ventricular outflow tract obstruction (LVOTO).^{4 7} In patients with persistent symptoms despite optimal medical therapy, invasive strategies such as surgical septal myectomy or alcohol septal ablation were considered.⁸ However, these procedures required specialised centres and experienced operators, entail procedural risks and may not be accessible to many patients, particularly in resource-limited settings.⁹ Therefore, effective, noninvasive, disease-specific therapies remain an important unmet clinical need.

Mavacamten has recently been introduced as the first selective cardiac myosin inhibitor targeting sarcomeric hypercontractility, thereby directly reducing dynamic outflow tract obstruction.¹⁰ Phase III randomised trials, including EXPLORER-HCM and VALOR-HCM, demonstrated that mavacamten significantly reduces left ventricular outflow tract gradients, improves New York Heart Association (NYHA) functional class, enhances exercise capacity and quality of life and decreases the proportion of patients eligible for septal reduction therapy (SRT).^{11 12} These findings led to regulatory approval in the USA under the Risk Evaluation and Mitigation Strategy programme and to their incorporation into contemporary European cardiology guidelines.^13–15

Beyond pivotal trials, accumulating observational data from real-world cohorts in the USA, Europe and Asia have reported consistent improvements in symptoms, functional class, outflow tract gradients and structural parameters, with relatively low rates of left ventricular ejection fraction (LVEF) reduction and treatment discontinuation when careful monitoring is applied.^{13 16–18} Large-scale studies have shown that the incidence of clinically significant systolic dysfunction and heart failure hospitalisation is low, and most patients remain within recommended dosing ranges with appropriate echocardiographic surveillance.^{13 14} Multicentre cohort studies have also demonstrated reductions in resting and provoked gradients, improvement of at least one NYHA class in a substantial proportion of patients, decreases in natriuretic peptide levels and favourable changes in diastolic and strain parameters.^17–19

Despite these encouraging findings, prospective real-world evidence remains limited in many non-Western and developing countries. In regions such as the Middle East, including Iran, access to novel therapies may be constrained by healthcare infrastructure, reimbursement policies and the absence of integrated national registries. Furthermore, long-term safety, effectiveness and treatment patterns in diverse ethnic and clinical contexts require further evaluation. The establishment of a comprehensive, unified data-collection system can support clinicians in optimising therapeutic decisions and provide policymakers with robust evidence to guide resource allocation and treatment protocols.

The PERSIA-HOCM study is therefore designed as a prospective, multicentre evaluation of mavacamten in routine clinical practice in Iran. In addition to assessing safety and symptomatic improvement, this project aims to contribute to the creation of a national database for patients with obstructive HCM, encompassing clinical, pharmacological and imaging data. By generating region-specific real-world evidence, this study seeks to inform clinical practice, strengthen local guideline development and clarify the role of mavacamten as an effective non-invasive therapeutic option for the management of symptomatic obstructive HCM.

Objectives

General objective

The overall objective of the PERSIA-HOCM study is to conduct a comprehensive real-world evaluation of the safety profile and symptom improvement associated with mavacamten therapy in Iranian patients with HOCM. Through prospective follow-up within routine clinical practice, the study seeks to generate structured national data on clinical effectiveness, tolerability and patterns of treatment implementation across participating referral cardiovascular centres.

Specific objectives

• Evaluate changes in symptom severity and functional capacity during follow-up using the NYHA functional classification.

• Assess longitudinal changes in echocardiographic parameters, including left ventricular outflow tract gradients, LVEF and other relevant structural and functional cardiac indices.

• Monitor laboratory trends over the course of treatment, with particular focus on biomarkers such as N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTn-I).

• Determine changes in health-related quality of life using a heart failure-specific quality of life questionnaire administered at predefined assessment time points.

• Define the safety profile of mavacamten through systematic documentation of adverse events (AEs), serious AEs (SAEs), hospitalisations and mortality throughout follow-up.

• Evaluate treatment adherence and real-world prescribing patterns by documenting mavacamten dosing, dose adjustments, and their underlying reasons, as well as compliance with scheduled follow-up visits.

To ensure that objectives were evaluated based on pre-defined, testable hypotheses rather than exclusively on descriptive post hoc reporting, each primary and exploratory endpoint was accompanied by paired null and alternative hypotheses and a corresponding statistical method, as outlined in table 1.

Table 1. Detailed outline of our hypotheses and the corresponding testing method.

Hypotheses	Testing method
Primary endpoints
H0: Mavacamten does not change the resting LVOT gradient in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after continuous comparison using paired-sample t-test and adjusted linear regression models
H1: Mavacamten significantly changes the resting LVOT gradient in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not change the provoked LVOT gradient in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after continuous comparison using paired-sample t-test and adjusted linear regression models
H1: Mavacamten significantly changes the provoked LVOT gradient in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not change the quality of life in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after continuous comparison using paired-sample t-test and adjusted linear regression models
H1: Mavacamten significantly changes the quality of life in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not change the NYHA function class in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after categorical comparison using McNemar test and adjusted multinomial regression models
H1: Mavacamten significantly changes the NYHA function class in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not change the level of heart failure biomarkers in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after continuous comparison using paired-sample t-test and adjusted linear regression models
H1: Mavacamten significantly changes the level of heart failure biomarkers in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not change the LVEF in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after continuous comparison using paired-sample t-test and adjusted linear regression models
H1: Mavacamten significantly changes the LVEF in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not lead to any serious adverse events in HOCM cases at short- and mid-term follow-up in a real-world setting.	Qualitative reporting of all safety outcome measures happened during the study
H1: Mavacamten leads to serious adverse events in HOCM cases at short- and mid-term follow-up in a real-world setting.
Exploratory endpoints
H0: Mavacamten does not change heart fibrosis based on CMR indices in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after continuous comparison using paired-sample T-test and adjusted linear regression models
H1: Mavacamten significantly changes heart fibrosis based on CMR indices in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not change pVO2 in HOCM cases at short- and mid-term follow-up in a real-world setting.	Before-after continuous comparison using paired-sample T-test and adjusted linear regression models
H1: Mavacamten significantly changes pVO2 in HOCM cases at short- and mid-term follow-up in a real-world setting.
H0: Mavacamten does not change the outcome in HOCM cases at short- and mid-term follow-up in a real-world setting based on genotype.	Combined quantitative and qualitative analysis of the continuous and categorical variables using logistic, polynomial and linear regression models
H1: Mavacamten significantly changes the outcome in HOCM cases at short- and mid-term follow-up in a real-world setting based on genotype.

CMR, cardiac magnetic resonance; HOCM, hypertrophic obstructive cardiomyopathy; LVEF, left ventricular ejection fraction; LVOT, left ventricular outlet tract; NYHA, New York Heart Association; pVO₂, peak oxygen uptake.

Methods and analysis

Study design and settings

This is a large, collaborative, real-world, prospective, multicentre, observational cohort study conducted in Iran, titled Prospective Evaluation of Real-World Safety, Symptoms Improvement and Adherence to Mavacamten in Iranian HOCM Patients (PERSIA-HOCM) (figure 1). The study follows a 2-year framework comprising 1 year of patient recruitment and 1 year of follow-up per enrolled participant, as specified in the protocol. The study is non-interventional, and the prescription of mavacamten, as well as all dose modifications, will be performed according to routine clinical practice and guideline-based decision-making including the Risk Evaluation and Mitigation Strategies (REMS) approved by the Food and Drug Administration. The study captures real-world data using structured paper case report form (CRF) and a centralised electronic CRF (eCRF) platform, in accordance with standard operating procedure (SOP) for each core’s responsibility during the investigation.

Figure 1. Methodological overview of the PERSIA-HOCM study. FDA, Food and Drug Administration; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SRT, septal reduction therapy.

Study setting

The study is coordinated by Rajaie Cardiovascular Institute and is sponsored by Abidi Pharmaceutical Company, which provides operational and logistical support. There are currently 19 participating referral cardiovascular centres across major provinces of Iran, including tertiary and specialised heart centres located in (figure 2):

Figure 2. Provinces containing participating referral centres.

• Tehran: Rajaie Cardiovascular Institute, Masih Daneshvari Hospital, Imam Khomeini Hospital, Rasoul Akram Hospital, Imam Hossein Hospital, and Modarres Hospital.

• Shiraz: Kosar Hospital, Peyvand Center.

• Isfahan: Chamran Hospital.

• Tabriz: Madani Hospital.

• Urmia: Seyed-o-Shohada Hospital.

• Mashhad: Imam Reza Hospital, Ghaem Hospital.

• Kermanshah: Imam Ali Hospital.

• Yazd: Afshar Hospital.

• Ahvaz: Imam Khomeini Hospital.

• Rasht: Heshmat Hospital.

• Mazandaran: Rouhani Hospital and Fatemeh-Zahra Hospital.

Study governance and roles

The present study consists of five major steps. Every group of the operators and investigators has specific responsibilities:

1. Study design, protocol finalising and institutional review board approval: This includes SOP, CRF and study protocol drafting and proposal submission and mainly conducted by the principal investigators (online supplemental figure 1).

2. Prior to the national Mavacamten launch and distribution (the study’s initial point): In this stage, the sponsor, data quality and validation committee and associate investigators±centre coordinators are carefully involved. Training sessions, printing forms and documents, designing the quality check pathway, managing data access protocols and electronic software development were among major duties here (online supplemental figure 2).

3. Data gathering: Data collection will thoroughly be done involving the associate investigators supervised by the principal researchers and data quality checkers. Patient support committee will also be accounted for treatment adherence check and adverse outcome reports and recording vital patient data. The sponsor must pay attention to the supporting funding and employees’ salary in addition to the bi-weekly meetings held to talk about feedback and any adjudication needed for serious adverse reactions (online supplemental figure 3).

4. Data validation: Data quality and validation committee has the full responsibility in this step. Checking the missing data, quality assessment comparing paper CRFs and Electronic CRFs, re-evaluation of any outlier data and inform the primary investigator in the corresponding centre to explain what might happen to the patient data, handling feedback meetings, and taking care of edition requests by the collaborators asking them to explain their reasons for editing the previously filled CRFs comprises the key assignments in current stage (online supplemental figure 4).

5. Reporting study findings: Every 6 months during the 2-year study period, a statistical report will be published as a brief report. Principal investigators and data validation committee take care of this step. All outcomes and safety reports will be analysed. The ICJME authorship criteria will be the guide for the final drafted paper (online supplemental figure 5).

Eligibility criteria

Inclusion criteria

Participants will be eligible for enrolment if they meet all of the following criteria:

• Definite diagnosis of HOCM according to American Heart Association (AHA)/European Society of Cardiology (ESC) criteria, defined by a maximal left ventricular (LV) wall thickness ≥1.5 cm, or ≥1.3 cm in the presence of a positive family history of HCM.

• Age ≥18 years and body weight ≥45 kg.

• Symptomatic heart failure corresponding to NYHA functional class II or higher.

• LVOT gradient ≥50 mm Hg at rest or following provocation (eg, Valsalva manoeuvre).

Genetic assessments for pathogenic HCM-associated variants were not considered as entry requirement for study entry. This approach is consistent with AHA 2024 Guidelines, major mavacamten trials (eg, Explorer-HCM, Valor-HCM), and real-world inspired studies.^{2 11 17 20}

Exclusion criteria

Participants will be excluded if any of the following conditions are present:

• Baseline LVEF <55% on echocardiography at study entry.

• Diagnosis of non-obstructive hypertrophic cardiomyopathy (non-HOCM).

• Refusal or inability to provide written informed consent.

• Pregnancy, intention to become pregnant during treatment, or failure to use reliable contraception during treatment and for up to 4 months after the last dose of mavacamten.

• Concomitant use of strong CYP2C19 inhibitors, moderate to strong CYP3A4 inhibitors or moderate to strong CYP2C19/CYP3A4 inducers that cannot be discontinued or replaced according to the protocol (including but not limited to fluvoxamine, high-dose fluoxetine (>20 mg), clomipramine, imipramine, carbamazepine, phenytoin, phenobarbital, bosentan, dexamethasone, rifampin, primidone, voriconazole, ketoconazole, itraconazole, danazol, amiodarone, clarithromycin, erythromycin, ciprofloxacin, diltiazem, verapamil, isoniazid, omeprazole, esomeprazole, cimetidine, grapefruit extract and selected antiviral agents for HIV or hepatitis).

• Treatment with disopyramide or ranolazine within 14 days prior to study entry or during the study period.

• Concomitant use of cardiotoxic medications is considered clinically inappropriate when determined by the treating physician. Use of either a BB or a calcium-channel blocker (CCB) alone is permitted if the physician decides; however, simultaneous BB and CCB therapy during mavacamten treatment is prohibited when clinically inappropriate.

• SRT within 6 months prior to study entry or planned during the study period.

Per the study design, confirmed HOCM patients who are expected to begin mavacamten treatment and pass the study criteria will receive information about the study and be asked if they are willing to participate. If so, they will be recruited to the study.

Minimum required sample size for before-after studies was calculated using the formula developed by Machin et al publicly available at the MedCalc website. Using a before-after mean difference from a similar study by Desai et al,¹⁷ with 90% power and a 0.05 alpha, we estimated a minimum sample size of 23 patients. Anticipating a 20% loss to follow-up, the final sample size was adjusted to 30 patients. If the minimum sample size is not reached during the 1-year enrolment period, a 6-month extension will be added. Only after the additional time, if the minimum required sample size was not reached, the study would be terminated. However, based on the rule of thumb, principal senior investigators expect at least 100 patients to be recruited.

Mavacamten treatment

Mavacamten will be prescribed in accordance with the AHA 2024 guideline recommendations as a second-line therapeutic option in patients with obstructive HCM who remain symptomatic despite treatment with either a BB or a calcium channel blocker. Eligible patients will enter the study after providing written informed consent and will be enrolled into the baseline phase prior to treatment initiation. The initial dose of mavacamten, as defined in the study protocol, is 5 mg once daily, and the maximum permitted daily dose is 15 mg. Mavacamten will be available in capsule formulations of 2.5 mg, 5 mg, 10 mg and 15 mg to allow protocol-guided titration. The starting dose (mg/day) will be systematically documented in the CRF at baseline.

Mavacamten will be prescribed in routine clinical care in Iran and distributed through authorised channels affiliated with participating cardiovascular referral centres. In Iran, following the required regulatory approvals by the national food and drug administration and the ministry of health, Dr. Abidi Pharmaceutical Company has established the production line for mavacamten, and distribution will occur through authorised cardiovascular referral centres. Treatment initiation and continuation will follow established clinical judgement and guideline-based practice without protocol-driven intervention. Participating physicians will receive structured training in diagnostic criteria, therapeutic algorithms, principles of dose titration and standardised data recording procedures. Participants will be provided with a patient information booklet and an echocardiography visit tracking card. Regular follow-up will include clinical assessment and scheduled echocardiographic monitoring, with appointment reminders provided by telephone and text messages to ensure adherence. Treatment outcomes, safety parameters and dose modifications will be collected and reported periodically throughout the study.

Concomitant cardiovascular therapies will be comprehensively documented at study entry and throughout follow-up, including BBs, disopyramide, CCBs, ranolazine or hydralazine, sacubitril/valsartan, mineralocorticoid receptor antagonists and other relevant background treatments. This documentation will allow evaluation of potential pharmacologic interactions, adherence to protocol-defined medication constraints and assessment of real-world prescribing patterns alongside mavacamten therapy.

Treatment adjustment

Dose adjustments will be made based on the REMS protocol relying on patient response, safety issues, concomitant medications and metabolic interactions. In patients receiving a weak-to-moderate CYP2C19 inhibitor or a moderate-to-strong CYP3A4 inhibitor during the study period, treatment will be initiated at a reduced starting dose of 2.5 mg daily. If a strong CYP3A4 inhibitor or a moderate CYP2C19 inhibitor is introduced, the mavacamten dose will be reduced by one dose level in accordance with the protocol.

Medications requiring dose reduction or careful adjustment include sertraline, fluoxetine (≤20 mg), grapefruit extract, isoniazid, omeprazole, esomeprazole, cimetidine, verapamil, ciprofloxacin, erythromycin, methimazole, ketoconazole, itraconazole, danazol, diltiazem, clarithromycin, amiodarone and commonly used antiviral agents for HIV or hepatitis treatment. In all such cases, dosing decisions will be made according to protocol-defined guidance and clinical judgement. Any subsequent dose modifications will be recorded during follow-up visits in accordance with prespecified treatment guidance and clinical evaluation.

Study timeline and follow-up schedule

The study is conducted over 2 years, consisting of a 1-year recruitment period followed by an exact 1-year follow-up for each enrolled participant. This structure ensures that all patients will be prospectively observed for up to 12 months after initiation of mavacamten therapy. Participants undergo periodic clinical follow-up at approximately 4-week intervals. Echocardiographic assessments are scheduled at predefined time points, including weeks 4, 8, 12 and 24, with additional evaluations performed as clinically indicated or in accordance with protocol-defined requirements. These structured visits allow systematic monitoring of LV function, LVOT gradient and treatment response, as well as timely detection of safety signals. To enhance adherence to scheduled visits and minimise loss to follow-up, the Patient Support and Follow-up Committee maintains regular contact with participants through structured telephone calls and short message service reminders. Standardised call procedures will be implemented to reduce variability and potential reporting bias, and all patient-reported information will be documented systematically while preserving confidentiality.

Data sources and data collection procedures

Baseline data will be collected using the standardised baseline CRF and entered into both the paper CRF and the centralised electronic platform. At study entry, detailed demographic information will be recorded, including patient identification code, contact information, date of diagnosis and current NYHA functional class. Dominant symptoms such as dyspnoea, palpitations, chest pain, fatigue and peripheral oedema will be documented systematically.

