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Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children With Uncontrolled Asthma (GenARA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03015610
Recruitment Status : Recruiting
First Posted : January 10, 2017
Last Update Posted : February 7, 2019
Thrasher Research Fund
Nemours Children's Clinic
Information provided by (Responsible Party):
Jason Lang, M.D., M.P.H., Duke University

Tracking Information
First Submitted Date  ICMJE December 13, 2016
First Posted Date  ICMJE January 10, 2017
Last Update Posted Date February 7, 2019
Actual Study Start Date  ICMJE October 31, 2017
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 7, 2017)
Change in Asthma Control Questionnaire (ACQ) from Screening through Week 26 [ Time Frame: Measured at weeks -2 (screening), 0 (baseline), 8, 16, 26 ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03015610 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2017)
  • 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 ]
    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.
  • Change in Asthma Symptom Utility Index (ASUI) from Screening through Week 26 [ Time Frame: Measured at weeks -2 (screening), 0 (baseline), 8, 16, 26 ]
    Questionnaire measures changes in asthma control.
  • Annualized rate of asthma exacerbations [ Time Frame: Week 0 (baseline) through Week 26 ]
    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.
  • Annualized rate of Episodes of Poor Asthma Control (EPAC) [ Time Frame: Week 0 (baseline) through Week 26 ]
    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.
  • Annualized rate of respiratory tract infection (RTI) [ Time Frame: Week 0 (baseline) through Week 26 ]
    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.
  • Change in Lung Function Testing from Screening through Week 26 [ Time Frame: Measured at week -2 (screening), week 26 ]
    Forced Expiratory Volume in 1 Second (FEV1) measurement
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children With Uncontrolled Asthma
Official Title  ICMJE Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children With Uncontrolled Asthma
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Asthma
  • Gastroesophageal Reflux
Intervention  ICMJE
  • Drug: commercially available lansoprazole
    these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily lansoprazole for 24 weeks
    Other Name: once daily
  • Drug: matched placebo
    these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily placebo for 24 weeks
    Other Name: once daily
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    participants will receive oral blinded matched placebo once daily
    Intervention: Drug: matched placebo
  • Experimental: Genotype-guided Lansoprazole
    participants will receive oral blinded commercially available lansoprazole once daily with a dose appropriate for the participant's metabolizer phenotype
    Intervention: Drug: commercially available lansoprazole
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 7, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2020
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age: 6-17 year olds with documented clinician-diagnosed asthma
  • Evidence of recent uncontrolled asthma (must meet at least one of the following). This convention for defining poorly-controlled asthma has been successfully used in a large pediatric trial.

    • ACQ > 1.2
    • Use of short-acting beta-agonist for asthma symptoms twice/week or more on average over the past month
    • Nocturnal awakenings with asthma symptoms more than once per week on average over the last month
    • Two or more emergency department visits, unscheduled provider visits, prednisone courses or hospitalizations for asthma in the past 12 months
  • Currently on stable dose of daily inhaled corticosteroid medication (ICS) for asthma control equivalent to 88mcg of fluticasone or greater for at least 6 weeks from the time of enrollment. Participant must be on National Asthma Education and Prevention Program (NAEPP) controller step 2, 3 or 4.
  • Currently with mild GERD symptoms reported at V1 defined by a score on the Pediatric GERD Symptom Assessment Score greater than 15 and less than 80. GSAS ranges from 0 to >440.

Exclusion Criteria:

  • Taking daily CYP2C19 substrates, inducers or inhibitors medication
  • Past or current history of moderate-severe GERD or related disorders (erosive esophagitis, peptic ulcer disease, eosinophilic esophagitis) which in the opinion of the pediatric gastroenterology safety specialist/study physician requires treatment with acid-blocking agents;
  • Daily use of a PPI for more than 4 consecutive weeks in the past 6 months;
  • previous intubation for asthma,
  • admission to intensive care unit for more than 24 hours for asthma in the past year,
  • Previous surgery involving the esophagus or stomach (anti-reflux surgery, peptic ulcer surgery, trachea-esophageal fistula repair);
  • Forced expiratory volume in 1 second (FEV1) < 60% of predicted at enrollment;
  • Any major chronic illness that would interfere with participation in the intervention or completion of the study procedures;
  • History of phenylketonuria (PKU);
  • Medication use: treatment of GERD symptoms with over-the-counter antacids 4 days/week or more on average over past month;
  • Theophylline preparations, azoles, anti-coagulants, insulin for Type 1 diabetes, digitalis, oral iron supplements when administered for iron deficiency within 1 month;
  • Any investigational drugs within the past 2 months;
  • Drug Allergies: previous allergic reaction from lansoprazole or other proton pump inhibitor medication or adverse reaction to aspartame;
  • Inability to complete baseline measurements in a satisfactory manner according to the judgment of the research coordinator or site PI;
  • Less than 75% completion of daily diary for asthma symptoms, SABA use and ICS medication adherence during the run-in period;
  • Plan for family to move from study location within the next 6 months.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Joan Wilson, BSN 919-681-8739
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03015610
Other Study ID Numbers  ICMJE Pro00079073
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jason Lang, M.D., M.P.H., Duke University
Study Sponsor  ICMJE Jason Lang, M.D., M.P.H.
Collaborators  ICMJE
  • Thrasher Research Fund
  • Nemours Children's Clinic
Investigators  ICMJE
Principal Investigator: Jason E Lang, MD, MPH Duke University Health System
PRS Account Duke University
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP