<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/NCT03015610</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00079073</org_study_id>
    <nct_id>NCT03015610</nct_id>
  </id_info>
  <brief_title>Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children With Uncontrolled Asthma</brief_title>
  <acronym>GenARA</acronym>
  <official_title>Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children With Uncontrolled Asthma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jason Lang, M.D., M.P.H.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Thrasher Research Fund</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Nemours Children's Clinic</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</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>
      This study will evaluate the effect of CYP2C19 and ABCB1 genes on pharmacokinetics of&#xD;
      lansoprazole in children with mild gastroesophageal reflux (GER) and uncontrolled asthma. It&#xD;
      will determine if genotype-guided lansoprazole dosing of lansoprazole improves GER and asthma&#xD;
      control.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND: Poorly controlled asthma especially in children remains a major public health&#xD;
      problem. Many children with poor asthma control experience gastroesophageal reflux (GERD).&#xD;
      The effect of mild GERD on asthma remains controversial despite studies involving proton-pump&#xD;
      inhibitors (PPIs) assessing their effect on asthma. Past inconsistent findings regarding the&#xD;
      effect of PPIs on asthma control may have resulted from ineffective dosing strategies of&#xD;
      proton-pump inhibitors employed in these studies. Drug levels and efficacy vary widely in the&#xD;
      population and depend on genetics. Dosing in children which adjusts for the gene CYP2C19 may&#xD;
      improve efficacy and reduce side-effects leading to improved asthma control.&#xD;
&#xD;
      HYPOTHESIS: #1: The investigators hypothesize that genotype-tailored lansoprazole dosing will&#xD;
      reduce asthma symptoms in children with mild symptoms of GERD compared to placebo. #2:&#xD;
      CYP2C19 and ABCB1 genetic variants influence the pharmacokinetics (drug levels) of&#xD;
      lansoprazole as determined by population pharmacokinetic modeling.&#xD;
&#xD;
      METHODS: The investigators will conduct a 6-month randomized controlled trial comparing&#xD;
      genotype-tailored lansoprazole dosing versus matched placebo in the control of asthma&#xD;
      symptoms in 6-17 year olds with asthma and mild reflux. All participants will have baseline&#xD;
      pharmacokinetics analysis following a single genotype-tailored dose to assess the effects of&#xD;
      CYP2C19 and ABCB1.&#xD;
&#xD;
      IMPACT: These results would be a major advance in the science of safe dosing of proton-pump&#xD;
      inhibitors in children and for the management of the millions of children struggling with&#xD;
      reflux and asthma.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 31, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 3</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Asthma Control Questionnaire (ACQ) from Screening through Week 26</measure>
    <time_frame>Measured at weeks -2 (screening), 0 (baseline), 8, 16, 26</time_frame>
    <description>The ACQ considers a broad set of common indicators of asthma control including use of bronchodilators, cough, nocturnal symptoms, level of activity, and pulmonary function.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in GERD Symptom Assessment Questionnaire Score (GSAS) from Screening through Week 26</measure>
    <time_frame>Measured at weeks -2 (screening), 0 (baseline), 4, 8, 12,16, 20, 26</time_frame>
    <description>A 10-item tool that has been validated in children in the assessment of gastroesophageal reflux disease related symptoms such as chest/abdominal pain, pain/choking with eating, swallowing dysfunction, regurgitation and nausea. It assesses symptom frequency and severity from the previous 7-days on an 8-point scale with 0 and 7 indicating the least and greatest severity, respectively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Asthma Symptom Utility Index (ASUI) from Screening through Week 26</measure>
    <time_frame>Measured at weeks -2 (screening), 0 (baseline), 8, 16, 26</time_frame>
    <description>Questionnaire measures changes in asthma control.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Annualized rate of asthma exacerbations</measure>
    <time_frame>Week 0 (baseline) through Week 26</time_frame>
    <description>An exacerbation will be defined per the recommendations of the NIH Asthma Exacerbation Taskforce and will be defined as a worsening of asthma requiring the use of a systemic corticosteroid (at least 3 days of prednisolone/ prednisone or ≥1 days of dexamethasone) to prevent asthma worsening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Annualized rate of Episodes of Poor Asthma Control (EPAC)</measure>
