Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children With Uncontrolled Asthma
Phase: PHASE3
Conditions: Asthma, Gastroesophageal Reflux
Sponsor: Jason Lang, M.D., M.P.H.

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Thrasher Foundation – GENARA   
 
 
 
 
 
 
 
 
Version 8.0
IND # 130170 
 
 
 
 
 
 
 
 
 
 
Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children with Uncontrolled Asthma
(GenARA)
Funding Agency:
Thrasher Research Fund
Phase III-IV Trial
Protocol Date:
December 13, 2021
Protocol Version:
7.0
IND Number:
130170
    NCT ID:                                                                 NCT03015610
Jason E. Lang, MD, MPH
Assoc Professor of Pediatric MSRB-1  
203 Research Drive
BOX 2644 MED CTR
Duke University School of Medicine 
Durham, NC 27710
P (919) 684-8657
C (919) 717-9960
F (919) 668-3750
e-mail: jason.lang@duke.edu
Principal Investigator (IND 

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Statement of Compliance 
 
 
 
 
 
This trial will be conducted in compliance with the protocol, International Council for Harmonisation (ICH) 
guideline E6: Good Clinical Practice (GCP): Consolidated Guideline, and the applicable regulatory 
requirements from the Canadian and United States Federal Regulations.  The US regulations include but 
are not limited to 45 CFR 46 (Human Subjects Protection), 21 CFR 312 (Investigational New Drug), 21 CFR 
part 50 (Protection of Human Subjects, incorporating Subpart D Additional Safeguards for Children in 
Clinical Investigations, and 21 CFR part 56 (Institutional Review Board [IRB]) as well as international 
regulatory requirements, if applicable. 
 
 
All individuals responsible for the design and/or conduct of this study have completed Human Subjects 
Protection Training and are qualified to be conducting this research. 

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SITE PRINCIPAL INVESTIGATOR STATEMENT 
 
 
I have read the protocol, including all appendices, and the product label, and I agree that it contains all 
necessary details for my staff and me to conduct this study as described. I will personally oversee the 
conduct of this study as outlined herein and will make a reasonable effort to complete the study within the 
time designated. I agree to make all reasonable efforts to adhere to the attached protocol. 
 
 
I will provide all study personnel under my supervision with copies of the protocol and access to all 
information provided by the sponsor or the sponsor’s representative. I will discuss this material with study 
personnel to ensure that they are fully informed about the effectiveness and safety parameters and the 
conduct of the study in general. I am aware that, before beginning this study, the Institutional Review Board 
(IRB) responsible for such matters must approve this protocol in the clinical facility where it will be 
conducted. 
 
I agree to provide all participants with informed consent forms, as required by government and International 
Conference on Harmonisation regulations. I further agree to report to the sponsor or its representative any 
adverse events in accordance with the terms of this protocol and the U.S. Code of Federal Regulations, 
Title 21, part 312.64 and ICH GCP 4.11. 
 
 
 
Site Principal Investigator Name (Print) 
 
 
 
 
Signature 
Date 

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STUDY PRINCIPAL INVESTIGATOR / IND SPONSOR SIGNATURE 
 
 
 
 
The signature below documents the review and approval of this protocol and the attachments (e.g., 
package inserts), and provides the necessary assurances that this clinical study will be conducted 
according to all stipulations of the protocol, including all statements regarding confidentiality and according 
to local legal and regulatory requirements and to the principles outlined in applicable U.S. federal 
regulations and ICH guidelines. 
 
 
 
Jason E. Lang, MD, MPH 
GENARA Study Principal 
Investigator Name 
 
 
 
 
 
Signature 
Date 

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Table of Contents 
 
Page 
 
1. 
Key Roles………………………………………………………………………………………………………
 
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Background Information & Scientific 
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2.1. Summary of Study Background 
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2.2. Scientific Rationale…………………………………………………………………………………………..
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2.2.1. 
Relationship between GERD and Asthma………………………………………………………..
 
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2.2.2. 
Pharmacokinetics and treatment efficacy of PPIs depend on the CYP2C19 gene……….
 
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2.2.3. 
Effect of CYP2C19 genetic variation on responsiveness to PPI……………………………..
 
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2.2.4. 
Importance of CYP2C19 variation in PPI-related adverse side effects………………………..
 
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2.2.5. 
Rationale for five diplotypes/phenotypes and dosing adjustment…………………………..
 
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2.2.6. 
Pharmacokinetics of PPIs may also depend on ABCB1 genotype………………………….
 
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2.3. Potential Risks and Benefits……………………………………………………………………………….
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2.3.1. 
Potential Risks………………………………………………………………………………………...
 
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2.3.2. 
Potential Benefits……………………………………………………………………………………..
 
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2.3.3. 
Compensation…………………………………………………………………………………………
 
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3. 
Objectives……………………………………………………………………………………………………...
 
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3.1. Study Outcome measures…………………………………………………………………………………..
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3.1.1. 
Primary Outcome Measures………………………………………………………………………...
 
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3.1.2. 
Secondary Outcome Measures…………………………………………………………………….
 
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4. 
Study Design………………………………………………………………………………………………….
 
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5. 
Study Population:…………………………………………………………………………………………….

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5.1. Selection of the study population…………………………………………………………………………
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5.2. Enrollment Criteria…………………………………………………………………………………………...
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5.2.1. 
Inclusion Criteria……………………………………………………………………………………...
 
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5.2.2. 
Exclusion Criteria……………………………………………………………………………………..
 
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5.2.3. 
Exclusion considerations…………………………………………………………………………...
 
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5.2.4. 
Inclusion of females and minorities……………………………………………………………….
 
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5.2.5. 
Screen Failure 
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5.3. Treatment Assignment Procedures……………………………………………………………………….
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5.3.1. 
Additional Participant Enrollment…………………………………………………………………
 
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5.3.2. 
Randomization procedures…………………………………………………………………………
 
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5.3.3. 
Masking Procedures………………………………………………………………………………….
 
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5.3.4. 
Reasons for Participant Withdrawal………………………………………………………………
 
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5.3.5. 
Termination of Study…………………………………………………………………………………
 
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6. 
Study Procedures……………………………………………………………………………………………
 
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6.1. Summary of Procedures…………………………………………………………………………………….
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6.2. Screening…………………………………………………………………………………………………...…
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6.2.1. 
Run-in…………………………………………………………………………………………………...
 
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6.3. Baseline Assessments………………………………………………………………………………………
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6.3.1. 
Baseline Assessments: Visit 1……………………………………………………………………..
 
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6.3.2. 
Baseline Assessments: Visit 2……………………………………………………………………..
 
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6.3.3. 
Follow-up Procedures………………………………………………………………………………..
 
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7. 
Study Intervention/Product Description……………………………………………………………........
 
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7.1. Drug Administration………………………………………………………………………………………….

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7.1.1. 
Drug will be given Once daily………………………………………………………………………
 
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7.1.2. 
Study Drug Delivery………………………………………………………………………………….
 
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7.1.3. 
Confirmation of Study Drug Receipt………………………………………………………………
 
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7.2. Investigational New Drug (IND): commercially available lansoprazole…………………………….
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7.3. Pharmacology and Toxicology Information……………………………………………………………..
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8. 
Safety Procedures……………………………………………………………………………………………
 
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8.1. Methods and Timing for Assessing, Recording and Analyzing Safety Parameters……………..
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8.2. Adverse Event…………………………………………………………………………………………………
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8.3. Unexpected Adverse Event…………………………………………………………………………………
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8.4. Events of Special Interest…………………………………………………………………………………...
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8.5. Guidelines for Determining Causality…………………………………………………………………….
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8.5.1. 
Serious adverse event…………………………………………………………………………….…
 
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8.6. Guidelines for Assessing Intensity of an Adverse Event……………………………………………..
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8.7. Identification of Events and Timeframe for Reporting………………………………………………...
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8.8. Follow-up of Adverse Events………………………………………………………………………………
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8.9. Discontinuation of a Participant Due to Adverse Events……………………………………………..
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8.10.1. 
Regulatory Reporting………………………………………………………………………………...
 
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8.10.2. 
Safety Oversight………………………………………………………………………………………
 
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8.11. Justification for PPI placebo……………………………………………………………………………….
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8.12. Asthma Safety Parameters………………………………………………………………………………….
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8.12.1. 
Assessment and Documentation of Asthma Action Plan at Visit 1…………………………
 
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8.12.2. 
Daily Diary Card documentation of medication adherence…………………………………...
 
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8.12.3. 
Clinic Visit and Phone Contacts to monitor asthma control………………………………….
 
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8.12.4. 
Plans for asthma worsening………………………………………………………………………..
 
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8.13. GERD Safety Parameters……………………………………………………………………………………
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8.13.1. 
GERD non-pharmacologic management counseling…………………………………………..
 
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8.13.2. 
Clinic visit and phone contacts to monitor GERD severity…………………………………...
 
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8.13.3. 
Plans for GERD worsening………………………………………………………………………….
 
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8.13.4. 
Additional protections for children………………………………………………………………..
 
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9. 
Clinical monitoring…………………………………………………………………………………………...
 
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10. 
Data Analysis & Statistical Considerations……………………………………………………………..
 
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10.1. Analyses for Lansoprazole treatment effect…………………………………………………………….
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10.2. Analyses of genotype/haplotype associations…………………………………………………………
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10.3. Sample size and Power calculations……………………………………………………………………..
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11. 
Privacy, Data Storage & Confidentiality………………………………………………………………….
 
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11.1. Participant confidentiality…………………………………………………………………………………..
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12. 
Quality Control and Quality Assurance…………………………………………………………………..
 
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12.1. Data handling and record keeping………………………………………………………………………...
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12.2. Data Management Responsibilities……………………………………………………………………….
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12.3. Data Capture Methods……………………………………………………………………………………….
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12.4. Study Records Retention……………………………………………………………………………………
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12.5. Protocol Deviations…………………………………………………………………………………………..
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13. 
Ethics/Protection of Human Participants………………………………………………………………..
 
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13.1. Ethical Standard………………………………………………………………………………………………
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13.2. Institutional Review Board………………………………………………………………………………….
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13.3. Consent Process……………………………………………………………………………………………...
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13.4. Recruitment……………………………………………………………………………………………………
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13.5. Study Discontinuation……………………………………………………………………………………….
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14. 
References:……………………………………………………………………………………………………
 
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  15.    …………………………………………………………………………………………………… 58  
     …………………………………………………………………………………………... 
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ASUI 
Asthma Symptom utility index 
AUC 
Area under the curve 
DAS 
Duke Asthma Score 
DSMB 
data and safety monitoring board 
EM 
Extensive metabolizer 
EPAC 
Episodes of Poor Asthma Control 
FEV1 
Forced expiratory volume in 1 second 
GERD 
Gastroesophageal reflux disease 
GSAS 
GERD Symptom Assessment Questionnaire Score 
HPLC 
High Performance Liquid Chromatography 
ICS 
Inhaled corticosteroid medication 
IM 
Intermediate metabolizer 
IRB 
institutional review Board 
LC/MS/MS 
Liquid Chromatography/Mass Spectroscopy (2 Analyzers) 
NAEPP 
National Asthma Education and Prevention Program 
NASPGHAN North American Society for Pediatric Gastroenterology, 
Hepatology and Nutrition 
NM 
Normal metabolizer 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
OFV 
objective function value 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetics 
PM 
Poor metabolizer 
PMI 
Precision Medicine Initiative 
PPI 
Proton pump inhibitor 
RCT 
Randomized controlled trial 
RTI 
Respiratory Tract Infection 
SABA 
Short-Acting Beta Agonist 
SF 
Surgical gastric fundoplication 
SNP 
Single nucleotide polymorphism 
UM 
Ultra-rapid metabolizer 
URI 
Upper respiratory infection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL HISTORY OF CHANGES 
Version 
Date 
Summary of Changes 
1.0 
 
N/A Original protocol 
2.0 
 
Removal of open label oral lansoprazole dose at V2 
and PK blood draws 
Addition of Dr. Tarig Ali-Dinar to Key Personnel (Co-
Investigator) (Key Roles section) 
Removal of references to Appendix throughout 
document 
Change of compensation to reflect less time-
consuming and fewer invasive procedures (total 
compensation was $230 and now $120) 
Change of post-randomization in-person research 
visits to telehealth visits 
Replacement of daily diary cards with electronic 
diaries 
Addition of home spirometry 
 
3.0 
 
Addition of  
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
 
Protocol Title: 
Genotype-tailored Treatment of Symptomatic Acid-Reflux in Children with Uncontrolled 
Asthma (GenARA) 
Phase: 
III/IV 
 
Product: 
Lansoprazole 
 
    Objectives: 
Primary: to determine if genotype-tailored PPI dosing significantly improves asthma symptoms 
in children with mild GERD and poorly controlled asthma. 
Exploratory: to determine if genotype-tailored PPI dosing (a) significantly increases the risk for 
respiratory tract infection (RTI) 
Study Design: 
Two center randomized, placebo-controlled, genotype-tailored, double masked efficacy 
study 
Study Population:    Inclusion Criteria 
o 
Age: 6-17-year-old with documented clinician-diagnosed asthma 
o 
Evidence of recent uncontrolled asthma (must meet at least one of the following).  
• 
ACQ > 1.25 
• 
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 
o 
Currently on daily inhaled corticosteroid medication (ICS) for asthma control equivalent to 
88 mcg of fluticasone or greater for at least 6 weeks from the time of enrollment. Participant 
must be on NAEPP controller step 2, 3, 4 or 5 (5) (See Appendix B). Must be taking at on 
average >2days per week. 
o 
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. 
o 
 
o 
Access to internet-connected device 
 
Exclusion Criteria 
 
o 
Taking daily CYP2C19 substrates, inducers or inhibitors medication 
o 
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. 
o 
Daily use (i.e. 7 days/week) of a PPI for more than 4 consecutive weeks in the past 6 months; 
o 
previous intubation for asthma, 
o 
Previous surgery involving the esophagus or stomach (anti-reflux surgery, peptic ulcer surgery, 
trachea-esophageal fistula repair). 
o 
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. 
Current pregnancy, or recent pregnancy and currently lactating; females enrolled must agree to 
practice an adequate birth control method (abstinence, combination, barrier/spermicide, OCP) 
for the duration of the study. 

