<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03277170</url>
  </required_header>
  <id_info>
    <org_study_id>000</org_study_id>
    <nct_id>NCT03277170</nct_id>
  </id_info>
  <brief_title>Pragmatic RCT of High-dose Oral Montelukast for Moderate and Severe Pediatric Acute Asthma Exacerbations</brief_title>
  <official_title>Pragmatic RCT of High-dose Oral Montelukast for Moderate and Severe Pediatric Acute Asthma Exacerbations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Objective: To determine the extent to which high-dose (30mg) oral montelukast, added to&#xD;
      standard treatment in children with moderate and severe acute exacerbations improves&#xD;
      outcomes.&#xD;
&#xD;
      Central Hypothesis: High-dose oral montelukast, added to standard treatment in children aged&#xD;
      5 to 17 years with moderate and severe acute asthma exacerbations, rapidly improves lung&#xD;
      function, clinical severity, hospitalization rate and 72-hour symptom burden.&#xD;
&#xD;
      Secondary Hypotheses:&#xD;
&#xD;
        1. There are greater effects of high-dose oral montelukast on lung function and on the&#xD;
           secondary outcomes in the presence of respiratory viral detection or&#xD;
           leukotriene-mediated inflammation; and&#xD;
&#xD;
        2. There is an interaction between viral detection and urinary leukotriene 4 level with&#xD;
           treatment-response.&#xD;
&#xD;
      Design: A two-arm, parallel randomized controlled trial of high-dose oral montelukast versus&#xD;
      identical placebo, as add-on to standard treatment of systemic corticosteroid (SCS) and&#xD;
      inhaled short-acting Beta-2-agonist (SABA), in children aged 5 to 17 years with moderate and&#xD;
      severe acute asthma exacerbations.&#xD;
&#xD;
      Intervention: High-dose oral montelukast added to standard treatment as one&#xD;
      treatment-allocation arm, in comparison with standard treatment as the 2nd&#xD;
      treatment-allocation arm.&#xD;
&#xD;
      Primary and Important Secondary Endpoints: For the Primary Aim, the primary outcome measure&#xD;
      to be compared between arms will be change of %-predicted airway resistance by impulse&#xD;
      oscillometry (IOS) at 5Hz (%R5) at 2 hours after treatment initiation. Secondary outcomes&#xD;
      will include improvement of %-predicted FEV1 (%FEV1), clinical severity measured using the&#xD;
      validated Acute Asthma Intensity Research Score (AAIRS), hospitalization rate, and 72 hour&#xD;
      symptom burden using the Pediatric Asthma Caregiver Diary (PACD). For the Secondary Aim, the&#xD;
      investigators will determine (1) The effects of high-dose oral montelukast on lung function&#xD;
      and on our secondary outcomes in the presence of nasal viruses and of greater&#xD;
      leukotriene-mediated inflammation; and (2) The degree of interaction between viral detection&#xD;
      and urinary leukotriene E4 (LTE4) level with treatment-response.&#xD;
&#xD;
      Laboratory evaluations: The primary outcome (change of %R5) and select secondary outcomes&#xD;
      (%FEV1, AAIRS, LTE4) will be measured before and again at 2 hours after treatment initiation.&#xD;
      The other secondary outcomes will be measured at the time of hospitalization decision-making&#xD;
      by the clinical team (hospitalization rate) or at 72-hours after treatment initiation (PACD).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study overview: The approach to testing the central hypothesis will be to conduct a two-arm,&#xD;
      parallel randomized controlled trial of high-dose (30mg) montelukast versus identical&#xD;
      placebo, as add-on to standard treatment of SCS and inhaled SABA, in children aged 5 to 17&#xD;
      years with moderate and severe acute asthma exacerbations. Although this aim will enable us&#xD;
      to test each hypothesis, the ability to test each hypothesis is independent of the others.&#xD;
&#xD;
      Randomization: The investigators will use randomly-permuted blocks of 4 to 8 to minimize&#xD;
      seasonal bias of exacerbation precipitants that may have independent associations with&#xD;
      treatment-response.&#xD;
&#xD;
      Masking of treatment-allocation and outcome-ascertainment: Investigator or clinical team&#xD;
      knowledge of treatment allocation may influence assessment of outcomes. Allocation&#xD;
      concealment will minimize this bias. The investigators will adhere to established procedures&#xD;
      to maintain masking of participants, CTAs, and data analysts.&#xD;
&#xD;
      Aim 1: Testing the primary hypothesis The investigators will measure lung function before and&#xD;
      after 2-hours of treatment using airway resistance by impulse oscillometry at 5Hz (%R5).&#xD;
&#xD;
      Expected outcomes of the primary aim: The investigators expect that high-dose montelukast&#xD;
      will result in a minimum 15% greater improvement in %R5 and a 10% improvement of %FEV1&#xD;
      between pre-treatment and 2-hours after dosing in comparison with standard treatment. The&#xD;
      investigators base this expectation on (1) The known contribution of leukotrienes to airway&#xD;
      inflammation during acute asthma exacerbations;8-11 (2) Knowledge that corticosteroids do not&#xD;
      inhibit leukotriene synthesis in vivo;7 (3) High-quality trials of IV montelukast in patients&#xD;
      with moderate and severe acute asthma exacerbations by Camargo and colleagues that&#xD;
      demonstrated rapid and sustained improvement of lung function and decreased need for&#xD;
      SCS;25,26 and (4) The pharmacokinetics of IV and oral montelukast indicating that serum&#xD;
      levels after high-dose oral montelukast are comparable to the IV doses used in the Camargo&#xD;
      trials.29,69-72 The investigators expect that high-dose montelukast will result in meaningful&#xD;
      improvement of clinical severity, hospitalization rate, and 72-hour symptom burden.&#xD;
&#xD;
      Secondary Aim and testing the secondary hypothesis: Respiratory viral detection Specimen&#xD;
      processing. The investigators will obtain a nasal swab from each participant before&#xD;
      treatment. PCR testing for respiratory viruses will be conducted in the laboratory of Dr.&#xD;
      Natasha Halasa (Co-I). Nasal and throat swabs combined in 3 ml sterile M4RT transport medium&#xD;
      (Remel) will undergo immediate refrigeration at 2-8oC, followed by transportation within 24&#xD;
      hours on ice to the Halasa Lab for processing. Five aliquots in 2-ml screw-cap cyrovials will&#xD;
      be prepared three ~0.85-ml volumes in original transport medium and two ~0.2-ml volumes in&#xD;
      commercial lysis buffer compatible with extraction methods employed in the Halasa Lab.&#xD;
      Aliquots will be flash-frozen prior to storage at -80oC to maximize viral stability and&#xD;
      specimen quality.&#xD;
&#xD;
      PCR detection of respiratory viruses: Testing for influenza A, B, and C; RSV; adenovirus;&#xD;
      enterovirus; human metapneumovirus; human rhinovirus; parainfluenza 1-4; coronavirus 229E,&#xD;
      NL63, OC43, and HKU1; and human bocavirus can be performed according to established protocols&#xD;
      using optimized target-specific primers and FAM/BHQ1-congugated hydrolysis probes, AgPath-ID&#xD;
      One Step RT-PCR chemistry (Applied Biosystems), and StepOnePlus Real Time PCR System. Total&#xD;
      nucleic acid extraction will be performed using the Roche MagNA Pure LC automated extraction&#xD;
      system capable of high-throughput specimen processing to yield exceedingly pure RNA. Based on&#xD;
      an assay cutoff of Ct equal to 40, specimens demonstrating Ct values less than or equal to 40&#xD;
      for viral sequence signatures will be considered positive for the targets in question.&#xD;
      Specimens negative (Ct greater than 40) for RNAseP will be retested using the same&#xD;
      preparation of nucleic acid and further tested using a fresh extract if the original extract&#xD;
      repeatedly produces a negative result. Specimens persistently demonstrating RNAseP Ct values&#xD;
      greater than 40 will be deemed indeterminate for negative viral targets. Viral target&#xD;
      detection in RNAseP-negative specimens will be considered true-positive assuming processing&#xD;
      and plate controls produce expected patterns of results.&#xD;
&#xD;
      Urinary LTE4 measurement will be by the Vanderbilt Eicosanoid Core Laboratory. Expected&#xD;
      outcomes of the secondary aim: First, the investigators expect that there will be a high&#xD;
      incidence of viral respiratory detection in the cohort, based on reports from Johnston,&#xD;
      Khetsuriani and others. Respiratory viral detection does not imply viral respiratory&#xD;
      infection (VRI). Nonetheless, the investigators anticipate that there will be (1) Greater&#xD;
      effects of montelukast on lung function in participants with respiratory virus detected in&#xD;
      comparison with those who do not have virus detected; (2) Greater effects of montelukast on&#xD;
      lung function in proportion to urinary LTE4 levels; and (3) An interaction between viral&#xD;
      detection and urinary LTE4 level on treatment-response.&#xD;
&#xD;
      Power Calculation and Statistical Approach: Power calculation for this research is based on&#xD;
      the primary outcome measure, %R5 by IOS.&#xD;
&#xD;
      The primary outcome measure will be %R5 because this IOS parameter measures total airway&#xD;
      resistance. The data from 192 children aged 5 to 17 years with acute asthma exacerbations&#xD;
      include an SD for pre-treatment %R5 of 71.7% and a correlation coefficient (r) of 0.52&#xD;
      between pre-treatment and 2-hour %R5. For residual variance the investigators considered a&#xD;
      linear regression model with the 2-hour value as the outcome and the pre-treatment value as&#xD;
      an adjustment variable. With 125 participants having complete IOS data in each of the two&#xD;