    <time_frame>Week 0 (baseline) through Week 26</time_frame>
    <description>A study EPAC will be present if the participant meets any of the following criteria, (1) addition of systemic corticosteroid medication for asthma as above, (2) any unscheduled visit to a non-study related health care provider (ED, urgent care, hospital) for asthma symptoms, (3) increased use of rescue Short-Acting Beta Agonists (SABA) by more than 4 additional puffs (or more than 2 additional nebulizations) above baseline amount determined at enrollment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Annualized rate of respiratory tract infection (RTI)</measure>
    <time_frame>Week 0 (baseline) through Week 26</time_frame>
    <description>Participants/Caregivers will be asked to document symptoms of RTI on daily diary cards per consensus definitions. RTI symptoms will include: (1) runny nose; (2) stuffy or blocked nose or noisy breathing; (3) cough; (4) fever, feels hot, or has chills; (5) sore throat; and (6) sneezing.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Lung Function Testing from Screening through Week 26</measure>
    <time_frame>Measured at week -2 (screening), week 26</time_frame>
    <description>Forced Expiratory Volume in 1 Second (FEV1) measurement</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">110</enrollment>
  <condition>Asthma</condition>
  <condition>Gastroesophageal Reflux</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>participants will receive oral blinded matched placebo once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Genotype-guided Lansoprazole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>participants will receive oral blinded commercially available lansoprazole once daily with a dose appropriate for the participant's metabolizer phenotype</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>commercially available lansoprazole</intervention_name>
    <description>these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily lansoprazole for 24 weeks</description>
    <arm_group_label>Genotype-guided Lansoprazole</arm_group_label>
    <other_name>once daily</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>matched placebo</intervention_name>
    <description>these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily placebo for 24 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>once daily</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age: 6-17 year olds with documented clinician-diagnosed asthma&#xD;
&#xD;
          -  Evidence of recent uncontrolled asthma (must meet at least one of the following). This&#xD;
             convention for defining poorly-controlled asthma has been successfully used in a large&#xD;
             pediatric trial.&#xD;
&#xD;
               -  ACQ &gt; 1.2&#xD;
&#xD;
               -  Use of short-acting beta-agonist for asthma symptoms twice/week or more on&#xD;
                  average over the past month&#xD;
&#xD;
               -  Nocturnal awakenings with asthma symptoms more than once per week on average over&#xD;
                  the last month&#xD;
&#xD;
               -  Two or more emergency department visits, unscheduled provider visits, prednisone&#xD;
                  courses or hospitalizations for asthma in the past 12 months&#xD;
&#xD;
          -  Currently on stable dose of daily inhaled corticosteroid medication (ICS) for asthma&#xD;
             control equivalent to 88mcg of fluticasone or greater for at least 6 weeks from the&#xD;
             time of enrollment. Participant must be on National Asthma Education and Prevention&#xD;
             Program (NAEPP) controller step 2, 3 or 4.&#xD;
&#xD;
          -  Currently with mild GERD symptoms reported at V1 defined by a score on the Pediatric&#xD;
             GERD Symptom Assessment Score greater than 15 and less than 80. GSAS ranges from 0 to&#xD;
             &gt;440.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Taking daily CYP2C19 substrates, inducers or inhibitors medication&#xD;
&#xD;
          -  Past or current history of moderate-severe GERD or related disorders (erosive&#xD;
             esophagitis, peptic ulcer disease, eosinophilic esophagitis) which in the opinion of&#xD;
             the pediatric gastroenterology safety specialist/study physician requires treatment&#xD;
             with acid-blocking agents;&#xD;
&#xD;
          -  Daily use of a PPI for more than 4 consecutive weeks in the past 6 months;&#xD;
&#xD;
          -  previous intubation for asthma,&#xD;
&#xD;
          -  admission to intensive care unit for more than 24 hours for asthma in the past year,&#xD;
&#xD;