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Number of 
Participants/
sites: 
Duration of 
Participation
:
Outcomes:
o
History of phenylketonuria (PKU).
o
Medication use: treatment of GERD symptoms with over-the-counter antacids 4 days/week 
or more on average over past month.
o
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 30 days.
o
Drug Allergies: previous allergic reaction from lansoprazole or other proton pump inhibitor 
medication or adverse reaction to aspartame.
o
Inability to complete baseline measurements in a satisfactory manner according to the judgment of 
the research coordinator or site PI.
o
Less than 70% completion of all fields in daily diary for asthma symptoms, SABA use and ICS 
medication adherence during the run-in period.
o
Plan for family to move from study location within the next 6 months.
64 participants randomized / 2 sites
26 weeks (2-week run-in +24-week intervention) 
Primary: change in ACQ
Secondary: change in GSAS, ASUI; Annualized rate of exacerbation, EPAC, RTI 
Dose Schedule:
Participants will then receive a single blinded daily dose (lansoprazole or placebo) by mouth 
daily for 24 weeks.
Daily Dosing (and volume)
phenotype
%change*
<30kg
≥30kg
UM
100% ↑
30mg 
(10ml)
60mg 
(20ml)
EM
50% ↑
22.5mg 
(7.5ml)
45mg 
(15ml)
NM
0%
15mg 
(5ml)
30mg 
(10ml)
IM
30% ↓
10.5mg 
(3.5ml)
21mg 
(7ml)
PM
60% ↓
6mg 
(2ml)
12mg 
(4ml)
* - change from FDA recommended dose

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1. Key Roles 
 
For questions regarding this protocol, contact: 
Study Principal Investigator (IND Sponsor): 
 
Jason E. Lang, MD, MPH 
Division of Pediatric Pulmonary 
and Sleep Medicine 
Duke Health Center Creekstone 
4709 Creekstone Drive 
                                            Durham, North Carolina 27703 
Office (919) 684-3960 cell (919) 717-9960 Fax (919) 668-3750 
e-mail: jason.lang@duke.edu 
 
Study Co-Principal Investigator: 
 
Tarig Ali-Dinar 
Division of Pediatric Pulmonary and Sleep Medicine 
2400 Pratt Street 
Durham, North Carolina 27705 
Office (919) 684 9914 
cell (305) 972 9696 
Fax (919) 668-2292 
e-mail:Tarig.alidinar@duke.edu 
 
Project Leader:  
Joan Wilson RN 
Research Program Leader 
Department of Pediatrics, Duke University Medical Center 
Divisions of Allergy/Immunology, and Pulmonary/Sleep Medicine 
Hanes House Room 354 
315 Trent Dr. 
Durham, NC 27710 
Phone 919-681-8739 
 
Jacksonville Clinical Site PI: 
 
Kathryn Blake, Pharm.D., BCPS, FCCP 
Director, Center for Pharmacogenomics and Translational Research 
Principal Research Scientist 
Nemours Children's Specialty Care 
Biomedical Research Department 1st Floor 
807 Children's Way 
Jacksonville, FL 32207 
office: (904) 697-3806 (Cisco Extension 55-3806) 
cell: (904) 686-5047 
fax: (904) 697-3799 
email:kathryn.blake@nemours.org 
 
Sub-Investigators: Sub-investigators are included in the signature log and consent 
form(s) at each clinical site. 

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FDA Contact: 
 Laura Musse, RN, MS, CRNP 
Regulatory Health Project Manager 
Division of Pulmonary, Allergy, and Rheumatology Products 
ODE II| Office of New Drugs |CDER 
10903 New Hampshire Avenue WO22, Room # 3316 
Silver Spring, MD 20993 
240-402-3720 
301-796-9728 
Laura.Musse@fda.hhs.gov 
 
Sponsor Contact: 
Brittni Smith, PhD 
Thrasher Research Fund 
68 S. Main Street, Suite 400 
Salt Lake City, UT 84101 
ph: 801-240-4720 
fax: 801-240-1625 
email: SmithBA@Thrasherresearch.org 

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2. Background Information & Scientific Rationale 
2.1. Summary of Study Background Information 
New approaches are needed to control asthma because breakthrough asthma symptoms continue to 
cause suffering, cost, and disability, particularly in high-risk groups such as children and patients with 
co-morbidities. Asthma now affects roughly 1 in 10 children (7). Despite the longstanding presence of 
published guidelines (5), asthma remains difficult to control in many patients particularly minority 
children (8) and children with co-morbid conditions such as obesity (9) and gastro-esophageal reflux 
disease symptoms (10). Year after year asthma is a leading cause of urgent care visits, ED visits, 
hospitalizations and ICU admissions (11). Asthma also causes chronic relapsing symptoms that do not 
always lead to healthcare utilization but causes chronic disability and diminished quality-of-life. Chronic 
mild symptoms can lead to frequent self-medication, reduced sleep quality, impaired concentration in 
school and reduced extracurricular participation. The presence of obesity and GERD are associated 
with more of these chronic symptoms and lower quality of life in asthmatic children (6). Personalized 
approaches tailored to at-risk, high 
morbidity groups hold promise for improving 
asthma care. Years of evidence suggest a 
link between GERD and asthma (12-19), 
and recently we have shown that GERD 
symptoms are closely associated with 
asthma symptoms in children. Decades of 
data resulting from animal models (20-23), 
epidemiologic studies (12, 17), human 
esophageal acid instillation studies (24-33), 
pH probe asthma symptom correspondence 
studies (34), surgical fundoplication follow- 
up studies (35-39), and anti-GERD drug 
studies (40-43) all strongly suggest a link 
exists between GERD and asthma. These 
findings support the mechanism of gastric 
refluxate moving into the esophagus and 
activating acid-sensitive esophageal nerve 
fibers which cause vagus nerve-mediated 
airway triggering, or cough which is 
attributed to asthma. Using a large 
longitudinal analysis, we found that children 
with baseline GERD are at an increased risk of developing subsequent physician-diagnosed asthma 
(figure 1). We recently discovered a direct association between increasing GERD symptoms and 
asthma symptoms scores in overweight and obese children (figure 2). Overweight and obese children 
had significantly worse asthma symptoms compared to similar leans (44). When we adjusted for GERD 
scores, the greater asthma symptoms reported in obese children were abolished suggesting that 
GERD may be mediating asthma (44).We also found that a second replicate cohort showed a 
significant association between GERD scores and asthma scores in both lean and obese asthmatic 
children (45). As much as 85% of asthmatic children experience clinically significant GERD (46), and 
we recently published that >95% of overweight/obese asthmatic children reported two or more different 
GERD-related symptoms just in the preceding 7 days (6). Overall, these data support the idea that PPI 
intervention would improve asthma control in children with symptomatic GERD. Past trials studying the 
effect of acid-blockers on asthma symptoms have shown promising but inconsistent results which we 
propose is the result of a predictable PPI pharmacogenetic effect. The current literature suggests that 
anti-GERD medications do not consistently improve asthma outcomes in a diverse cohort of patients 
with GERD symptoms. However, a close review of the literature shows that among the majority of 
controlled studies there is consistently some efficacy signal that is unlikely due to chance.  What is 

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more likely is that current conventional PPI dosing is effective only for particular PPI responder groups. 
Current FDA-approved “conventional” lansoprazole dosing in children recommends just two different 
doses for children up through adolescence based on weight (<15kg: 15mg once daily; ≥15kg: 30mg 
once daily). Two recent systematic reviews concluded that PPIs most likely help subsets of patients 
with asthma (12, 47). Our preliminary work suggests that “PPI responders” are those with the normal 
PPI metabolizer phenotype who do not require dosing adjustments. Fewer PPI studies have been 
conducted in asthmatic children, however there is some evidence for significant asthma improvements 
with anti-GERD therapy (40-42). Partial or inconsistent response from a drug that is known to have 
variable clearance within the population (as do PPIs) is suggestive of a pharmacogenetic effect. 
 
