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

MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies (MEKinRAS) - Randomized Controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Cardiomegaly; Noonan Syndrome
• Intervention / Treatment: Drug: Trametinib tablet; Drug: Standard therapy

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 Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Maciej Kołodziej, MD; Phone Number: 22-317-95-37; Email: maciej.kolodziej@wum.edu.pl
• Study Contact Backup: Name: Halszka Kamińska, MD; Phone Number: 22-317-9444; Email: halszka.kaminska@wum.edu.pl

Study Locations

• Poland
  • Warsaw, Poland, 02-091
    • Recruiting
    • Department of Paediatrics, The Medical University of Warsaw, Poland
    • Contact: Halszka Kamińska, MD; Phone Number: 22-317-9444; Email: halszka.kaminska@wum.edu.pl
    • Contact: Maciej Kołodziej, MD; Phone Number: 223179535; Email: maciek.kolodziej@gmail.com
    • Principal Investigator: Maciej Kołodziej, MD
    • Sub-Investigator: Hlaszka Kamińskia, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trametynib; Trametynib in 0,025mg/kg dose orally once daily	Drug: Trametinib tablet; Trametynib orally once daily in 0,025mg/kg dose
Active Comparator: Standard therapy; Disopiramide and Beta-blocker orally	Drug: Standard therapy; Disopiramide and Beta blockers orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effectiveness of the trametynib treatment on cardiac hyperthropy	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.	1 year
Effectiveness of the trametynib treatment on laboratory enzymes levels	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.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MEK kinase activity	Assessment of MEK kinase activity before treatment and after 6 months of its duration, in the patients' blood samples	6 months
Effectivness of the trametynib treatment assessed in the cardia magnetic resonance	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)	1 year

Collaborators and Investigators

• Sponsor: Medical University of Warsaw
• Investigators: Principal Investigator: MAciej Kołodziej, MD, Medical University of Warsaw

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: August 12, 2024
• First Submitted That Met QC Criteria: August 12, 2024
• First Posted (Actual): August 15, 2024

Study Record Updates

• Last Update Posted (Actual): August 15, 2024
• Last Update Submitted That Met QC Criteria: August 12, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Children; Cardiomyopathy; Noonan syndrome; MEK kinase; RASOpathies
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Musculoskeletal Diseases; Connective Tissue Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomegaly; Cardiomyopathy, Hypertrophic; Noonan Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: KB/16/2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No