A comprehensive medical history will be obtained, including prior cardiovascular and systemic conditions and relevant interventions. Trained investigators are responsible for collecting these data by asking patients closed-ended (yes/no) questions about conditions of interest. These include atrial fibrillation, syncope or presyncope, coronary artery disease, chronic kidney disease, hepatic dysfunction, prior stroke, sustained arrhythmias requiring hospitalisation, implantable cardioverter-defibrillator implantation, SRT and other clinically significant comorbidities. Family history of HCM and, if available, genetic test results will also be recorded.

Medication history at baseline will be documented in detail, including BBs, calcium-channel blockers, disopyramide, sacubitril/valsartan, Angiotensin-converting enzyme (ACE) inhibitors, Angiotensin receptor blockers (ARBs), diuretics, antiplatelet agents, anticoagulants and other relevant cardiovascular therapies. Particular attention will be given to drugs that affect the CYP2C19 and CYP3A4 pathways, with drugs classified as moderate or strong inhibitors or inducers according to predefined categories. Detailed inquiries aimed at harvesting these data from patients will also be closed-ended (yes/no) questions asked by the investigator.

Vital signs will be measured and recorded at enrolment, including height, weight, systolic and diastolic blood pressure (SBP/DBP), heart rate (HR) and respiratory rate (RR). Baseline echocardiographic parameters will be comprehensively documented. These include interventricular septal thickness, maximum LV wall thickness, left atrial (LA) volume index, LA diameter, LVEF, resting and provoked (Valsalva) LVOT gradients, presence of mitral regurgitation, LV end-diastolic and end-systolic volume indices and early diastolic mitral annular velocity. Laboratory investigations at baseline include complete blood count, renal function parameters (including blood urea nitrogen and creatinine), liver function tests (Aspartate Amino-transferase (AST), Alanine Amino-transferase (ALT), Alkaline Phosphatase (ALP)), NT-proBNP and cTn-I (with unit specification). Participating centres all use identical assays for cTn-I (quantitative fluorescence immunoassay) and NT-proBNP (electro-chemiluminescence immunoassay) measurements. Pregnancy status will be assessed through β-human chorionic gonadotropin testing prior to treatment initiation when applicable.

Although genetic testing or cardiac magnetic resonance (CMR) imaging was not required for enrolment, participants who had previously undergone testing for pathogenic HCM variants or CMR imaging, as well as those who chose to pursue either, were asked to bring their results for registration. Because genotype status and CMR imaging were only available for a subset of participants, associated outcomes with them were pre-specified as exploratory rather than main outcomes, detailed in table 1. The starting dose of mavacamten, expressed in milligrams per day, will be recorded at baseline. Concomitant therapies at treatment initiation will be documented in detail to allow assessment of potential interactions and background management strategies. In addition, a structured heart failure-specific quality of life questionnaire will be administered at baseline to establish a baseline reference for longitudinal assessment of symptom burden and functional status throughout follow-up.

Considering the operational limitations in the clinical settings of participating centres, real-time entry of data into the CRF electronic platform was not feasible across centres. To mitigate related risks while transcribing data, a standardised CRF paper, uniform in structure and format, is distributed across centres. Completed CRF papers are collected by the coordinator or associate investigator at the end of each clinical session and transcribed into the central electronic portal within 24 hours. All investigators and coordinators involved in gathering and transcribing the data are properly trained to reduce data variability. Original paper CRFs are kept at the originating centre in secure, access-controlled storage, remaining available for verification.

Follow-up visits and data collection

CRF components are briefly illustrated in figure 3. At each scheduled follow-up visit, excluding week 12 and month 12, data will be collected using the standardised follow-up CRF (V.1). Clinical status will be reassessed, including documentation of the NYHA functional class and vital signs such as SBP and DBP, HR and RR. Echocardiographic parameters will be recorded using the same core domains evaluated at baseline, including interventricular septal thickness, maximum LV wall thickness, LA volume index and diameter, LVEF, resting and provoked LVOT gradients, presence of mitral regurgitation, LV end-diastolic and end-systolic volume indices, and early diastolic mitral annular velocity.

Figure 3. Overview of CRF components. CRF, case report form.

Mavacamten treatment status will be reviewed at each visit. Any dose modification will be documented, including whether a change occurred, the updated daily dose, and the predefined reason for adjustment (such as AEs, reduction in LVEF, inadequate response according to guideline thresholds or symptom recurrence). Concomitant cardiovascular therapies will also be updated.

Since the previous visit, all hospitalisations have been recorded with their corresponding causes and dates. Vital status will be assessed systematically; if death has occurred, the date and primary cause of death will be documented. A structured adverse event checklist will be completed at every visit, covering cardiovascular events (eg, acute myocardial infarction, angina, atrial fibrillation), neurologic events (eg, stroke, syncope, altered level of consciousness), renal and hepatic dysfunction, gastrointestinal and respiratory symptoms, hypotension and other clinically important AEs.

