Clinical Trial Sponsors: Vanderbilt University Medical Center

  Source:		NCT03277170

    		Pragmatic RCT of High-dose Oral Montelukast
     		for Moderate and Severe Pediatric
			Acute Asthma Exacerbations

			Not yet recruiting

			First Update September 6, 2017
			Last Update October 9, 2018

			Brief Summary
			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).

			Detailed Description
			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.

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