RAS/MAPK pathway modulation with simvastatin in children with Noonan syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

Background: Noonan syndrome (NS) is a relatively common developmental disorder caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, leading to multisystem involvement including short stature, skeletal abnormalities, cardiac defects, and neurocognitive impairment. Preclinical studies suggest that statins attenuate RAS/MAPK pathway hyperactivation and improve neurocognitive deficits, growth impairment, and survival in experimental models. However, no randomised controlled trial has evaluated the efficacy and safety of statin therapy in children with NS. We aimed to evaluate the efficacy and safety of simvastatin in children with NS. Methods: In this national, multicentre, double-blind, placebo-controlled phase 3 trial conducted across 13 French centres, children aged 6-15 years with genetically confirmed NS and growth impairment were randomly assigned (1:1) to receive oral simvastatin (10 mg/day during month 1, 20 mg/day during month 2, then 20 or 40 mg/day according to age) or matching placebo once daily for 12 months. The primary outcome was the change in serum insulin-like growth factor 1 (IGF-1) levels. Secondary outcomes included growth, bone, cardiac, metabolic, and behavioural parameters. Analyses followed the intention-to-treat principle using mixed-effects and adjusted regression models. The trial was prospectively registered at ClinicalTrials.gov (NCT02713945). Findings: Fifty-three children were randomised (26 simvastatin, 27 placebo), and 49/53 (92.5%) completed the study. After 12 months, simvastatin did not significantly improve IGF-1 levels compared with placebo (between-group difference -0.08 log ng/mL, 95% CI -0.18 to 0.01; p = 0.08). No differences were observed between groups for height, growth velocity, bone mineral density, metabolic measures, or behavioural outcomes. Simvastatin was associated with lower circulating Dickkopf-related protein 1 (DKK1) concentrations (-0.27, 95% CI -0.52 to -0.01; p = 0.04), a biomarker of bone metabolism, and a higher ratio of early-to-late diastolic mitral annular velocity (Ea/Aa ratio) (0.27, 95% CI -0.004 to 0.55; p = 0.05), an echocardiographic parameter related to left ventricular diastolic function. However, these isolated findings were of borderline statistical significance, and were not accompanied by corresponding clinical improvements. Treatment was generally well tolerated. One serious adverse event occurred in the simvastatin group and was considered doubtfully related to study treatment. Interpretation: In children with NS, 12 months of simvastatin did not result in significant improvements in the primary endpoint or in major outcomes of clinical relevance under the conditions tested. Changes in DKK1 concentrations and the Ea/Aa ratio should be interpreted cautiously as exploratory secondary findings requiring confirmation in adequately powered studies. Further research is needed to explore alternative treatment strategies and more direct approaches to RAS/MAPK pathway modulation. Funding: French Ministry of Health.