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

Medical University of Warsaw

Status and phase: Enrolling; Phase 2

Conditions: Cardiomegaly; Noonan Syndrome

Treatments: Drug: Standard therapy; Drug: Trametinib tablet

Study type: Interventional

Funder types: Other

Identifiers

NCT06555237

KB/16/2024

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: 1 day to 18 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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40 participants in 2 patient groups

Trametynib

Experimental group

Description:

Trametynib in 0,025mg/kg dose orally once daily

Treatment:

Drug: Trametinib tablet

Standard therapy

Active Comparator group

Description:

Disopiramide and Beta-blocker orally

Treatment:

Drug: Standard therapy