Dose Escalation Clinical Trial of High-dose Oral Montelukast to Inform Future RCT in Children With Acute Asthma Exacerbations
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 90
- 试验地点
- 2
- 主要终点
- Montelukast plasma level
研究概览
简要总结
This research will establish a mg/kg dose for a future RCT to determine the efficacy of high-dose oral montelukast for children with moderate and severe acute asthma exacerbations.
Aim: Perform an adaptive, double-masked randomized controlled trial (RCT) of high-dose oral montelukast, with escalating mg/kg dose levels determined by PK-guided dose modeling, added to standard treatment versus standard treatment alone, in children with exacerbations that are moderate or severe after initial treatment with inhaled albuterol.
Hypothesis 1: High-dose oral montelukast achieves peak plasma concentration (Cmax) >1,700 ng/ml in >86% of at least one of three sequential participant groups with escalating weight-based (milligram/kilogram or mg/kg) doses between groups.
Hypothesis 2: Participants randomized to high-dose oral montelukast have a 2 point or greater improvement of the validated Acute Asthma Intensity Research Score (AAIRS) at 4 hours post-treatment in comparison with control group participants.
Hypothesis 3: Among montelukast recipients, Cmax correlates with change of the AAIRS at 4 hours, after adjustment for pre-treatment exacerbation severity and systemic leukotriene stress measured using pre-treatment plasma leukotriene E4 (LTE4).
详细描述
Study design parameters Design: 2-arm, phase 3 double-blind RCT Intervention: Oral montelukast sprinkles or identical placebo Dose escalation: Doses between 2 mg/kg and 3 mg/kg based on pharmacokinetic modeling after each group of 5 participants.
Montelukast is a potent LT-receptor antagonist and is FDA approved at a daily oral dose of 4-5 mg for chronic asthma and allergic rhinitis in children. It is also a potent bronchodilator. In randomized controlled trials (RCT) of adults with moderate and severe exacerbations and inadequate response to inhaled albuterol, intravenous (IV) montelukast caused rapid (within 10 minutes) and sustained improvement of lung function in all subjects, without selecting for CCS non-responsiveness. This underscores the potential clinical impact of reducing LT-mediated inflammation during exacerbations. However, the standard 5 mg oral dose does not achieve peak plasma levels (Cmax) comparable to the IV doses used in these RCTs, and IV montelukast is not available.
The investigators' preliminary pharmacokinetic (PK) study in children with acute exacerbations demonstrated that 30 mg oral montelukast (mean 1.0 mg/kg) achieves Cmax >1,700 ng/ml in 40% of participants. This is a Cmax expected after doses used in the adult RCTs above. The primary hypothesis for this research is that the investigators will identify a weight-based oral montelukast dose that reliably achieves Cmax >1,700 ng/ml by examining 3 escalating dose levels between 2 and 3 mg/kg. Dose escalation will be optimized using computerized, PK-guided dose modeling that will be updated after each group of 5 participants among 45 randomized to receive montelukast. The investigators further hypothesize that high-dose montelukast meaningfully decreases exacerbation severity, measured using the validated Acute Asthma Intensity Research Score (AAIRS).
Participants will be randomized to receive montelukast powder USP in Ora-Blend suspending agent or identical placebo. Montelukast (MK) dose will begin at 2 mg/kg. Peak MK plasma concentration (Cmax) will be measured after each group of 5 participants randomized to MK. MK dose for subsequent participant groups will be escalated if Cmax is <1,700 ng/ml for >14% of participants at current mg/kg dose level.
INCLUSION CRITERIA
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
We will use randomly-permuted 1:1 blocks of 10 to minimize seasonal bias of exacerbation precipitants that may have independent associations with treatment-response. The study biostatistician will use the randomizeR package in R statistical software to provide the randomization schedule. A Research Electronic Data Capture (REDCap) database will be built that will incorporate the randomization sequence. When the investigators place an electronic medical record order (eStar) order for drug, the randomization database will designate randomized treatment allocation to the pharmacy. Pharmacy will prepare appropriate drug. The REDCap database will email and text the study pharmacist performing plasma assays, pharmacy staff, and the investigators 24 hours after the 5th participant is randomized to MK within each dose group. This will alert the investigators to pause enrollment until MK assays are completed and the mg/kg MK dose is determined for the next dose group.
入排标准
- 年龄范围
- 4 Years 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Child aged 4 - 12 years with doctor-diagnosed asthma
- •Presents to the Vanderbilt Children's Hospital with an acute asthma exacerbation that is moderate or severe (AAIRS >7) after initial treatment with inhaled albuterol
- •The parent agrees to phone and/or mail follow-up at 2-3 weeks for completion of SCARED and side-effect questionnaires.
排除标准
- •Gestational age < 34 weeks
- •acute or chronic liver disease
- •allergy to montelukast
- •female with any evidence of Tanner stage 2 or greater breast development
- •gastroesophageal reflux requiring acid-blocking medication
- •history of anxiety disorder, depression and/or other neuropsychiatric disorder except ADHD
- •positive on question 1 or 2 of the Columbia Suicide Severity Rating Scale (CSSR-S)
- •score >25 on the 82-point Screen for Child Anxiety Related Disorders (SCARED) questionnaire
- •Patients currently receiving daily montelukast (4 or 5 mg) will not be excluded from study participation.
研究组 & 干预措施
High-dose oral montelukast plus standard treatment
Escalating dose-levels of oral montelukast between 2 mg/kg and 3 mg/kg determined by pharmacokinetic-guided dose modeling, added to standard, guideline-based treatment (systemic corticosteroid, inhaled albuterol, and possible treatment adjuncts such as IV magnesium, determined by evidence-based asthma clinical practice guideline).
干预措施: Montelukast Oral Granules (Drug)
High-dose oral montelukast plus standard treatment
Escalating dose-levels of oral montelukast between 2 mg/kg and 3 mg/kg determined by pharmacokinetic-guided dose modeling, added to standard, guideline-based treatment (systemic corticosteroid, inhaled albuterol, and possible treatment adjuncts such as IV magnesium, determined by evidence-based asthma clinical practice guideline).
干预措施: Albuterol (Drug)
Identical placebo plus standard treatment
Guideline-based treatment (systemic corticosteroid, inhaled albuterol, and possible treatment adjuncts such as IV magnesium, determined by evidence-based asthma clinical practice guideline).
干预措施: Corticosteroid (Drug)
High-dose oral montelukast plus standard treatment
Escalating dose-levels of oral montelukast between 2 mg/kg and 3 mg/kg determined by pharmacokinetic-guided dose modeling, added to standard, guideline-based treatment (systemic corticosteroid, inhaled albuterol, and possible treatment adjuncts such as IV magnesium, determined by evidence-based asthma clinical practice guideline).
干预措施: Corticosteroid (Drug)
Identical placebo plus standard treatment
Guideline-based treatment (systemic corticosteroid, inhaled albuterol, and possible treatment adjuncts such as IV magnesium, determined by evidence-based asthma clinical practice guideline).
干预措施: Albuterol (Drug)
结局指标
主要结局
Montelukast plasma level
时间窗: 4 hours
Peak montelukast plasma level
次要结局
- Change of Acute Asthma Intensity Research Score(4 hours)
- Airway resistance by impulse oscillometry (IOS)(4 hours)
研究者
Donald Hayes Arnold
Professor of Pediatrics and Emergency Medicine
Vanderbilt University Medical Center