MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies

Phase 2

Recruiting

• Conditions: Cardiomegaly; Noonan Syndrome
• Interventions: Drug: Trametinib tablet; Drug: Standard therapy

• Registration Number: NCT06555237
• Lead Sponsor: Medical University of Warsaw

Brief Summary

The goal of this study is to evaluate the effectiveness of trametinib treatment in patients with Hyperthropic cardiomyopathy and a genetic mutation in the RAS/MAPK pathway.

Detailed Description

Introduction RASopathies are a group of genetic diseases caused by mutations in the mitogen-activated kinase (RAS-MAPK) pathway. These mutations affect many processes and are the cause of numerous genetic syndromes (including Noonan syndrome) in the course of which severe hypertrophic cardiomyopathy (HCM) develops. MEK kinase inhibitors are used to treat cancers with mutations in the RAS-MAPK pathway in adults. So far, single cases of HCM treatment in patients with RASopathies have been described, with rapid improvement in both laboratory and echocardiographic parameters and regression of myocardial hypertrophy. Due to the described effectiveness, it is reasonable to verify these effects in a well-designed randomized study on a large group of patients.

Objective To evaluate the effectiveness of trametinib treatment in patients with HCM and a genetic mutation in the RAS/MAPK pathway.

Methodology

Randomized, open-label study. The study will include patients aged 0 to 18 with:

* mutation in the RAS/MAPK pathway confirmed by genetic tests

* HCM diagnosed by echocardiography

In the first phase of the study (3 months), patients will be randomly assigned to one of two groups:

* the intervention group will receive trametinib and standard treatment (beta-blocker and disopyramide)

* the control group will receive only standard treatment. Once this phase is complete, patients will be assessed. If higher effectiveness is demonstrated in the intervention group, in the second phase of the study, patients in the intervention group will continue their current treatment and patients in the control group will receive trametinib treatment. Each group will receive trametinib for 12 months.

Importance of the study The study results will provide grounds for routine introduction of MEK kinase inhibitors for the treatment of patients with HCM due to RASopathy. If effectiveness is demonstrated, this group will gain a simple, non-invasive and causal treatment option.

Study Timeline

• Status Verified: 2024-08
• Study Start: 2024-08-01
• Study First Submitted: 2024-08-12
• Study First Submitted QC: 2024-08-12
• Last Update Submitted: 2024-08-12
• Study First Posted: 2024-08-15
• Last Update Posted: 2024-08-15
• Primary Completion: 2026-08-01
• Study Completion: 2026-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• patient with diagnosed RASopathy
• patient with diagnosed hypertrophic cardiomyopathy
• signed innform consent

Exclusion Criteria

• contraindications to treatment with propranolol (drug hypersensitivity, atrioventricular block, severe bradycardia) disopyramide (drug hypersensitivity, WPW syndrome, atrioventricular block, QT prolongation) trametinib (drug hypersensitivity)
• lack of consent of the child's guardians to participate in the study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Trametynib	Trametinib tablet	Trametynib in 0,025mg/kg dose orally once daily
Standard therapy	Standard therapy	Disopiramide and Beta-blocker orally

Primary Outcome Measures

Name	Time	Method
Effectiveness of the trametynib treatment on cardiac hyperthropy	1 year	Reduction of cardiac hypertrophy and/or LVOTO at 6 and 12 months of treatment and at 3 months of follow-up after treatment discontinuation using echocardiographic examination.
Effectiveness of the trametynib treatment on laboratory enzymes levels	1 year	Decrease in cardiac enzyme levels (NT-pro-BNP and high-sensitivity troponin I) determined in the 6th and 12th month of treatment and in the 3rd month of observation after its discontinuation.

Secondary Outcome Measures

Name	Time	Method
MEK kinase activity	6 months	Assessment of MEK kinase activity before treatment and after 6 months of its duration, in the patients' blood samples
Effectivness of the trametynib treatment assessed in the cardia magnetic resonance	1 year	reduction of cardiac hypertrophy in magnetic resonance imaging in the age group of 7-18 years not requiring general anesthesia (comparison of results before inclusion in the study, after 12 months of trametinib treatment and after the end of follow-up after its discontinuation)

Trial Locations

Locations (1)

Department of Paediatrics, The Medical University of Warsaw, Poland; 🇵🇱 Warsaw, Poland