      treatment-allocations arms, the investigators will have 90% power to detect a minimal&#xD;
      difference of %R5 of 14% between montelukast and placebo with one interim data analysis&#xD;
      conducted when 50% of the subjects have accrued. In order to account for missing IOS data in&#xD;
      up to 15% of participants, dropouts and missing data the investigators propose to enroll 330&#xD;
      participants with 165 randomized to each RCT arm.&#xD;
&#xD;
      The investigators will also examine additional IOS parameters as outcomes, including those&#xD;
      representing large (R20) and small airway function (R5 to R20, X5 and XA), as well as change&#xD;
      of %-predicted FEV1 (%FEV1) and of the AAIRS bedside severity score between pre-treatment and&#xD;
      2-hours. Because the investigators anticipate that approximately 50% of the cohort with&#xD;
      moderate and severe exacerbations will be able to provide spirometry meeting ATS quality and&#xD;
      reproducibility criteria, there may be insufficient power to detect meaningful differences&#xD;
      for this outcome. However, the investigators will be able to score the AAIRS in all&#xD;
      participants and thus anticipate sufficient power to detect a minimum 2 point difference of&#xD;
      this 17 point severity score between montelukast and placebo arms.&#xD;
&#xD;
      Statistical approach Primary statistical inferential test: Outcomes are measured on a&#xD;
      continuous scale and will be analyzed using linear regression and include treatment indicator&#xD;
      and baseline value as covariates. The investigators will estimate the bias corrected mean&#xD;
      effect of treatment with corresponding 95% confidence intervals that taken into account one&#xD;
      planned interim analyses. The investigators will ascertain that the assumptions of&#xD;
      inferential tests are satisfied for all analyses. If assumptions are violated, alternatively&#xD;
      the investigators will use the proportional odds ordinal logistic regression model which&#xD;
      generalizes the non-parametric Wilcoxon rank sum test to a regression setting.&#xD;
&#xD;
      Secondary tests for effect modification by viral detection and urinary LTE4 level: As noted&#xD;
      above, the investigators anticipate an interaction of viral detection and urinary LTE4 level&#xD;
      on montelukast treatment-response. Additional subgroup analyses by age groups, pretreatment&#xD;
      severity (moderate versus severe) and exclusion of participants with rapid response (10&#xD;
      minute) to albuterol are also of interest. To test secondary hypotheses that the treatment&#xD;
      effect is modified by covariates, the investigators will fit separate models that also&#xD;
      include the interaction of the covariate with the treatment effect. Using the sample size&#xD;
      assumptions above and additionally anticipating that 60% to 80% of subjects will have viral&#xD;
      detection at baseline, the investigators will have 80% power to detect a 25% to 31%&#xD;
      modification of the treatment effect. The investigators will report the results of all&#xD;
      subgroup analyses conducted regardless of statistical significance.&#xD;
&#xD;
      Intention-to-treat-analysis and inferential test assumptions. Analyses will conform to the&#xD;
      principle of intention-to-treat. All randomized participants will be included in the primary&#xD;
      and secondary analyses in their assigned treatment allocation groups.&#xD;
&#xD;
      Stopping rules for use by the Data Safety and Monitoring Committee Stopping boundaries and&#xD;
      design operating characteristics were investigated using the RCT-design R package. This&#xD;
      package provides a comprehensive suite of functions for evaluating, monitoring, analyzing,&#xD;
      and reporting clinical trial designs. While finalized stopping rules will be developed and&#xD;
      agreed on by investigators during the R61 startup phase, the investigators summarize some&#xD;
      current results. Using the Emerson and Flemming (1989) symmetric test125 with an assumed&#xD;
      treatment effect of 14% and standard deviation of 34%, the investigators would stop the trial&#xD;
      early at the interim analysis for futility if estimated treatment effect is 0.0% or lower and&#xD;
      stop early for efficacy if the treatment effect is 17.0% or greater. If the true treatment&#xD;
      effect is 14%, there is an estimated 32% chance of stopping early. Should the trial continue&#xD;
      to full enrollment, the bias adjusted treatment effect will be significant for efficacy if it&#xD;
      is estimated to be 8.5% or larger.&#xD;
&#xD;
      Missing data will be handled by joint modeling of the treatment effect and informative&#xD;
      missing data.&#xD;
&#xD;
      The investigators expect that outcome data on some subjects will be missing, and this data&#xD;
