BabyMERIT Trial to Test Trametinib for Severe Infantile Hypertrophic Cardiomyopathy

Researchers at the Icahn School of Medicine at Mount Sinai will lead a national clinical trial evaluating whether trametinib can improve outcomes in infants with Noonan syndrome or closely related RASopathies who develop severe hypertrophic cardiomyopathy and heart failure. The National Heart, Lung, and Blood Institute, part of the National Institutes of Health, awarded Mount Sinai $946,567 for the first year of the BabyMERIT trial, with recommended costs of approximately $4.06 million over six years if subsequent phases are approved. The prospective study will be conducted through the NIH-funded Pediatric Heart Network and is designed to assess a targeted therapy for a rare, life-threatening condition; the funding award and planned trial do not establish that trametinib is safe or effective.

Noonan syndrome and related genetic disorders, collectively known as RASopathies, involve changes in the RAS-MAPK signaling pathway, which has an important role in cell growth and development. Cardiovascular abnormalities occur in 80% to 90% of people with Noonan syndrome, and hypertrophic cardiomyopathy is present in approximately 20%. The condition causes the heart muscle to become abnormally thick, and some infants develop severe disease and heart failure early in life.

BabyMERIT focuses on this severe infantile presentation rather than on the full spectrum of Noonan syndrome or all forms of hypertrophic cardiomyopathy. The trial addresses an urgent need for prospective evidence on treatment options for infants with RASopathy-associated hypertrophic cardiomyopathy. Investigators said the study builds on evidence that targeting the RAS-MAPK pathway may improve the cardiac condition, while emphasizing that the new study is needed to evaluate both potential benefits and risks.

The project is also intended to establish clinical and data-coordination infrastructure for examining a condition that can make affected infants critically ill very early in life. Standardized collection of cardiac imaging, biomarker data and clinical outcomes across participating centers will allow investigators to study the disease systematically. Mount Sinai will serve as the BabyMERIT Clinical Coordinating Center, while Carelon Research/New England Research Institutes will serve as the Data Coordinating Center.

The latter organization has received NIH funding totaling more than $4.43 million over six years. Together, the awards provide more than $8.5 million for the trial’s clinical and data-coordination infrastructure. Bruce D. Gelb, MD, of Mount Sinai, and Jane W. Newburger, MD, MPH, of Boston Children’s Hospital, are the Clinical Coordinating Center principal investigators.

Their work with the Pediatric Heart Network will support collaboration among centers across the United States and coordinated collection of data on treatment effects and safety. Researchers plan to enroll 25 infants in the prospective treatment arm. Eligible participants must be older than 28 days and younger than six months and must have Noonan syndrome or a closely related RASopathy, hypertrophic cardiomyopathy and severe heart failure requiring hospitalization.

The small planned sample reflects the specialized nature of the group being studied, and the investigators will document adverse events as well as potential changes in heart function and disease-related outcomes. BabyMERIT will use a single-arm, open-label design, meaning that all 25 enrolled infants will receive trametinib and both participants and clinicians will know the treatment being given. Researchers will compare the prospective treatment arm with a real-world evidence cohort of approximately 100 infants who received standard-of-care treatment between 2015 and the study period.

The comparison group is not described as a randomized control group. Although the design can provide structured prospective information about treated infants, the absence of concurrent randomization and the use of an open-label regimen will be important considerations when interpreting differences between the treatment arm and the historical real-world cohort. Infants in the treatment arm will receive trametinib for 12 months and then enter observation for up to 12 additional months to monitor for relapse.

Infants whose disease relapses may be eligible for retreatment for up to another 12 months. The primary endpoint is a composite of death, heart transplantation or septal myectomy by 12 months. Septal myectomy is open-heart surgery used to treat hypertrophic cardiomyopathy.

The composite therefore combines three outcomes—mortality, the need for a heart transplant and the need for surgery—rather than providing a single continuous measure of cardiac function. The planned observation period will also show whether cardiac disease returns after the initial treatment course and how infants respond if they are treated again. In addition to the primary endpoint, researchers will assess heart function, heart failure, biomarkers, relapse, response to retreatment and adverse events.

Cardiac imaging and biomarker testing will receive centralized review through Pediatric Heart Network core laboratories, supporting consistent evaluation across participating sites. Participants will also be monitored closely for potential adverse effects involving the skin, eyes and heart, as well as changes in blood counts and kidney, liver or thyroid function. This surveillance will provide information about both the course of the heart condition and the broader safety profile of trametinib in infants younger than six months.

The scientific question is whether inhibiting signaling in the molecular pathway implicated in RASopathies can change the course of severe hypertrophic cardiomyopathy in infancy. BabyMERIT is a test of a precision-medicine approach, not an established treatment, and the announcement does not report enrollment results, treatment responses, survival data or evidence of efficacy. Its small treatment arm and nonrandomized historical comparison will limit the strength of conclusions that can be drawn if the groups differ in ways beyond treatment.

Results will depend on completion of treatment, follow-up and analysis of the specified endpoints. Even so, the trial will provide prospective clinical and safety data intended to guide future research and care for infants with this rare RASopathy-associated condition.

Subject of Research: A national single-arm trial of trametinib for severe hypertrophic cardiomyopathy in infants with Noonan syndrome and related RASopathies

Article Title: Mount Sinai to lead national trial of targeted therapy for infants with noonan syndrome and severe hypertrophic cardiomyopathy

Article References: Mount Sinai to lead national trial of targeted therapy for infants with noonan syndrome and severe hypertrophic cardiomyopathy. Original publication (Bibliographic details unavailable.)

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Keywords: BabyMERIT trial, trametinib, Noonan syndrome, RASopathies, hypertrophic cardiomyopathy, infant heart failure, RAS-MAPK pathway, Pediatric Heart Network, precision medicine, clinical trial, Mount, Sinai