2.2. Scientific Rationale 
 
2.2.1. 
Relationship between GERD and Asthma 
 
The relationship between symptomatic 
GERD and asthma has been long 
debated and remains unresolved. 
Cross sectional analyses (which show 
that one condition is more common in 
the other) do not contribute to the 
understanding of sequence and 
causality. However, as we have found 
in a recent large longitudinal cohort 
analysis in which all children were 
without asthma at baseline, antecedent 
GERD increases the risk for 
subsequent incident asthma (fig 1) 
compared to matched children without 
GERD. These findings from a large 
epidemiologic database are robust 
because the methodological approach 
addressed the traditional limitations of 
EHR database research, including 
adequate and compatible computer 
systems, inconsistent data standards across sites, lack of quality-control checks during data creation, 
collection and entry, and large-scale data cleaning. Though the mechanism for this epidemiologic 
association remains unclear, it is clear from these real-world longitudinal data involving >46,000 
children, GERD does antedate and increase the risk for later asthma. 
 
The mechanism that leads from GERD to incident asthma is likely to also be a factor in worsening 
asthma symptoms among children with underlying asthma. We recently found that overweight/obese 
children (n=35) with rigorously confirmed asthma had frequent GERD symptoms (>95% prevalence) 
and that scoring of GERD symptoms using a validated pediatric symptom measure (the GSAS) closely 
associated with severity of asthma symptoms (figure 2). A replicate cohort involving 306 children and 
adolescents with asthma also demonstrated significant association between GERD symptoms and 
asthma symptoms in all children regardless of obesity status (Leans: R=.317, p=.001; Obese: R=.507, 
p<.0001). Interestingly, this replicate cohort of 306 children with asthma excluded children with 
diagnosed GERD at the time of enrollment.  Among these children, the GSAS ranged from 0 to 276 
with a mean (SD) = 18.6 (29.5). Thus, to include only ‘mild’ GERD, we will exclude children at 
enrollment with a GSAS>80. This threshold is chosen as it was 2 SD above the mean GSAS for a 
group of children and adolescents without reported GERD at baseline. 

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2.2.2. 
Pharmacokinetics and treatment efficacy of PPIs depend on the highly polymorphic CYP2C19 
gene 
Despite documented variability in treatment response (48, 49), PPIs are generally viewed as the most 
efficacious group of acid-blocking agents because they overcome the redundant physiological control 
of acid secretion by inhibiting the gastric H+/K+ -ATPase, the final effector in the acid secretion pathway 
of gastric parietal cells. PPIs all act by covalently binding to the H+/K+-ATPase proton pump leading to 
reduced outflow of H+ ions into the canalicular space. Despite their short half-lives (1-4 hours), PPIs 
maintain their anti-secretory effect for 24-48 hours (50-52) (i.e., PPIs achieve a pharmacodynamic 
stead-state). PPIs are rapidly absorbed when taken orally, and clearances vary from 22-44% of liver 
blood flow in adults (53, 54) and children (55-58).  Most PPIs have distribution volumes that are 8%- 
20% of total body water and are metabolized mainly by CYP2C19. The CYP2C19 gene that encodes 
the CYP2C19 hepatic enzyme is located on chromosome 10q24.1-q24.3, has 9 exons and is highly 
polymorphic (59-61). The metabolism and pharmacokinetics of PPIs vary greatly from person-to-person 
because the CYP2C19 gene has both gain-of-function and loss-of-function alleles (2). The relatively 
common point mutation G681A (minor allele frequency: 10-30%) causes an aberrant splice site in exon 
5 resulting in a premature stop codon and a non-functional protein, and is responsible for the *2 allele 
(the most prevalent loss-of-function allele) which has significantly reduced clearance compared to 
normal metabolizers (NM)(62). Several losses of function alleles (*n=loss-of-function allele, e.g., 
CYP2C19 SNPs: *2 rs4244285; *3 rs4986893; *8 rs41291556; *9 rs17884712) reduce drug clearance 
and significantly increase AUC resulting in individuals being classified as either poor or intermediate 
metabolizers (PM or IM). CYP2C19*17 is a gain-of-function allele that has demonstrated increased 
transcriptional activity (63, 64) and appears to increase the clearance of PPIs. Depending on the 
CYP2C19 diplotype, individuals can be classified as poor metabolizers (PM; 2 *n alleles), normal 
metabolizers (NM; 2 wildtype (*1) alleles), intermediate metabolizers (IM; *1/*n), extensive metabolizers 
(EM; *1/*17) or ultra-rapid metabolizers (UM; *17/*17 alleles) (table 1).  The wild type (WT) CYP2C19*1 
alleles are associated with rapid clearance and are responsible for individuals being classified as 
normal metabolizers (NM)(60). Individuals carrying *1/*17 or *17/*17 alleles contribute to the extensive 
and ultrarapid metabolizer phenotypes (EM or UM), respectively (65, 66). Individuals carrying the 
*2/*17 diplotype have also been identified. The effect of *2/*17 diplotype on PPI AUC is not clear.  AUC 
in carriers of *2/*17 was higher in some studies compared to WT (67, 68) and similar to 
 
Table 1.  Definition of CYP2C19 Metabolizer Phenotype (1) 
ALLELEa 
GENOTYPE 
ALLELE ACTIVITY 
Metabolizer 
Phenotype 
Frequency (2) 
(pan-ethnic cohort) 
*1/*1 
Wild Type (WT) 
2 active alleles 
Normal 
Metabolizer (NM) 
41% 
*1/*n 
Heterozygous 
WT 
1 active allele 
1 inactive allele 
Intermediate 
Metabolizer (IM) 
21% 
*2/*2 or *n/*n 
Homozygous 
mutant 
2 inactive alleles 
Poor 
Metabolizer (PM) 
3% 
*1/*17 
Heterozygous 
WT 
1 active allele 
1 increased activity allele 
Extensive 
Metabolizer (EM) 
24% 
*17/*17 
Homozygous 
mutant 
2 increased activity alleles 
Ultrarapid 
Metabolizer (UM) 
4% 
*2/*17 
Heterozygous 
mutant 
1 inactive allele 
1 increased activity allele 
? 
6% 
a - *2, *3, *8, or *9 refer to loss-of-function (inactive) alleles; n – refers to any of the loss-of-function alleles, IM and PM will 
be combined in this proposal as PM based upon recent data (3). 