          -  Previous surgery involving the esophagus or stomach (anti-reflux surgery, peptic ulcer&#xD;
             surgery, trachea-esophageal fistula repair);&#xD;
&#xD;
          -  Forced expiratory volume in 1 second (FEV1) &lt; 60% of predicted at enrollment;&#xD;
&#xD;
          -  Any major chronic illness that would interfere with participation in the intervention&#xD;
             or completion of the study procedures;&#xD;
&#xD;
          -  History of phenylketonuria (PKU);&#xD;
&#xD;
          -  Medication use: treatment of GERD symptoms with over-the-counter antacids 4 days/week&#xD;
             or more on average over past month;&#xD;
&#xD;
          -  Theophylline preparations, azoles, anti-coagulants, insulin for Type 1 diabetes,&#xD;
             digitalis, oral iron supplements when administered for iron deficiency within 1 month;&#xD;
&#xD;
          -  Any investigational drugs within the past 2 months;&#xD;
&#xD;
          -  Drug Allergies: previous allergic reaction from lansoprazole or other proton pump&#xD;
             inhibitor medication or adverse reaction to aspartame;&#xD;
&#xD;
          -  Inability to complete baseline measurements in a satisfactory manner according to the&#xD;
             judgment of the research coordinator or site PI;&#xD;
&#xD;
          -  Less than 75% completion of daily diary for asthma symptoms, SABA use and ICS&#xD;
             medication adherence during the run-in period;&#xD;
&#xD;
          -  Plan for family to move from study location within the next 6 months.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jason E Lang, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke Health</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Joan Wilson, BSN</last_name>
    <phone>919-681-8739</phone>
    <email>joan.wilson@duke.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Nemours Children's Specialty Care</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32207</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kathryn Blake, Pharm.D.</last_name>
      <phone>904-697-3806</phone>
      <phone_ext>55-3806</phone_ext>
      <email>kathryn.blake@nemours.org</email>
    </contact>
    <investigator>
      <last_name>Kathryn Blake, Pharm.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joan Wilson, BSN</last_name>
      <phone>919-681-8739</phone>
      <email>joan.wilson@duke.edu</email>
    </contact>
    <investigator>
      <last_name>Jason E Lang, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 13, 2016</study_first_submitted>
  <study_first_submitted_qc>January 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 10, 2017</study_first_posted>
  <last_update_submitted>February 15, 2023</last_update_submitted>
  <last_update_submitted_qc>February 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Duke University</investigator_affiliation>
    <investigator_full_name>Jason Lang, M.D., M.P.H.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Personalized Medicine</keyword>
  <keyword>CYP2C19</keyword>
  <keyword>Lansoprazole</keyword>
  <keyword>Pharmacokinetics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastroesophageal Reflux</mesh_term>
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lansoprazole</mesh_term>
    <mesh_term>Dexlansoprazole</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03015610
org study id: Pro00079073
nct id: NCT03015610
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study will evaluate the effect of CYP2C19 and ABCB1 genes on pharmacokinetics of
      lansoprazole in children with mild gastroesophageal reflux (GER) and uncontrolled asthma. It
      will determine if genotype-guided lansoprazole dosing of lansoprazole improves GER and asthma
      control.
BACKGROUND: Poorly controlled asthma especially in children remains a major public health
      problem. Many children with poor asthma control experience gastroesophageal reflux (GERD).
      The effect of mild GERD on asthma remains controversial despite studies involving proton-pump
      inhibitors (PPIs) assessing their effect on asthma. Past inconsistent findings regarding the
      effect of PPIs on asthma control may have resulted from ineffective dosing strategies of
      proton-pump inhibitors employed in these studies. Drug levels and efficacy vary widely in the
      population and depend on genetics. Dosing in children which adjusts for the gene CYP2C19 may
      improve efficacy and reduce side-effects leading to improved asthma control.

      HYPOTHESIS: #1: The investigators hypothesize that genotype-tailored lansoprazole dosing will
      reduce asthma symptoms in children with mild symptoms of GERD compared to placebo. #2:
      CYP2C19 and ABCB1 genetic variants influence the pharmacokinetics (drug levels) of
      lansoprazole as determined by population pharmacokinetic modeling.