At week 12 and month 12, data will be collected using the follow-up CRF (V.2), which includes all items recorded in V.1, as well as laboratory assessments and expanded patient-reported measures. Laboratory testing at these time points includes NT-proBNP and cTn-I, with units explicitly documented. Furthermore, a comprehensive heart failure–specific quality of life questionnaire will be administered to assess symptom burden, physical limitations, sleep quality, gastrointestinal symptoms and overall functional status.

In accordance with the study protocol, patient-reported domains will be captured longitudinally during follow-up. These include monthly self-reported perceptions and emotional states, such as worry, restlessness, hopelessness, perceived burden of illness, awareness of symptom triggers and warning signs, and overall life satisfaction. In addition, patients will be asked to report treatment-related costs incurred during the preceding month, enabling evaluation of the economic burden associated with therapy in real-world settings.

Outcomes

Safety outcomes include the frequency and type of AEs, the occurrence of SAEs, hospitalisations during follow-up and all-cause mortality. These events will be systematically captured at each follow-up visit and adjudicated according to predefined procedures. Symptom improvement will be evaluated through longitudinal assessment of the NYHA functional class, with particular emphasis on changes in class distribution over time relative to baseline. Echocardiographic outcomes include changes in LVOT gradients at rest and with provocation, LVEF, interventricular septal thickness, maximum LV wall thickness, LA volume index and diameter, LV end-diastolic and end-systolic volume indices, and early diastolic mitral annular velocity. Laboratory outcomes focus on longitudinal changes in NT-proBNP and cTn-I levels.

The Iranian Questionnaire to Assess Quality of Life in Patients with Heart Failure (IHF-QoL) will be the quality of life assessment tool in the present study. This previously validated questionnaire will assess changes in symptom burden, physical limitation, sleep quality and overall well-being and generate a final cumulative score well suited for the Iranian cases.²¹ Patients will be handed the questionnaire and asked to answer it themselves. In addition, treatment patterns and adherence proxies will be evaluated through systematic documentation of dose modifications and their underlying reasons, as well as follow-up attendance. Completion of scheduled CRF and records maintained by the Patient Support and Follow-up Committee serve as objective indicators of follow-up compliance and real-world adherence to therapy.

Since cardiopulmonary testing, cardiac magnetic resonance imaging (CMR) and HOCM genotyping were not available in all centres, we decided to assign them as exploratory outcomes. The physicians, case by case, will ask each modality to be done then data collectors will gather data on the corresponding reports, including pVO2, cardiac fibrosis indices and HOCM genotype, to be analysed in upcoming reports.

Data management and quality assurance

Data will be captured using a dual-entry system comprising a standardised paper CRF and a centralised online eCRF platform. For each enrolled participant, both formats will be completed in parallel to ensure data integrity and traceability. Source documents, including echocardiography reports and laboratory results, will be uploaded to the online platform as supporting documentation. Particular attention will be given to the clarity and legibility of handwritten reports to minimise transcription errors and misinterpretation.

Data access governance, confidentiality safeguards and authorship documentation will be overseen by the Data Quality and Validation Committee. Personal identifiers will be encoded to enable blinded analysis where applicable, and access to centre-level data will be restricted in accordance with predefined authorisation rules. All procedures comply with protocol-defined confidentiality standards and long-term data retention policies.

A structured validation plan is implemented throughout the study period. This includes weekly data-extraction checks to identify inconsistencies or logical errors, systematic comparisons between paper CRFs and corresponding eCRF entries and monthly evaluations of missing data by variable and by participating centre. Findings from these assessments will be communicated through performance feedback loops to individual centres to promote corrective action and continuous quality improvement.

Operational monitoring will be conducted through biweekly meetings between principal investigators, associate investigators and sponsor representatives to review recruitment rates, data quality indicators and protocol adherence. In addition, dedicated training sessions will be organised to reduce inter-observer variability, particularly in echocardiographic measurements, thereby enhancing the reliability and reproducibility of structural and functional cardiac assessments across centres.

Safety monitoring and medication adherence

Safety monitoring will be embedded within routine clinical follow-up and reinforced through structured patient education at study entry. All enrolled participants will be informed of potential AEs associated with mavacamten therapy and provided with clear instructions for reporting them. Patients will be encouraged to promptly communicate any new or worsening symptoms to the designated Patient Support and Follow-up Committee using the predefined contact channels.