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WT in another (66). Our preliminary data from a study of lansoprazole support AUCs being similar 
among WT and *2/*17 carriers (figure 3) and will be considered as NM for the current study. Overall, 
the AUC following the administration of equal PPI doses given to adult PMs and EMs can vary 3-10-fold 
(53, 54, 69-71).  Importantly, little to no PK research among CYP2C19 metabolizer phenotypes has 
been conducted in children. 
2.2.3. 
Effect of CYP2C19 genetic variation on responsiveness to PPI 
Studies from both adults and children demonstrate that the 
efficacy of PPIs to treat GERD and related conditions are closely 
linked to plasma concentrations (58, 72-74).  Numerous studies 
in adults have shown that CYP2C19 variants markedly influence 
the PK and PD of PPI (53, 54, 59-61, 75-77). Patients needing 
acid-suppression who are extensive (EM) or ultra-rapid (UM) 
metabolizers have higher treatment failure rates compared to 
NMs when given conventional dosing (53, 54, 78). Additionally, 
H. pylori cure rates are significantly higher among PMs 
compared to EMs (69, 70) and higher doses of PPI are required 
to eradicate H pylori in EMs (70, 79). The same effect would be 
expected in children but has not been proven and thus pediatric 
PK studies are greatly needed. Some early reports suggested 
that CYP2C19 did not affect PPI levels in children, however 
recent studies have now demonstrated the importance 
CYP2C19 variants (66, 80, 81) on drug levels. For example, the 
clearance of pantoprazole was estimated in pediatric patients 
from birth to 16 years and was 70% lower in 
PMs compared to EMs (82). In a small number 
of patients, we recently found that metabolizer 
phenotype does affect PPI serum concentration 
in children (figure 3). Furthermore, our group 
has recently found a higher-than-expected 
prevalence of extensive and ultra-rapid 
metabolizer phenotypes (EM and UM) among a 
cohort of children failing PPI treatment and 
requiring surgical gastric fundoplication (SF) 
(figure 4). These data are consistent with 
EM+UM children needing genotype-tailored 
(increased) dosing of PPI to avoid treatment 
failures. Aim#2 of the current study will provide 
valuable data regarding the pharmacokinetics of 
PPIs in children stratified by CYP2C19 
genotype and metabolizer phenotype. This 
knowledge is significant because it is novel—we 
are not aware of any PK studies of PPIs in 
children which take into account genetic 
variation. Currently, the lansoprazole label 
describes possible drug-drug interactions with 
other drugs that are metabolized by CYP2C19, 
though current dosing recommendations do not 
utilize metabolizer phenotype to optimize 
dosing. Currently the PPI dosing for children is 
largely extrapolated from adult findings which 
for drugs used in children that are influenced by genetic variation is a major health and safety concern. 
Figure 4. Comparison of CYP2C19 
phenotype frequencies among children 
undergoing fundoplication surgery and 
matched controls. PM – poor metabolizer, 
NM – normal metabolizer, EM – extensive 
metabolizer. 
Figure 3: Diplotype of CYP2C19 affects lansoprazole 
pharmacokinetics in children. 
Phenotype 
Alleles 
Number (%) of 
Participants 
Mean ±SD LZ 
Con. ng/ml 
IM 
*1/*2 or *3 
13 (32%) 
303±165 
NM 
*1/*1 
11 (27%) 
199±137 
EM 
*1/*17 
11 (27%) 
168±146 
UM 
*17/*17 
2 (5%) 
156±123 
 
*2/*17 
4 (10%) 
201±57.1 
p=0.131, ANOVA test for linear trend 

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We compared drug levels following a single dose of conventionally dosed lansoprazole with CYP2C19 
genotype/metabolizer phenotype in 41 children with GERD and found a direct relationship between 
CYP2C19 diplotype and lansoprazole concentration (figure 3, p=.131, test for trend). Since serum PPI 
concentrations correlate with clinical response, diplotype is also very likely to be important in affecting 
both treatment success and risk of adverse events.  Our group recently found that EM children (n=21) 
on conventional PPI dosing and undergoing esophageal pH probe testing had inadequate acid-
blockade compared to NM+PM (n=53) (% time pH<4: 5.7 vs. 2.7, <.01; acid clearance (seconds): 
180.7 vs. 106.8, <.001). In addition, our group recently assessed all children who failed PPI therapy 
and subsequently underwent a surgical gastric fundoplication (SF) within our institution who also had 
available endoscopic tissue samples for DNA genotyping. We compared these children to race-
matched controls also taking PPI 
but who did not require fundoplication? 
The children failing PPI therapy and 
requiring fundoplication were significantly 
more likely to have the EM metabolizer 
phenotype compared to controls (41% 
vs. 25%, p<.01) (figure 4). In addition, 
significantly fewer children failing PPI 
and needing fundoplication had the PM 
metabolizer phenotype compared to 
controls (3% vs. 27%, p<.01). 
Collectively, these data strongly support 
our hypothesis that EM and UM children 
will benefit from a genotype-tailored 
(higher) dose of PPI to achieve optimal anti-secretory response. These findings are relevant to the 
current proposal because it argues that EM and UM children with GERD and asthma are being under- 
dosed on conventional PPI dosing. 
 
2.2.4. 
Importance of CYP2C19 variation in PPI-related adverse side effects 
In addition, treatment with PPI have consistently been associated with a number of adverse side-effects 
including C. difficile colitis (83-85) and respiratory infections (83, 86). We analyzed longitudinal data from 
36392 asthmatic children from 2000-2015 in the Nemours multi-state bioinformatics database. 
Asthmatic children recently prescribed a PPI were matched using a 1:4 ratio with similar asthmatic 
children (matched by race, ethnicity, sex, age at diagnosis, total observation period, and insurance 
status) with no previous PPI prescription, resulting in 2291 PPI (positive) and 9164 PPI (negative) 
children. Risk of incident acute and chronic aerodigestive infections were significantly greater following 
PPI (table 2). 
 