      METHODS: The investigators will conduct a 6-month randomized controlled trial comparing
      genotype-tailored lansoprazole dosing versus matched placebo in the control of asthma
      symptoms in 6-17 year olds with asthma and mild reflux. All participants will have baseline
      pharmacokinetics analysis following a single genotype-tailored dose to assess the effects of
      CYP2C19 and ABCB1.

      IMPACT: These results would be a major advance in the science of safe dosing of proton-pump
      inhibitors in children and for the management of the millions of children struggling with
      reflux and asthma.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change in Asthma Control Questionnaire (ACQ) from Screening through Week 26
time frame: Measured at weeks -2 (screening), 0 (baseline), 8, 16, 26
description: The ACQ considers a broad set of common indicators of asthma control including use of bronchodilators, cough, nocturnal symptoms, level of activity, and pulmonary function.
measure: Change in GERD Symptom Assessment Questionnaire Score (GSAS) from Screening through Week 26
time frame: Measured at weeks -2 (screening), 0 (baseline), 4, 8, 12,16, 20, 26
description: A 10-item tool that has been validated in children in the assessment of gastroesophageal reflux disease related symptoms such as chest/abdominal pain, pain/choking with eating, swallowing dysfunction, regurgitation and nausea. It assesses symptom frequency and severity from the previous 7-days on an 8-point scale with 0 and 7 indicating the least and greatest severity, respectively.
measure: Change in Asthma Symptom Utility Index (ASUI) from Screening through Week 26
time frame: Measured at weeks -2 (screening), 0 (baseline), 8, 16, 26
description: Questionnaire measures changes in asthma control.
measure: Annualized rate of asthma exacerbations
time frame: Week 0 (baseline) through Week 26
description: An exacerbation will be defined per the recommendations of the NIH Asthma Exacerbation Taskforce and will be defined as a worsening of asthma requiring the use of a systemic corticosteroid (at least 3 days of prednisolone/ prednisone or ≥1 days of dexamethasone) to prevent asthma worsening.
measure: Annualized rate of Episodes of Poor Asthma Control (EPAC)
time frame: Week 0 (baseline) through Week 26
description: A study EPAC will be present if the participant meets any of the following criteria, (1) addition of systemic corticosteroid medication for asthma as above, (2) any unscheduled visit to a non-study related health care provider (ED, urgent care, hospital) for asthma symptoms, (3) increased use of rescue Short-Acting Beta Agonists (SABA) by more than 4 additional puffs (or more than 2 additional nebulizations) above baseline amount determined at enrollment.
measure: Annualized rate of respiratory tract infection (RTI)
time frame: Week 0 (baseline) through Week 26
description: Participants/Caregivers will be asked to document symptoms of RTI on daily diary cards per consensus definitions. RTI symptoms will include: (1) runny nose; (2) stuffy or blocked nose or noisy breathing; (3) cough; (4) fever, feels hot, or has chills; (5) sore throat; and (6) sneezing.
measure: Change in Lung Function Testing from Screening through Week 26
time frame: Measured at week -2 (screening), week 26
description: Forced Expiratory Volume in 1 Second (FEV1) measurement
arm group label: Placebo
arm group type: Placebo Comparator
description: participants will receive oral blinded matched placebo once daily
arm group label: Genotype-guided Lansoprazole
arm group type: Experimental
description: participants will receive oral blinded commercially available lansoprazole once daily with a dose appropriate for the participant's metabolizer phenotype
intervention type: Drug
intervention name: commercially available lansoprazole
description: these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily lansoprazole for 24 weeks
arm group label: Genotype-guided Lansoprazole
other name: once daily
intervention type: Drug
intervention name: matched placebo
description: these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily placebo for 24 weeks
arm group label: Placebo
other name: once daily
criteria: 
gender: All
minimum age: 6 Years
maximum age: 17 Years
healthy volunteers: No
last name: Jason E Lang, MD, MPH
role: Principal Investigator
affiliation: Duke Health
last name: Joan Wilson, BSN
phone: 919-681-8739
email: joan.wilson@duke.edu
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Duke University
investigator full name: Jason Lang, M.D., M.P.H.
investigator title: Principal Investigator
mesh term: Gastroesophageal Reflux
mesh term: Asthma
mesh term: Lansoprazole
mesh term: Dexlansoprazole
sharing ipd: No