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

项目摘要 这项R34提案和未来R61/R33资助的RCT的目标是降低中度和重度脑梗死的严重程度。 儿童严重急性哮喘加重，充分和迅速地减少住院治疗。 这些住院不成比例地影响黑人和低收入儿童。它的出现往往是因为... kotriene（LT）诱导的气道炎症和支气管收缩对全身性 皮质类固醇（CCS）和吸入沙丁胺醇。LT的合成是由病毒性呼吸道感染和呼吸道过敏引起的。 gens是儿童中最常见的急性加重诱因。我们临床急需一种药物， 将迅速减少LT介导的气道炎症和支气管收缩。孟鲁司特（MK），一种强效 LT-受体拮抗剂可以解决这一需求。IV MK在血浆峰值时引起快速、持续的改善 中度和重度急性发作的成人中的水平（Cmax）约为1，700 ng/ml。IV MK不可用，并且 我们对急性发作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）在40%的受试者中达到Cmax 1，700 ng/ml。R34的目标是执行自适应，PK- 标准治疗加高剂量口服MK或相同安慰剂的指导、双盲RCT，3种Escalat， 通过PK指导的剂量建模确定的mg/kg MK剂量水平，在以下急性加重儿童中 沙丁胺醇初始治疗后中度或重度。我们将测试三个假设（1）高剂量口服 孟鲁司特在三个连续参与者组中的至少一个中>86%达到Cmax > 1，700 ng/ml， 组间基于体重的剂量递增（mg/kg）;（2）随机接受高剂量口服蒙特- 鲁司特对经验证的急性哮喘强度研究评分（AAIRS）有2分或以上的改善 与对照组参与者相比，治疗后4小时;和（3）在孟鲁司特接受者中， Cmax与4小时时AAIRS的变化相关。这项R34研究将产生必要的和足够的 为II期RCT（R61-R33资助）做出明确设计决策的知识， 重要的临床结果。未来的RCT将检验以下假设：最佳mg/kg MK剂量确定了 在这项研究中，R34作为一种额外的抗炎和支气管扩张药物， 中度和重度急性发作的儿童。这项研究的总体贡献将是确定一个 未来RCT口服MK的最佳mg/kg剂量。这项R34研究和未来RCT的意义 高剂量口服孟鲁司特将为急性加重提供急需的药物， 这种常见病的发病率。本研究的创新之处在于：（1）确定最佳mg/kg剂量， 未来的随机对照试验;（2）提供初步的疗效和剂量反应数据;（3）重新利用廉价的 以一种新的方式治疗哮喘急性发作儿童的未满足需求。完成这一改革-- 搜索将产生减少儿童哮喘急性发作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.