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

项目总结 这项R34提案和未来由R61/R33资助的RCT的目标是降低中度和 儿童的严重急性哮喘恶化，足以和足够快地减少住院人数。 这些住院治疗对黑人和低收入儿童的影响不成比例。它们经常发生是因为亮氨酸- 高三烯(LT)诱导的呼吸道炎症和支气管收缩对全身反应不完全 皮质类固醇(CCS)和吸入沙丁胺醇。它的合成是由病毒呼吸道感染和空气污染诱导的- 在儿童中，最常见的恶化诱因。我们在临床上非常需要一种药物 会迅速减轻LT介导的呼吸道炎症和支气管收缩。孟鲁司特(Montelukast)，一种有效的 受体拮抗剂，可以解决这一需要。静脉注射MK导致血浆峰值快速、持续改善 中度和重度恶化的成人的≈水平(Cmax)为1,700 ng/ml。IV MK不可用，并且 我们对急性加重期儿童的初步药代动力学(PK)研究发现，大剂量口服MK(平均 1.0 mg/kg)可使40%的受试者的Cmax达到1700 ng/ml。R34的目标是执行自适应的PK- 标准治疗加大剂量口服MK或相同安慰剂的引导双掩蔽RCT，3次升级- 通过PK引导剂量模型确定的ING mg/kg MK剂量水平，用于患有 沙丁胺醇初始治疗后的中度或重度。我们将检验三个假说(1)高剂量口服 孟鲁司特在至少三个连续参与者组中的至少一个中达到Cmax&>1700 ng/ml 以体重为基础的剂量(mg/kg)在组之间递增；(2)参与者被随机分为高剂量口服蒙脱尔组- 卢卡斯特在有效的急性哮喘强度研究评分(AAIRS)上有2分或更多的改善 与对照组参与者相比，治疗后4小时；以及(3)在孟鲁司特接受者中， CMAX与AAIRS在4h的变化相关。这项R34研究将产生必要的和充分的 为第二阶段RCT(R61-R33资助)做出最终设计决策的知识，并为 重要的临床结果。未来的随机对照试验将检验这样一种假设，即确定的最佳MK剂量为 在这项R34研究中，作为一种额外的抗炎和支气管扩张剂药物，在 患有中度和重度恶化的儿童。这项研究的总体贡献将是确定一个 口服MK的最佳剂量为未来随机对照试验。R34研究的意义和未来RCT的意义 大剂量口服孟鲁司特将为病情恶化提供急需的药物，以减少 这种常见病的发病率。这项研究的创新之处在于：(1)确定了最佳的毫克/公斤剂量 未来的随机对照试验；(2)提供初步疗效和剂量-反应数据；以及(3)重新用于廉价的 以一种新的方式解决哮喘恶化儿童未得到满足的需求。完成这项重新- 搜索将产生减少儿童哮喘恶化的发病率和健康负担的知识。

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.