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。