These data are consistent with PPI exposure increasing the risk for several acute and chronic 
respiratory and gastrointestinal infections which would be expected to worsen asthma symptoms. These 
data do not assess genotype. However, since IM and PM children make up roughly 25% of the 
population, a cohort this size would have the power to demonstrate an association between PPI and 
infections even if the effect was exclusive only to IM and PMs. In a study of 306 asthmatic children 
without significant GERD at baseline, we showed that PPI use at conventional doses for 6 months was 
associated with significantly greater sinusitis, strep throat and URI, using serial participant interviews (4). 
In a subsequent genetic sub-study, we showed that participants with one or more CYP2C19 loss-of- 
function alleles (IM or PM) had significantly higher serum lansoprazole levels compared to NM and 
were significantly more likely to suffer respiratory adverse events related to URI and strep/sore throat 
(3). Furthermore (and germane to this proposal), we showed that these same PM participants 
developed worse asthma control (triggered by URI) compared to NM after 4 months on conventional PPI 
Table 2: Proton Pump Inhibitors and Pediatric Infections 
ICD9 
Acute Conditions 
RR χ2 pvalue 
008.45_ 
Intestinal infection Clostridium difficile 
6.55 
1.48E-08 
461.8_ 
Other acute sinusitis 
2.64 
2.51E-05 
079.2_ 
Coxsackie virus infection  
2.19 
7.58E-03 
486_ 
Pneumonia, organism unspecified 
1.47 
3.08E-08 
461.9_ 
Acute sinusitis, unspecified 
1.28 
4.16E-09 
382.9_ 
Otitis media, unspecified 
1.21 
8.75E-06 
ICD9 
Chronic Conditions 
RR χ2 pvalue 
491.1_ 
Mucopurulent chronic bronchitis 
7.00 
3.69E-10 
473.2_ 
Chronic ethmoidal sinusitis 
5.25 
2.28E-08 
473.8_ 
Other chronic sinusitis 
4.76 
6.28E-24 
558.3_ 
Allergic gastroenteritis and colitis 
4.15 
1.00E-22 
473.9_ 
Unspecified sinusitis (chronic) 
2.13 
1.40E-37 
472.1_ 
Chronic pharyngitis 
1.97 
1.38E-03 
473.0_ 
Chronic maxillary sinusitis 
1.91 
1.31E-07 

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dosing (87). These data are important to the current proposal and to clinicians treating patients with 
GERD and asthma because conventional dosing of PPI in these IM and PM patients is likely to 
improve GERD symptoms at the cost of greater risk of URIs. Since URIs are the most common trigger 
for loss of asthma control in children, conventional dosing will ultimately not help asthma control. 
Instead, these children who have the IM or PM genotype could be given a genotype-tailored (lower) 
dose which will provide normal serum concentrations and improved GERD symptoms without the risk 
of excess URI. Aim#1 of our proposal employs a dosing adjustment based on pediatric PK principles 
from available data in children (1) to try to demonstrate that genotype-tailored PPI dosing improves 
both GERD symptoms and asthma in children. These results will have broad applicability because 
patients possessing significant CYP2C19 variants are a sizeable segment of the population. In fact, 
only about 40% of the population has the ‘normal’ (wildtype) metabolizer phenotype, while 
poor/intermediate (IM/PM), extensive (EM) and ultra-rapid (UM) metabolizer phenotypes make up 
24%, 24% and 4% of the population, respectively (2). 
 
2.2.5. 
Rationale for five diplotypes/phenotypes and dosing adjustment 
The CYP2C19 diplotypes and metabolizer phenotypes to be studied are described in Table 1. The 
frequencies of common diplotypes in our previous study (3), which comprised mainly Caucasians 
(38%) and African Americans (50%) were: *1/*1, 28%; *1/*n, 28%; and *1/*17, 34% where n refers to 
any of the loss-of-function SNPs.  These were similar to previous reports.  The frequencies of the less 
common diplotypes *2/*17 and *17/*17 were 5% and 3.5%, respectively (figure 3). If encountered, 
*2/*17 diplotype would be dosed as NM (no change from conventional) based on our prior figure 3 PK 
data. These data support the use of 5 distinct metabolizer phenotypes in children which warrant 
distinct dosing adjustments from the conventional two-tiered dosing. We have developed an 
evidenced-based dosing algorithm tailored to Extensive (EM), Ultra-rapid (UM), Intermediate (IM) and 
Poor metabolizers (PM) that is based on pediatric PK principles after analyzing the limited extant 
pediatric data (1). These estimates are also in agreement with that proposed by Furuta(78) but are as 
yet untested in children. 
 
 
2.2.6. 
Pharmacokinetics of PPIs may also depend on ABCB1 genotype 
SNPs in ABCB1, which encodes MDR1 (P-glycoprotein, P-gp), an efflux transporter expressed in the 
small intestine, colon and other tissue (88), may also influence the PK and PD of PPIs, which are 
substrates for MDR1(89). Three common SNPs:  C3435T (rs1045642), T1654C (rs1128503) (silent) 
and T2677G/A (rs2032582) have been reported to alter MDR1 expression and activity though results 
among studies are controversial (90). The C3435T SNP has been reported to influence the 
bioavailability of lansoprazole and other PPIs (89, 91-93) and possibly PPI pharmacodynamics (67) 
though more recent studies are controversial (94, 95).  Genotyping ABCB1 SNPs C3435T, T1654C, 
and T2677G/A captures a large portion of the observed haplotypes though haplotype association 
studies have been inconclusive (96). This project will explore the influence of genotypes and haplotyes 
of 3435/1654/2677 on the PK and PD of lansoprazole in children (all previous studies were done in 
adults). These studies are significant because they will identify whether common ABCB1SNPs need to 
be considered in guiding PPI dosing. 
 
2.3. 
Potential Risks and Benefits 
2.3.1. 
Potential Risks 
 
Risks of Blood Drawing 
There are small risks to blood sampling, usually some pain/discomfort with the blood stick and blood loss. 
Risks of Study Drug 

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Lansoprazole has been approved by the FDA for the indications GERD, duodenal ulcers, H. pylori 
eradication, benign gastric ulcer, NSAID-associated gastric ulcer, eosinophilic esophagitis, and pathological 
hypersecretory conditions.  It is approved by the FDA down to age 12 months.  Lansoprazole has been 
used in >10,000 patients in phase II and III clinical trials involving varying doses and durations and have 
been found to be well-tolerated in both short-term and long-term trials. Rarely (~1% of cases) patients have 
reported diarrhea, constipation, abdominal pain, and nausea with use of Lansoprazole. There is a risk of 
increased respiratory infections at the current conventional dosing. The current FDA label for Lansoprazole 
states that PPI therapy may be associated with increased risk for Clostridium difficile associated diarrhea. 
Long-term and multiple daily dose PPI therapy may be associated with an increased risk of osteoporosis- 
related fractures of the hip, write or spine, and hypomagnesemia has been reported rarely with prolonged 
treatment. 
 
The FDA does not recommend using lansoprazole for: 
• 
indications beside the above conditions. 
• 
children < 1 year of age. 
• 
prolonged periods (> 3 months). 
 
 
 
Risks of Study Participation. Participants in GenARA may be at risk for worsening of GERD symptoms. 
However, during the study all participants will be monitored closely for worsening of GERD symptoms by 
clinic and phone visits and there will be a GERD safety plan.  The first management strategy 
recommended in the recent NASPGHAN expert guidelines for pediatric GERD includes very specific 
evidence-based modifications to diet and lifestyle (97, 98). All participants in the trial (regardless of 
randomization) will receive the intervention of education about diet and lifestyle modifications to reduce 
GERD symptoms.  These therapies are outlined in the patient handout: GERD in Children and 
Adolescents, published jointly by the NASPGHAN and the American Academy of Pediatrics, which will be 
given to all subjects (see Appendix). Participants will also be monitored closely throughout the study for 
worsening of GERD symptoms.  A GERD rescue plan has been developed with consultation from the study 
pediatric gastroenterologist (see Section 8.11 Justification for PPI placebo/GERD Safety Plan and 
Appendix: GERD Safety Plan) and includes non-PPI antacid remedies. For patients with mild GERD and 
some persisting degree of asthma symptoms (i.e., GenARA participants), there exists equipoise regarding 
the role of long-term PPI use.  Participants randomized to PPI may have experienced improved asthma   
but there is an increased risk with long-term PPI use. Participants randomized to placebo may be more 
likely to have worsening of GERD and asthma symptoms but may also be at higher risk for adverse effects 
of long-term PPI use. Thus, use of a placebo-control with close safety monitoring in place is justifiable. 
 
