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

大剂量口服孟鲁司特的剂量递增临床试验为哮喘急性发作儿童的未来随机对照试验提供信息

• 批准号: 10649012
• 负责人: DONALD Hayes ARNOLD
• 金额: $ 39.98万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649012
• 关键词: Accident and Emergency department; Acute; Address; Adrenal Cortex Hormones; Adult; Affect; Aftercare; Agonist; Albuterol; Allergic rhinitis; Anti-Inflammatory Agents; Asthma; Black race; Bronchoconstriction; Bronchodilator Agents; Child; Chronic; Clinical; Clinical Trials; Control Groups; Data; Decision Making; Dose; Drug Kinetics; FDA approved; Funding; Future; Goals; Guidelines; Health; Hospitalization; Hospitalized Child; Hour; Individual; Inflammation; Inflammation Mediators; Inflammatory; Ingestion; Inhalation; Intravenous; Knowledge; Leukotriene Antagonists; Leukotriene E4; Leukotrienes; Low income; Lung diseases; Masks; Measures; Mediating; Medicine; Mission; Modeling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Oral; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Phase; Placebos; Plasma; Public Health; Randomized; Recommendation; Relapse; Research; Safety; Severities; Stress; Testing; Time; Update; Viral Respiratory Tract Infection; Weight; airborne allergen; airway inflammation; asthma exacerbation; computerized; cysteinyl-leukotriene; design; effective therapy; eosinophil; hospitalization rates; improved; improved outcome; inhibitor; innovation; mast cell; montelukast; novel; personalized medicine; pulmonary function; response; side effect; standard care; urinary

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.

项目摘要 该R34提案和未来R61/R33资助的RCT的目标是减少现代和 儿童严重急性哮喘加重，足够快地减少住院治疗。 这些住院不成比例地影响黑人和低收入儿童。它们经常发生是因为leu- Kotriene（LT）诱导的气道注入和支气管收缩对系统性不完全反应 皮质类固醇（CCS）和掺入专辑胶。 LT合成是由病毒呼吸道感染和Aeroaller-诱导的 Gens是儿童中最常见的加重触发者。我们对药物有关键的临床需求 将迅速减少LT介导的气道注射和支气管收缩。蒙特卡斯特（MK），有效 LT受体拮抗剂可能会满足这一需求。 IV MK在峰等离子体时引起快速，持续的改善 中度和严重加重的成年人中的水平约为1,700 ng/ml。 IV MK不可用，并且 我们对患有恶化儿童的初步药代动力学（PK）研究发现高剂量口服MK（平均 1.0 mg/kg）在40％的参与者中达到1,700 ng/ml的CMAX。 R34的目的是执行自适应PK- 标准治疗的指导，双掩盖的RCT以及高剂量口服MK或相同的安慰剂，有3个escalat- 由PK引导的剂量建模确定的Mg/kg MK剂量水平，患有病情的儿童 初次用紫红色治疗后中度或重度。我们将检验三个假设（1）高剂量口服 Montelukast成就CMAX> 1,700 ng/ml> 86％至少有三个顺序参与者组中的一个 基于体重的升级（mg/kg）剂量之间的剂量； （2）参与者随机分配给高剂量的口服蒙特 Lukast对经过验证的急性哮喘强度研究评分（AAIRS）有2分或更高的改善 治疗后4小时与对照组参与者相比； （3）在Montelukast接收者中， CMAX在4小时时与AAIRS的变化相关。这项R34研究将产生基本和足够的 知识为II期RCT做出确定的设计决策（R61-R33资助），足以实现 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 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改善结果 中度和严重加重的儿童。这项研究的总体贡献将是确定 未来RCT的最佳MG/kg口服MK剂量。这项R34研究和未来RCT的意义 高剂量的口服Montelukast将提供一种迫切需要的药物以减少 这种常见疾病的发病率。这项研究具有（1）确定最佳Mg/kg剂量的创新性 未来的RCT； （2）提供初步效率和剂量反应数据； （3）重新利用便宜的 药物以一种新颖的方式解决哮喘患儿童未满足的需求。完成此重新 搜索将产生知识，以减少儿童哮喘恶化的发病率和健康伯恩。