Dose escalation clinical trial of high-dose oral montelukast to inform future RCT in children with acute asthma exacerbations

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PROJECT SUMMARY The goal of this R34 proposal and the future R61/R33-funded RCT is to decrease the severity of moderate and severe acute asthma exacerbations in children, sufficiently and quickly enough to decrease hospitalizations. These hospitalizations disproportionately affect Black and low-income children. They often occur because leu- kotriene (LT) induced airway inflammation and bronchoconstriction are incompletely responsive to systemic corticosteroid (CCS) and inhaled albuterol. LT synthesis is induced by viral respiratory infections and aeroaller- gens, the most common exacerbation triggers in children. We have a critical clinical need for a medication that will rapidly decrease LT-mediated airway inflammation and bronchoconstriction. Montelukast (MK), a potent LT-receptor antagonist, may address this need. IV MK caused rapid, sustained improvement at peak plasma levels (Cmax) of ≈1,700 ng/ml in adults with moderate and severe exacerbations. IV MK is not available, and our preliminary pharmacokinetic (PK) study in children with exacerbations found that high-dose oral MK (mean 1.0 mg/kg) achieves Cmax of 1,700 ng/ml in 40% of participants. The R34 Aim is to perform an adaptive, PK- guided, double-masked RCT of standard treatment plus high-dose oral MK or identical placebo, with 3 escalat- ing mg/kg MK dose-levels determined by PK-guided dose modeling, in children with exacerbations that are moderate or severe after initial treatment with albuterol. We will test three Hypotheses (1) High-dose oral montelukast achieves 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; (2) Participants randomized to high-dose oral monte- lukast have a 2 point or greater improvement of the validated Acute Asthma Intensity Research Score (AAIRS) 4 hours post-treatment in comparison with control group participants; and (3) Among montelukast recipients, Cmax correlates with change of the AAIRS at 4 hours. This R34 research will yield essential and sufficient knowledge to make definitive design decisions for a Phase II RCT (R61-R33 funded), adequately powered for important clinical outcomes. The future RCT will test the hypothesis that the optimal mg/kg MK dose identified in this R34 research improves outcomes as an additional anti-inflammatory and bronchodilator medication in children with moderate and severe exacerbations. The overall Contribution of this research will be to identify an optimal mg/kg dose of oral MK for the future RCT. The Significance of this R34 research and of the future RCT is that high-dose oral montelukast will provide a critically needed medication for exacerbations to decrease the morbidity of this common illness. This research is Innovative by (1) Identifying an optimal mg/kg dose for the future RCT; (2) Providing preliminary efficacy and dose-response data; and (3) Repurposing an inexpensive drug in a novel way to address an unmet need in children with asthma exacerbations. Completion of this re- search will yield knowledge to decrease the morbidity and health burden of asthma exacerbations in children.