Overall, the risks of this trial are small due to the baseline disease severity of participants, the nature of 
the interventions, the risk reduction safeguards and the safety of the testing procedures. 
 
Minimizing risk: 
• 
We have minimized these risks by studying lansoprazole at a dose which is likely to reduce side- 
effects since we will be giving participants with slower metabolism a lower dose. 
• 
We will review safety data with an independent Data & Safety Monitoring Committee, chaired by Dr. 
Christine Sorkness. 
• 
We will follow participants closely with a daily diary card plan and frequent phone and clinic visits to 
assess for adverse events and worsening of asthma or GERD symptoms. 
• 
Asthma and GERD safety plans have been developed to reduce the risk of SAEs. 
 

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2.3.2. 
Potential Benefits 
Lansoprazole may improve GERD symptoms and asthma symptoms together and reduce the risk for 
asthma exacerbations. Although improvements to asthma are not proven, increase in asthma control 
and decrease risk of exacerbations are potential benefits for participants enrolled in the study who 
receive lansoprazole. Conclusions drawn from this study will benefit children with both GERD and 
asthma in the future through better understanding of dose response and characterization of the safety 
profile of lansoprazole. Research coordinator will also train the participant and caregiver how to detect 
respiratory tract illnesses and how to perform nasal secretion collection and storage. Participant 
Training: participant and caregiver will be trained on the format and expectations of documentation of 
the daily e-diary. Completion of the e-diary will include completion of daily asthma medication, daily 
study drug receipt, asthma symptoms and any adverse symptoms. The participant will also be given 
patient handout information on Asthma Management and Lifestyle interventions to help reduce GERD 
symptoms.   
Research coordinators will perform lifestyle counseling to participant and caregivers regarding asthma 
management and management of GERD. Counseling may improve general health knowledge and self-
management of asthma and GERD. 
 
2.3.3. 
Compensation 
Subjects will be fairly compensated for their time and effort. (maximum of $120) 
       At the end of the screening visit, all subjects will receive $20. 
       At the completion of a successful visit 2 (randomization), subjects will receive $50.  
       At the completion of visit 5, subjects will receive $50 
 
 
3. Objectives 
 
Primary: to determine if genotype-tailored PPI dosing significantly improves asthma symptoms in 
children with mild GERD and poorly controlled asthma. 
Exploratory: to determine if genotype-tailored PPI dosing (a) significantly increases the risk for 
respiratory tract infection (RTI) 
 
 
3.1. Study Outcome measures 
 
3.1.1. 
Primary Outcome Measures 
 
Primary Outcome: We will use the ‘Juniper’ Asthma Control Questionnaire (ACQ) as the 
primary outcome. It has been used in many well-designed multi-center asthma trials in adults and 
children (4, 99). This instrument has been validated for young school-age children and adults and 
used successfully in clinical trials with parents answering the questions for children younger than 
11 years. 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. The ACQ is 
a good choice for primary outcome measure because:  1) it is a sensitive measure of asthma 
control (with a change of 0.4-0.5 in score reflecting a clinically meaningful difference in asthma 
control), 2) it is validated for children and adults in Spanish and English, and 3) its simplicity. 
Authorization for use has been obtained in advance from Professor Juniper. 
 
3.1.2. 
Secondary Outcome Measures 
 
o Change in GSAS, ASUI; 
o Annualized rate of exacerbations, EPAC, RTI; 
 

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3.1.2.1. 
GERD Symptom Assessment Questionnaire Score (GSAS) 
GERD symptoms will be measured using the Pediatric GERD Symptom Assessment 
Questionnaire (GSAS) which is a 10-item tool[40] 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. Use of the 
GSAS has informed the cut-off 15 or greater as having significant GERD symptoms (44). 
We chose a maximum value of 80 for inclusion on account of this was 2 SD from the 
mean GSAS for untreated children without baseline GERD(4, 100). 
 
3.1.2.2. 
Asthma Symptom Utility Index (ASUI) 
ASUI will measure changes in asthma control. 
 
3.1.2.3. 
Annualized rate of asthma exacerbations 
An exacerbation will be defined per the recommendations of the NIH Asthma 
Exacerbation Taskforce (101) 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. Families will be encouraged to call the 
GenARA research coordinator with any increase in asthma symptoms. Management of 
asthma symptoms and criteria for initiating SABA and/or oral steroids are outlined in detail 
in the Appendix: Safety Plan for GenARA participants who experience increased asthma 
symptoms.  If a subject seeks care outside of the GenARAtrial and receives oral steroids 
for asthma exacerbation this will be recorded as an exacerbation. 
 
3.1.2.4. 
Annualized rate of Episodes of Poor Asthma Control (EPAC) 
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 SABA by more than 4 additional puffs (or more 
than 2 additional nebulization) above baseline amount determined at enrollment. 
 
3.1.2.5. 
Annualized rate of respiratory tract infection (RTI). Participant/caregiver report 
Participants will be asked to document symptoms of RTI on daily diary cards per 
consensus definitions (102, 103). 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. We used definitions of respiratory tract illness that have been 
previously used in pediatric studies and has been adapted from the literature by an expert 
panel (103-106). An RTI will be defined as two symptoms for at least one full day or one 
symptom for two consecutive days (107). Structured phone follow-up visits and in-person 
clinical visits will occur every 4 weeks and will assess and document inter-current 
incidence of RTI, in a manner similar to what we have used in past pediatric trials (4). Past 
studies have shown that patients can reliably recall respiratory symptoms over several 
weeks (4, 108). 
 
3.1.2.6. 
Lung Function Testing 
We will use an approved spirometric system, which will be appropriately calibrated, 
and procedures conducted per American Thoracic Society standards (109). Outcomes 
will include forced vital capacity (FVC), forced expiratory volume 1 second (FEV1), and 
FEV1/FVC. Raw data and percent predicted values will be recorded and based on 

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accepted normative data. Percent predicted values will be computed using the same 
predicted lung function equations used in table 3 below in accordance with the NIH- 
AsthmaNet consortium. 
 
Table 3: Predicted Lung Function Equations 
Race/Ethnicity 
Designation 
Age 5 
Age 6-12 
13 or older 
Black 
Female: Caucasian x .85* 
Male: Caucasian x .91* 
African 
American** 
African American# 
Caucasian 
Caucasian* 
Caucasian** 
Caucasian# 
Asian 
Caucasian x .88* 
Caucasian x .88** 
Caucasian x .88# 
Hispanic 
Caucasian* 
Hispanic*** 
Mexican American# 
*Eigen, Bieler, Grant, Christoph, Terrill, Heilman, Ambrosius, Tepper. Spirometric pulmonary function in healthy preschool 
children. Am J Respir Crit Care Med 2001;163:619-23. 
** Wang, Dockery, Wypij, Fay, Ferris. Pulmonary function between 6 and 18 years of age. Pediatr Pulmonol. 1993;15:75-88. 
*** Hsu, Jenkins, Hsi, Bourhofer, Thompson, Tanakowa, Hsieh. Ventilatory functions of normal children and young adults – 
Mexican-American, white, and black. I. Spirometry. Pediatrics. 1979; 95(1):14-23. 
#Hankinson, Odencrantz, Fedan. Spirometric reference values from a sample of the general US population. Am J Respir Crit 
Care Med 1999; 159:179-87. 
 
