HCM, Heart Failure (Pediatric), Noonan Syndrome and Other Rasopathy
Conditions
Keywords
Noonan Syndrome, RAS-HCM, RASopathy, Heart failure, trametinib, MEK inhibitor
Brief summary
This project seeks to perform a Phase 3 clinical trial to test whether an FDA-approved cancer drug called trametinib is effective in treating young infants with genetic conditions called RASopathies and a severe, life-threatening heart problem called hypertrophic cardiomyopathy. The purpose of this research is to demonstrate that trametinib is effective in preventing these sick babies from dying, receiving a heart transplant or undergoing heart surgery to remove extra heart muscle over a one-year period. In addition, the investigators will determine how often this heart problem comes back when the trametinib treatment is stopped.
Interventions
DRUGTrametinib
Participants will begin 0.025 mg/kg of oral trametinib once daily for up to 12 months. Dose will be adjusted for weight at each study visit. A 12-month surveillance phase follows cessation of treatment. If the participant experiences a RAS-HCM relapse during the surveillance phase, they will restart oral trametinib once daily for up to 12 additional months.
Sponsors
Carelon Research
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Echocardiographic studies will be reviewed centrally by the Echocardiography Core Laboratory at Boston Children's Hospital under a workflow that blinds the reader to treatment assignment and participant identity.
Eligibility
Sex/Gender
ALL
Age
28 Days to 6 Months
Healthy volunteers
No
Inclusion criteria
* Molecular genetic diagnosis of a RASopathy signaling through the RAS/MAPK pathway as identified by molecular assays performed in a Clinical Laboratory Improvements of 1988 (CLIA) or similarly certified laboratories. Qualifying genotypes will included variants in any gene causing Noonan, Costello or cardiofaciocutaneous syndrome curated as pathogenic or likely pathogenic and consistent with the genetic mechanism (i.e., one allele in genes acting in an autosomal dominant manner and two alleles in trans for the autosomal recessive form of LZTR1-related Noonan syndrome). * Diagnosis of HCM, as defined by LV and interventricular septal wall thickness with a z-score \> 2 by echocardiography * Age ≥ 28 days and ≤ 6 months * Ross classification of HF of III or IV * Hospitalization * In the opinion of the site investigator, ability to comply with study protocol requirements * Signed informed consent for the trial by a parent or legal guardian
Exclusion criteria
* PTPN11 pathogenic/likely pathogenic variants causing NSML * Prior treatment with a MEK inhibitor * Requiring treatment with strong inhibitors of CYP2C19 and CYP3A4, strong inducers of CYP3A4, and substrates of CYP2C9 with a narrow therapeutic index * Platelet count \< 50,000/µL * Neoplastic disorder requiring treatment (e.g., juvenile myelomonocytic leukemia)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to first occurrence of death, heart transplantation, or LV septal myectomy to relieve LV outflow tract obstruction | From qualifying hospital admission through 12 months after the qualifying hospital admission | This is a composite time-to-event outcome. An event is defined as the first occurrence of any of the following: death, heart transplantation, or LV septal myectomy to relieve LV outflow tract obstruction. For participants experiencing more than one component event, only the first event contributes to the primary endpoint. Participants who do not experience any component event are censored according to the prespecified analysis rules. The treatment arms will be compared using Kaplan-Meier methods and the log-rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time from qualifying hospital admission to death | From qualifying hospital admission through 12 months after the qualifying hospital admission | Time-to-event outcome defined as the time from the qualifying hospital admission to death from any cause. Participants who do not experience death during the assessment period will be censored according to the prespecified analysis rules. Treatment arms will be compared using Kaplan-Meier methods and the log-rank test. |
| Change from baseline in LV posterior wall thickness z-score at 12 months | Baseline and 12 months after qualifying hospital admission | Change in LV posterior wall z-score from baseline to 12 months. The change is calculated as the 12-month LV posterior wall z-score minus the baseline LV posterior wall z-score. Treatment groups will be compared using ANCOVA with treatment group as a fixed factor and baseline z-score as a covariate. All measurements and z-scores performed centrally at the Boston Children's Hospital Echocardiography Core Lab. |
| Ross class at 12 months | 12 months after qualifying hospital admission | Ross class is an ordinal measure with 4 categories (Class I-IV), with higher classes indicating greater severity of heart failure symptoms. Ross class at 12 months will be compared between the treatment arms using an ordinal regression model adjusted for baseline Ross class. |
| Change from baseline in log-transformed BNP at 12 months | Baseline and 12 months after qualifying hospital admission | Change in log-transformed BNP from baseline to 12 months. The change is calculated as the 12-month value minus the baseline value. Treatment groups will be compared using ANCOVA with treatment group as a fixed factor and baseline log-transformed BNP/NT-proBN as a covariate. |
| Time to first occurrence of death, heart transplantation, or LV septal myectomy to relieve LV outflow tract obstruction | From qualifying hospital admission through 24 months after the qualifying hospital admission | This is a composite time-to-event outcome. An event is defined as the first occurrence of any of the following: death, heart transplantation, or LV septal myectomy to relieve LV outflow tract obstruction. For participants experiencing more than one component event, only the first event contributes to the primary endpoint. Participants who do not experience any component event are censored according to the prespecified analysis rules. The treatment arms will be compared using Kaplan-Meier methods and the log-rank test. |
| Relapse-related (descriptive) | from hospitalization till 24 months of follow-up | frequency, timing, and nature of HCM relapse after trametinib cessation; echocardiographic and clinical factors at relapse; response of relapsed RAS-HCM to restarting trametinib over 12 months. |
| Trametinib-related adverse events | from hospitalization till 24 months of follow-up | type, severity (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade), expectedness, and relationship of all AEs and SAEs to trametinib, with focused listings for dermatologic, ophthalmologic, and cardiac AEs |
Outcome results
None listed