Pragmatic RCT of High-dose Oral Montelukast for Moderate and Severe Pediatric Acute Asthma Exacerbations
Pragmatic RCT of High-dose Oral Montelukast for Moderate and Severe Pediatric Acute Asthma Exacerbations
Objective: To determine the extent to which high-dose (30mg) oral montelukast, added to
 standard treatment in children with moderate and severe acute exacerbations improves
 outcomes.

 Central Hypothesis: High-dose oral montelukast, added to standard treatment in children aged
 5 to 17 years with moderate and severe acute asthma exacerbations, rapidly improves lung
 function, clinical severity, hospitalization rate and 72-hour symptom burden.

 Secondary Hypotheses:

 1. There are greater effects of high-dose oral montelukast on lung function and on the
 secondary outcomes in the presence of respiratory viral detection or
 leukotriene-mediated inflammation; and

 2. There is an interaction between viral detection and urinary leukotriene 4 level with
 treatment-response.

 Design: A two-arm, parallel randomized controlled trial of high-dose oral montelukast versus
 identical placebo, as add-on to standard treatment of systemic corticosteroid (SCS) and
 inhaled short-acting Beta-2-agonist (SABA), in children aged 5 to 17 years with moderate and
 severe acute asthma exacerbations.

 Intervention: High-dose oral montelukast added to standard treatment as one
 treatment-allocation arm, in comparison with standard treatment as the 2nd
 treatment-allocation arm.

 Primary and Important Secondary Endpoints: For the Primary Aim, the primary outcome measure
 to be compared between arms will be change of %-predicted airway resistance by impulse
 oscillometry (IOS) at 5Hz (%R5) at 2 hours after treatment initiation. Secondary outcomes
 will include improvement of %-predicted FEV1 (%FEV1), clinical severity measured using the
 validated Acute Asthma Intensity Research Score (AAIRS), hospitalization rate, and 72 hour
 symptom burden using the Pediatric Asthma Caregiver Diary (PACD). For the Secondary Aim, the
 investigators will determine (1) The effects of high-dose oral montelukast on lung function
 and on our secondary outcomes in the presence of nasal viruses and of greater
 leukotriene-mediated inflammation; and (2) The degree of interaction between viral detection
 and urinary leukotriene E4 (LTE4) level with treatment-response.

 Laboratory evaluations: The primary outcome (change of %R5) and select secondary outcomes
 (%FEV1, AAIRS, LTE4) will be measured before and again at 2 hours after treatment initiation.
 The other secondary outcomes will be measured at the time of hospitalization decision-making
 by the clinical team (hospitalization rate) or at 72-hours after treatment initiation (PACD).
Study overview: The approach to testing the central hypothesis will be to conduct a two-arm,
 parallel randomized controlled trial of high-dose (30mg) montelukast versus identical
 placebo, as add-on to standard treatment of SCS and inhaled SABA, in children aged 5 to 17
 years with moderate and severe acute asthma exacerbations. Although this aim will enable us
 to test each hypothesis, the ability to test each hypothesis is independent of the others.

 Randomization: The investigators will use randomly-permuted blocks of 4 to 8 to minimize
 seasonal bias of exacerbation precipitants that may have independent associations with
 treatment-response.

 Masking of treatment-allocation and outcome-ascertainment: Investigator or clinical team
 knowledge of treatment allocation may influence assessment of outcomes. Allocation
 concealment will minimize this bias. The investigators will adhere to established procedures
 to maintain masking of participants, CTAs, and data analysts.

 Aim 1: Testing the primary hypothesis The investigators will measure lung function before and
 after 2-hours of treatment using airway resistance by impulse oscillometry at 5Hz (%R5).

 Expected outcomes of the primary aim: The investigators expect that high-dose montelukast
 will result in a minimum 15% greater improvement in %R5 and a 10% improvement of %FEV1
 between pre-treatment and 2-hours after dosing in comparison with standard treatment. The
 investigators base this expectation on (1) The known contribution of leukotrienes to airway
 inflammation during acute asthma exacerbations;8-11 (2) Knowledge that corticosteroids do not
 inhibit leukotriene synthesis in vivo;7 (3) High-quality trials of IV montelukast in patients
 with moderate and severe acute asthma exacerbations by Camargo and colleagues that
 demonstrated rapid and sustained improvement of lung function and decreased need for
 SCS;25,26 and (4) The pharmacokinetics of IV and oral montelukast indicating that serum
 levels after high-dose oral montelukast are comparable to the IV doses used in the Camargo
 trials.29,69-72 The investigators expect that high-dose montelukast will result in meaningful
 improvement of clinical severity, hospitalization rate, and 72-hour symptom burden.

 Secondary Aim and testing the secondary hypothesis: Respiratory viral detection Specimen
 processing. The investigators will obtain a nasal swab from each participant before
 treatment. PCR testing for respiratory viruses will be conducted in the laboratory of Dr.
 Natasha Halasa (Co-I). Nasal and throat swabs combined in 3 ml sterile M4RT transport medium
 (Remel) will undergo immediate refrigeration at 2-8oC, followed by transportation within 24
 hours on ice to the Halasa Lab for processing. Five aliquots in 2-ml screw-cap cyrovials will
 be prepared three ~0.85-ml volumes in original transport medium and two ~0.2-ml volumes in
 commercial lysis buffer compatible with extraction methods employed in the Halasa Lab.
 Aliquots will be flash-frozen prior to storage at -80oC to maximize viral stability and
 specimen quality.

 PCR detection of respiratory viruses: Testing for influenza A, B, and C; RSV; adenovirus;
 enterovirus; human metapneumovirus; human rhinovirus; parainfluenza 1-4; coronavirus 229E,
 NL63, OC43, and HKU1; and human bocavirus can be performed according to established protocols
 using optimized target-specific primers and FAM/BHQ1-congugated hydrolysis probes, AgPath-ID
 One Step RT-PCR chemistry (Applied Biosystems), and StepOnePlus Real Time PCR System. Total
 nucleic acid extraction will be performed using the Roche MagNA Pure LC automated extraction
 system capable of high-throughput specimen processing to yield exceedingly pure RNA. Based on
 an assay cutoff of Ct equal to 40, specimens demonstrating Ct values less than or equal to 40
 for viral sequence signatures will be considered positive for the targets in question.
 Specimens negative (Ct greater than 40) for RNAseP will be retested using the same
 preparation of nucleic acid and further tested using a fresh extract if the original extract
 repeatedly produces a negative result. Specimens persistently demonstrating RNAseP Ct values
 greater than 40 will be deemed indeterminate for negative viral targets. Viral target
 detection in RNAseP-negative specimens will be considered true-positive assuming processing
 and plate controls produce expected patterns of results.

 Urinary LTE4 measurement will be by the Vanderbilt Eicosanoid Core Laboratory. Expected
 outcomes of the secondary aim: First, the investigators expect that there will be a high
 incidence of viral respiratory detection in the cohort, based on reports from Johnston,
 Khetsuriani and others. Respiratory viral detection does not imply viral respiratory
 infection (VRI). Nonetheless, the investigators anticipate that there will be (1) Greater
 effects of montelukast on lung function in participants with respiratory virus detected in
 comparison with those who do not have virus detected; (2) Greater effects of montelukast on
 lung function in proportion to urinary LTE4 levels; and (3) An interaction between viral
 detection and urinary LTE4 level on treatment-response.

 Power Calculation and Statistical Approach: Power calculation for this research is based on
 the primary outcome measure, %R5 by IOS.

 The primary outcome measure will be %R5 because this IOS parameter measures total airway
 resistance. The data from 192 children aged 5 to 17 years with acute asthma exacerbations
 include an SD for pre-treatment %R5 of 71.7% and a correlation coefficient (r) of 0.52
 between pre-treatment and 2-hour %R5. For residual variance the investigators considered a
 linear regression model with the 2-hour value as the outcome and the pre-treatment value as
 an adjustment variable. With 125 participants having complete IOS data in each of the two
 treatment-allocations arms, the investigators will have 90% power to detect a minimal
 difference of %R5 of 14% between montelukast and placebo with one interim data analysis
 conducted when 50% of the subjects have accrued. In order to account for missing IOS data in
 up to 15% of participants, dropouts and missing data the investigators propose to enroll 330
 participants with 165 randomized to each RCT arm.

