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 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 中度和重度急性加重成人中的血药浓度（Cmax）≥ 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， 中度和重度加重的儿童。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。