      will not be missing (completely) at random. In particular, FEV1 measurements will be more&#xD;
      difficult to obtain on subjects with more severe exacerbations. Failing to account for the&#xD;
      informative missingness could bias the estimate of the treatment effect, so the investigators&#xD;
      will consider joint models for the missing data and estimated treatment effect.126,127&#xD;
      Sensitivity analyses in which the treatment is estimated using different models for the&#xD;
      missing data will be conducted to determine the robustness of the treatment effect estimate.&#xD;
      Detailed analyses will specify that the missing data models will be created before data&#xD;
      collection, during the R61 startup phase.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">September 1, 2025</start_date>
  <completion_date type="Anticipated">September 5, 2029</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2028</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Two-arm, parallel randomized controlled trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Study drug (montelukast granules) and identical control will be prepared by the Vanderbilt Investigational Drug service. Participants will be randomized by computerized program by study biostatistician.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change of percent-predicted airway resistance at 5Hz (%R5) by impulse oscillometry</measure>
    <time_frame>Before and 2-hours after treatment with montelukast or placebo</time_frame>
    <description>Change of percent-predicted airway resistance at 5Hz (%R5) by impulse oscillometrypost montelukast or control administration</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of percent-predicted forced expiratory volume in 1-second (FEV1)</measure>
    <time_frame>Before and 2-hours after treatment with montelukast or placebo</time_frame>
    <description>Change of percent-predicted forced expiratory volume in 1-second (FEV1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of the Acute Asthma Intensity Research Score (AAIRS)</measure>
    <time_frame>Before and 2-hours after treatment with montelukast or placebo</time_frame>
    <description>Change of the Acute Asthma Intensity Research Score (AAIRS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Leukotriene E4 (LTE4)</measure>
    <time_frame>Before treatment with montelukast or placebo</time_frame>
    <description>Leukotriene E4 (LTE4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>72-hours symptom burden measured using the pediatric asthma caregiver diary (PACD)</measure>
    <time_frame>Before and at 72-hours after treatment with montelukast or placebo</time_frame>
    <description>72-hours symptom burden measured using the pediatric asthma caregiver diary (PACD)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalization rate</measure>
    <time_frame>8-hours after treatment with montelukast or placebo</time_frame>
    <description>Hospitalization rate</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">320</enrollment>
  <condition>Asthma; Status</condition>
  <condition>Asthma in Children</condition>
  <condition>Asthma Acute</condition>
  <condition>Asthma Attack</condition>
  <condition>Acute Asthma Exacerbation</condition>
  <arm_group>
    <arm_group_label>High-dose Montelukast Oral Granules</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 mg (high-dose) oral montelukast granules mixed in apple sauce will be administered orally immediately after informed consent and assent are obtained.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Identical placebo mixed in apple sauce will be administered orally immediately after informed consent and assent are obtained.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Montelukast Oral Granules</intervention_name>
    <description>Montelukast granules, 30 mg, mixed with applesauce</description>
    <arm_group_label>High-dose Montelukast Oral Granules</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Singulair</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Age 5 to 17 years, inclusive&#xD;
&#xD;
          -  Parental report of asthma diagnosis by a health care provider&#xD;
&#xD;
          -  At least one previous wheezing episode treated with albuterol&#xD;
&#xD;
          -  Moderate or severe acute asthma exacerbation measured using the validated AAIRS&#xD;
             bedside asthma severity score&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Prior study enrollment&#xD;
&#xD;
          -  Chronic lung disease other than asthma&#xD;
&#xD;
          -  History of prematurity less than 34 weeks gestational age&#xD;
&#xD;
          -  Acute or chronic liver disease&#xD;
&#xD;
          -  Presence of tracheostomy&#xD;
&#xD;
          -  Use of noninvasive ventilation at home&#xD;
&#xD;
          -  Need for immediate airway intervention (e.g., endotracheal intubation or noninvasive&#xD;
             ventilation)&#xD;
&#xD;