 The investigators will also examine additional IOS parameters as outcomes, including those
 representing large (R20) and small airway function (R5 to R20, X5 and XA), as well as change
 of %-predicted FEV1 (%FEV1) and of the AAIRS bedside severity score between pre-treatment and
 2-hours. Because the investigators anticipate that approximately 50% of the cohort with
 moderate and severe exacerbations will be able to provide spirometry meeting ATS quality and
 reproducibility criteria, there may be insufficient power to detect meaningful differences
 for this outcome. However, the investigators will be able to score the AAIRS in all
 participants and thus anticipate sufficient power to detect a minimum 2 point difference of
 this 17 point severity score between montelukast and placebo arms.

 Statistical approach Primary statistical inferential test: Outcomes are measured on a
 continuous scale and will be analyzed using linear regression and include treatment indicator
 and baseline value as covariates. The investigators will estimate the bias corrected mean
 effect of treatment with corresponding 95% confidence intervals that taken into account one
 planned interim analyses. The investigators will ascertain that the assumptions of
 inferential tests are satisfied for all analyses. If assumptions are violated, alternatively
 the investigators will use the proportional odds ordinal logistic regression model which
 generalizes the non-parametric Wilcoxon rank sum test to a regression setting.

 Secondary tests for effect modification by viral detection and urinary LTE4 level: As noted
 above, the investigators anticipate an interaction of viral detection and urinary LTE4 level
 on montelukast treatment-response. Additional subgroup analyses by age groups, pretreatment
 severity (moderate versus severe) and exclusion of participants with rapid response (10
 minute) to albuterol are also of interest. To test secondary hypotheses that the treatment
 effect is modified by covariates, the investigators will fit separate models that also
 include the interaction of the covariate with the treatment effect. Using the sample size
 assumptions above and additionally anticipating that 60% to 80% of subjects will have viral
 detection at baseline, the investigators will have 80% power to detect a 25% to 31%
 modification of the treatment effect. The investigators will report the results of all
 subgroup analyses conducted regardless of statistical significance.

 Intention-to-treat-analysis and inferential test assumptions. Analyses will conform to the
 principle of intention-to-treat. All randomized participants will be included in the primary
 and secondary analyses in their assigned treatment allocation groups.

 Stopping rules for use by the Data Safety and Monitoring Committee Stopping boundaries and
 design operating characteristics were investigated using the RCT-design R package. This
 package provides a comprehensive suite of functions for evaluating, monitoring, analyzing,
 and reporting clinical trial designs. While finalized stopping rules will be developed and
 agreed on by investigators during the R61 startup phase, the investigators summarize some
 current results. Using the Emerson and Flemming (1989) symmetric test125 with an assumed
 treatment effect of 14% and standard deviation of 34%, the investigators would stop the trial
 early at the interim analysis for futility if estimated treatment effect is 0.0% or lower and
 stop early for efficacy if the treatment effect is 17.0% or greater. If the true treatment
 effect is 14%, there is an estimated 32% chance of stopping early. Should the trial continue
 to full enrollment, the bias adjusted treatment effect will be significant for efficacy if it
 is estimated to be 8.5% or larger.

 Missing data will be handled by joint modeling of the treatment effect and informative
 missing data.

 The investigators expect that outcome data on some subjects will be missing, and this data
 will not be missing (completely) at random. In particular, FEV1 measurements will be more
 difficult to obtain on subjects with more severe exacerbations. Failing to account for the
 informative missingness could bias the estimate of the treatment effect, so the investigators
 will consider joint models for the missing data and estimated treatment effect.126,127
 Sensitivity analyses in which the treatment is estimated using different models for the
 missing data will be conducted to determine the robustness of the treatment effect estimate.
 Detailed analyses will specify that the missing data models will be created before data
 collection, during the R61 startup phase.
Inclusion criteria:

 -  Age 5 to 17 years, inclusive

 -  Parental report of asthma diagnosis by a health care provider

 -  At least one previous wheezing episode treated with albuterol

 -  Moderate or severe acute asthma exacerbation measured using the validated AAIRS
 bedside asthma severity score

 Exclusion criteria:

 -  Prior study enrollment

 -  Chronic lung disease other than asthma

 -  History of prematurity less than 34 weeks gestational age

 -  Acute or chronic liver disease

 -  Presence of tracheostomy

 -  Use of noninvasive ventilation at home

 -  Need for immediate airway intervention (e.g., endotracheal intubation or noninvasive
 ventilation)

 -  Allergy to montelukast

 -  Pregnancy

 -  Tuberculosis

 -  Gastroesophageal reflux requiring acid-blocking medication; and

 -  Prior use of an LTRA (e.g., montelukast)