Serious AEs will be subject to immediate reporting. On notification, the Patient Support and Follow-up Committee documents the event and promptly informs the principal investigators in accordance with protocol-defined procedures. Hospitalisations, life-threatening events, significant clinical deterioration and deaths will be handled with priority to ensure timely assessment and documentation.

All reported AEs and dose modifications undergo structured adjudication by the principal investigators. This adjudication framework evaluates the temporal relationship between the event and mavacamten exposure, the presence of alternative etiologies and consistency with known safety profiles. Dose adjustments related to safety concerns, including reductions, temporary interruptions or discontinuations, will be reviewed to ensure alignment with the predefined treatment algorithm and clinical guidelines.

The Medication Adherence Rating Scale (MARS) is a worldwide accepted questionnaire to evaluate how patients stick with their treatment regimen.²² It comprises 10 questions assessing the probable reasons for patient drug nonadherence. The Persian version was previously validated in the existing literature.²³ The patient support committee asks the questionnaire from each patient every month and meticulously records the answers.

Statistical analysis plan

Table 1 thoroughly describes the null and alternative hypotheses and the corresponding statistical tests. All statistical analyses will be performed according to a predefined analysis framework. Descriptive statistics will be used to summarise baseline characteristics and follow-up findings. Categorical variables will be presented as frequencies and percentages, whereas continuous variables will be reported as means and SD. The extent of missing data and loss to follow-up will be documented and considered in the interpretation of findings.

Pre- and post-treatment comparisons will be conducted for key clinical domains. Changes in NYHA functional class proportions over time will be evaluated using the McNemar test for paired categorical data. Longitudinal changes in echocardiographic indices, including LVOT gradients, LVEF and other structural or functional parameters, will be analysed using paired-sample t-tests. Similarly, laboratory indices such as NT-proBNP and cTn-I levels will be compared using paired-sample t-tests. Quality-of-life measures derived from the structured questionnaire will also be analysed using paired-sample t-tests to assess within-patient change over time. Safety analyses focus on descriptive reporting of the frequency and type of recorded AEs, including serious AEs, hospitalisations and mortality.

All statistical analyses will be performed using R software (V.4.5.1). A two-sided p-value of less than 0.05 will be considered statistically significant. Interim analyses are planned at 6-month intervals over the 2-year study period, with reporting format and dissemination strategy determined according to the predefined plan established by the Data Quality and Validation Committee.

Patient and public involvement

Patient involvement in this study will be operationally defined as follow-up support and structured communication, rather than participation in study design or methodological development. The Patient Support and Follow-up Committee plays an active role in maintaining regular contact with enrolled participants, facilitating appointment reminders, responding to patient inquiries and systematically documenting patient-reported symptoms and AEs. This structured interaction enhances adherence to scheduled visits and improves completeness of longitudinal data capture.

In accordance with the Standard Operating Procedure, the committee’s role will be limited to support, follow-up coordination and accurate recording of patient-reported information. Patients and public representatives will not be involved in the co-design of study objectives, methodology, statistical planning or outcome selection. The scope of involvement will therefore be supportive and operational, aimed at ensuring data quality, monitoring safety and maintaining follow-up continuity within the study’s real-world framework.

Study status

The study will be conducted in accordance with the approved protocol, V.1, as outlined in the Standard Operating Procedure and Study Protocol documents. The project is designed as a prospective multicentre observational study and is currently being implemented in accordance with the predefined governance and operational framework. The recruitment period spans 1 year, during which eligible patients with hypertrophic obstructive cardiomyopathy will be enrolled across participating centres. Each enrolled participant will be followed for 1 year after initiation of mavacamten therapy. Accordingly, the total study duration will be 2 years, comprising 1 year of recruitment and 1 year of follow-up per participant.

Discussion

Cardiac myosin inhibition has redefined the therapeutic rationale in HOCM by targeting the proximal sarcomeric driver of hypercontractility rather than providing solely downstream symptomatic relief.²⁴ Mavacamten, a selective cardiac myosin inhibitor, reduces actin–myosin cross-bridge formation and thereby attenuates dynamic LVOTO. This mechanism is directly aligned with the haemodynamic substrate underlying exertional dyspnoea, exercise limitation and heart failure symptoms in HOCM.^{25 26}

Randomized Clinical Trials (RCTs) constitute the principal evidence base supporting the efficacy and safety of mavacamten, although they are conducted under stringent inclusion criteria, intensive monitoring and protocolised dose titration. In EXPLORER-HCM, mavacamten improved clinical status and patient-reported outcomes while significantly reducing LVOT gradients in symptomatic HOCM under controlled trial conditions.²⁷ In VALOR-HCM, mavacamten reduced the proportion of patients who continued to meet guideline criteria for or elected SRT, supporting its role as a noninvasive therapeutic option for individuals otherwise approaching invasive intervention.¹⁵ Long-term follow-up and extension data indicate sustained reductions in LVOT gradients and durable symptomatic benefit, while confirming that transient and reversible reductions in LVEF may occur in a minority of patients, necessitating structured surveillance and dose adjustment.^{20 28}