          -  Allergy to montelukast&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Tuberculosis&#xD;
&#xD;
          -  Gastroesophageal reflux requiring acid-blocking medication; and&#xD;
&#xD;
          -  Prior use of an LTRA (e.g., montelukast)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Donald H Arnold, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University School of Medicine, Department of Pediatrics</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Donald H Arnold, MD, MPH</last_name>
    <phone>615-936-4898</phone>
    <email>don.arnold@vanderbilt.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Vanderbilt Children's Hospital</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Arnold DH, Bowman N, Reiss TF, Hartert TV, Seger DL. Adverse events are rare after single-dose montelukast exposures in children. Clin Toxicol (Phila). 2018 Jan;56(1):25-29. doi: 10.1080/15563650.2017.1337123. Epub 2017 Jun 22.</citation>
    <PMID>28639856</PMID>
  </results_reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>September 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <last_update_submitted>November 5, 2022</last_update_submitted>
  <last_update_submitted_qc>November 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Donald H Arnold</investigator_full_name>
    <investigator_title>Professor of Pediatrics and Emergency Medicine</investigator_title>
  </responsible_party>
  <keyword>acute asthma exacerbation</keyword>
  <keyword>pediatric asthma</keyword>
  <keyword>leukotriene receptor antagonist</keyword>
  <keyword>montelukast</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Montelukast</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>This plan is to be developed in concert with our IRB.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03277170
org study id: 000
nct id: NCT03277170
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Two-arm, parallel randomized controlled trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Study drug (montelukast granules) and identical control will be prepared by the Vanderbilt Investigational Drug service. Participants will be randomized by computerized program by study biostatistician.
measure: Change of percent-predicted airway resistance at 5Hz (%R5) by impulse oscillometry
time frame: Before and 2-hours after treatment with montelukast or placebo
description: Change of percent-predicted airway resistance at 5Hz (%R5) by impulse oscillometrypost montelukast or control administration
measure: Change of percent-predicted forced expiratory volume in 1-second (FEV1)
time frame: Before and 2-hours after treatment with montelukast or placebo
description: Change of percent-predicted forced expiratory volume in 1-second (FEV1)
measure: Change of the Acute Asthma Intensity Research Score (AAIRS)
time frame: Before and 2-hours after treatment with montelukast or placebo
description: Change of the Acute Asthma Intensity Research Score (AAIRS)
measure: Leukotriene E4 (LTE4)
time frame: Before treatment with montelukast or placebo
description: Leukotriene E4 (LTE4)
measure: 72-hours symptom burden measured using the pediatric asthma caregiver diary (PACD)
time frame: Before and at 72-hours after treatment with montelukast or placebo
description: 72-hours symptom burden measured using the pediatric asthma caregiver diary (PACD)
measure: Hospitalization rate
time frame: 8-hours after treatment with montelukast or placebo
description: Hospitalization rate
arm group label: High-dose Montelukast Oral Granules
arm group type: Experimental
description: 30 mg (high-dose) oral montelukast granules mixed in apple sauce will be administered orally immediately after informed consent and assent are obtained.
arm group label: Placebo
arm group type: Placebo Comparator
description: Identical placebo mixed in apple sauce will be administered orally immediately after informed consent and assent are obtained.
intervention type: Drug
intervention name: Montelukast Oral Granules
description: Montelukast granules, 30 mg, mixed with applesauce
arm group label: High-dose Montelukast Oral Granules
arm group label: Placebo
other name: Singulair
criteria: 
gender: All
minimum age: 5 Years
maximum age: 17 Years
healthy volunteers: No
last name: Donald H Arnold, MD, MPH
role: Principal Investigator
affiliation: Vanderbilt University School of Medicine, Department of Pediatrics
last name: Donald H Arnold, MD, MPH
phone: 615-936-4898
email: don.arnold@vanderbilt.edu
facility: 
country: United States
citation: Arnold DH, Bowman N, Reiss TF, Hartert TV, Seger DL. Adverse events are rare after single-dose montelukast exposures in children. Clin Toxicol (Phila). 2018 Jan;56(1):25-29. doi: 10.1080/15563650.2017.1337123. Epub 2017 Jun 22.
PMID: 28639856
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Donald H Arnold
investigator title: Professor of Pediatrics and Emergency Medicine
mesh term: Asthma
mesh term: Montelukast
sharing ipd: Undecided
ipd description: This plan is to be developed in concert with our IRB.