Adaptive clinical trial with pharmacokinetic-guided optimization of weight-based oral montelukast dose in children with acute asthma exacerbations

Background: Children with acute asthma exacerbations are frequently hospitalized due to insufficient response to inhaled β-agonist and systemic corticosteroid treatments. Leukotriene (LT) mediated airway inflammation does not respond to these medications and contributes to insufficient clinical response that often necessitates hospitalization. Montelukast (MK) is a potent LT receptor antagonist, and IV MK caused rapid clinical improvement in adults with exacerbations, though the IV form is not FDA approved or currently available. Methods: This is a phase 2, adaptive, double-masked RCT of high-dose oral MK, with escalating mg/kg dose levels informed by PK-guided modeling, added to standard treatment versus standard treatment alone, in children with exacerbations that are moderate or severe after initial treatment with inhaled albuterol. Study hypotheses are that-High-dose oral MK achieves peak plasma levels (Cmax)>1,700 ng/ml in >86% of at least one of three sequential participant groups with escalating weight-based (mg/kg) doses between groups; participants randomized to high-dose oral MK have a 2 point or greater improvement of the validated acute asthma intensity research score (AAIRS) at 4 hours post-treatment in comparison with control group participants; and among MK recipients, Cmax correlates with change of the AAIRS at 4 hours, after adjustment for pre-treatment exacerbation severity, respiratory viral detection, and systemic LT stress measured using plasma LTE4. Conclusions: This research will provide critical data for dosing and design decisions for a future randomized trial sufficiently powered to definitively determine efficacy in this population. Trial Registration: NCT 05819541.