Despite these robust RCT findings, important limitations in external validity remain. Patients encountered in routine clinical practice may differ substantially from trial populations in terms of comorbidity burden, polypharmacy, including CYP-mediated interaction risk, access to specialised monitoring and variability in echocardiographic acquisition and interpretation. Emerging observational cohorts have reported effectiveness and safety outcomes broadly consistent with RCT data, including improvements in symptoms and LVOT obstruction with low rates of serious AEs. However, prospective and systematically collected real-world evidence remains limited, particularly in underrepresented regions and heterogeneous health systems.

The objective of the PERSIA-HOCM study is to provide evidence on the use of mavacamten in HOCM on a prospective basis in a region-specific setting. Although there has been convincing evidence of the efficacy of mavacamten from pivotal randomised clinical trials, the actual experience in practice includes much wider patient populations with varying degrees of concomitant disorders and polypharmacy as well as different capabilities of monitoring patients. This ongoing multicentre cohort will be able to investigate important aspects that still remain unclear and underexplored beyond trials: prescribing and dose titration of the drug in routine clinical practice, the frequency and rationale for dose modifications and interruption of treatment, the possibility of implementing systematic assessments of LVOT physiology and systolic function and comprehensive data capture on safety events and patient-reported outcomes. The study will help to determine whether the benefits of the treatment reported in clinical trials can be confirmed on a regular practice basis and what factors associated with implementation of cardiac myosin inhibition should be considered in this regard.

In conclusion, it can be stated that there is now convincing evidence provided by RCTs and other studies that suggest that mavacamten is a safe and efficacious target-directed pharmacological agent for symptomatic HOCM. However, more evidence on implementation, monitoring and outcomes of the treatment is needed. In the context of the Middle Eastern health system, PERSIA-HOCM will help to understand real-life evidence of mavacamten and integrate the approach into management pathways for HOCM.

Ethics and dissemination

Ethics approval

The study is conducted in accordance with national research regulations and ethical standards governing observational clinical studies. Approval from the national medical ethics committee and the institutional review board was obtained prior to initiation of patient enrolment, in line with national regulatory instructions and institutional requirements (Code: IR.RHC.REC.1404.210).

Informed consent

Before enrolment, each eligible patient will attend a private consultation with a trained investigator or centre coordinator at the participating centre. In this meeting, the nature and aims of the study, the voluntary nature of participation, the personal and clinical data to be collected, data gathering and registration procedures, follow-up requirements, and the patient’s right to withdraw at any point without affecting their clinical care will be explained thoroughly. Moreover, patients will be given a patient information sheet that summarises this information in plain language.

After the session, patients are given a full week to consider participation before providing the written informed consent. Consent will be documented on a signed and dated form retained at the participating centre, in accordance with the requirements of Research Ethics Committee of Rajaie Cardiovascular, Medical and Research Institute and Iran National Committee for Ethics in Biomedical Research.

Confidentiality

Centralised eCRF platform, currently under development, per discussions and a signed contract between the study sponsor and the software design team, is expected to ensure robust security and traceability. The software will be hosted on a secure local server. Data encryption will be implemented to ensure privacy, prevent data breaches and protect against unauthorised access or interception during transit or storage. Unique usernames and passwords will be generated for any person who has access rights to the software. Moreover, the access level granted to anyone will be dependent on their role. For instance, only the quality check committee and the committee in charge of conducting analysis will have access to generate and extract aggregate data. Each user accesses the system through unique credentials, and an automated audit log will record all logins and logout events, data additions, edits, and deletions, along with user identity, timestamp, and the reason for any corrections. Original values will be retained in the log to preserve a complete version history of each record. Adjustments between paper CRF and eCRF records, explained earlier, will be similarly recorded in the log to preserve traceability of the data and validation.

Dissemination plan

Interim analyses will be conducted at 6-month intervals over the 2-year study period. The format and scope of interim reporting will be determined by the responsible committees in accordance with the predefined study plan. Upon completion of follow-up, a final manuscript will be prepared for submission to peer-reviewed international journals. In addition, study findings will be disseminated through national and international scientific conferences in accordance with the publication and reporting strategy established by the study governance framework.

Data availability statement

Data are available upon reasonable request.