4. Study Design 
 
We propose a 24-week prospective, randomized, blinded trial in 6–17-year-old children with 
inadequately controlled asthma and recent evidence of mild GERD symptoms (fig 5). At visit 1, 
saliva will be collected to isolate DNA and determine CYP2C19 genotype as previously described 
(3, 87). Genotyping will take place at Nemours Jacksonville under the direction of Drs. Mougey and 
Lima. Each participant’s metabolizer phenotype will be determined within 5 business days and 
classified according to table 1. These data will be entered into the secure Duke REDCap database 
(116) and shared with the respective research coordinator (Duke or Jacksonville). 
Following a 2-week run-in to demonstrate study adherence, participants will undergo 
randomization. Participants will be randomized to either genotype-tailored PPI dosing or matched 
placebo for the 24-week intervention.  
 
Participants will have close follow-up via phone visits (figure 5). The primary outcome during the 
intervention period will be change in Asthma Control Questionnaire (ACQ) at 6 months.  
Lansoprazole will be provided by CutisPharma, Inc. 

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5. Study Population: 
5.1. Selection of the study population 
Participants will be offered enrollment into the study via Institutional Review Board-approved 
methods including review of clinic schedules within the PI’s division and by IRB-approved 
advertisements. 
 
Consent: The study will be explained to the participant and caregiver by IRB-approved study staff 
(Principal Investigator, Co-Investigator, research coordinator or research assistant). Consent will 
be obtained by study staff specifically trained in obtaining consent. For children age 12-17, assent 
will also be obtained. 
 
 
5.2. Enrollment Criteria 
 
5.2.1. 
Inclusion Criteria 
• 
Documented informed consent from legal guardian prior to study procedures  
• 
Access to an iOS or Android enabled smartphone or tablet. 
• 
Age: 6–17-year-old 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 (4). 
 
ACQ > 1.25 
 
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 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 NAEPP controller step 2-5 (5). Must be taking on average > 2 days/week. 
• 
Currently with mild GERD symptoms (15>GSAS<80)(6) reported at V1.  GSAS ranges from 0 to 
>440. A score of 80 was felt to be a conservation cut-off as it corresponds to + 2 SD above the 
mean GSAS score for adolescents with asthma without a previous diagnosis of GERD (4, 100). 
 
5.2.2. 
Exclusion Criteria 
o Taking daily CYP2C19 substrates, inducers or inhibitors medication (see Appendix for 
CYP2C19 substrates, inducers, inhibitors); 
o Past or current history of 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. 
o Daily use (7 days/week) of a PPI for more than 4 consecutive weeks (or > 12 total weeks) in 
the 6 months. 
o previous intubation for asthma, 
o Previous surgery involving the esophagus or stomach (anti-reflux surgery, peptic ulcer 
surgery, trachea-esophageal fistula repair) 
o Forced expiratory volume in 1 second (FEV1) < 60% of predicted at enrollment. 
o Any major chronic illness in the opinion of the PI that would interfere with participation in the 
intervention or completion of the study procedures. 

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o Current pregnancy, or recent pregnancy and currently lactating; females enrolled must agree 
to practice an adequate birth control method (abstinence, combination, barrier/spermicide, 
OCP) for the duration of the study. 
o History of phenylketonuria (PKU); 
o Medication use: treatment of GERD symptoms with over-the-counter antacids four 
days/week or more on average over past month. 
o Theophylline preparations, azoles, anti-coagulants (warfarin/Coumadin), Atazanavir, 
Tacrolimus, methotrexate, insulin for Type 1 diabetes, digitalis, oral iron supplements when 
administered for iron deficiency within 1 month. 
o Any investigational drugs within the past 30 days. 
o Drug Allergies: previous allergic reaction from lansoprazole or other proton pump inhibitor 
medication or adverse reaction to aspartame; benzyl alcohol, corn starch, 
hydroxyethylcellulose, saccharin sodium, simethicone emulsion, sodium bicarbonate, sodium 
citrate (dihydrate), sorbitol solution, and sucralose. 
o Inability to complete study procedures in a satisfactory manner according to the judgment of 
the research coordinator or PI. 
o Less than 70% completion of all fields of daily diary (for asthma symptoms, SABA use and 
ICS medication adherence) during the run-in period; run-in can be extended by 1-2 weeks at 
the discretion of the site PI. 
o Plan for family to move from study location within the next 6 months. 
 
5.2.3. 
Exclusion considerations 
We have designed inclusion/exclusion criteria with help from pediatric experts in asthma and 
GERD to reduce risk. Children with poor lung function (<60% FEV1), past significant acid- 
related disease (erosive esophagitis, peptic ulcer disease, eosinophilic esophagitis), current 
GSAS > 80 at visit 1, or use of daily PPIs in past 12 months as defined above will not be 
enrolled. Children with a GSAS >80 after visit 1 will be given education about GERD 
symptoms and management and managed per the GERD Safety plan (see appendices). All 
enrollees at the first visit will have a thorough medical evaluation. Children who are found to 
have significant medical problems (chronic disease that would affect participation or acute 
disease requiring attention) will not be enrolled but instead will be triaged for appropriate care 
by Dr. Lang. If GSAS score becomes > 150, the case will be reviewed with the pediatric GI 
consultant for management. 
 
5.2.4. 
Inclusion of females and minorities 
No racial/ethnic groups or genders will be excluded from either aim. Past asthma trials in 
children at the Nemours Jacksonville and DUMC sites have recruited high proportions of 
African American and Hispanic/Latino children. 
 
              5.25.     Screen Failure 
                       Subject can re-enroll after 30 days of screen fail. Study staff will assign new study 
ID numbers after subject has been re-enrolled. Screen Failure: Generally, a screen failure will 
be someone who consented to participate in research but who was disqualified during screening 
procedures for various reasons, documented during the screening process. Reasons for the 
participant to fail screening may include, but are not limited to, the participant not meeting 
inclusion criteria or meeting exclusion criteria (ineligibility).  Participants who screen fail can be 
considered for re-enrollment after 30 days of the initial screen.  Study staff will assign a new 
study ID to these participants. 
 
 
5.3. Treatment Assignment Procedures 

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5.3.1. 
Additional Participant Enrollment 
If a participant is randomized (see 5.3.2) and does not receive more than 1 week of study drug, 
then an additional replacement participant may be enrolled. 
 
5.3.2. 
Randomization procedures 
Participants who satisfy all eligibility criteria will be randomized 1:1 (lansoprazole: placebo). 
The participant’s randomized treatment assignment will be obtained through the Duke REDCap 
enrollment/randomization system. Randomization will occur at visit 2. At visit 2, the research 
staff will complete a randomization eligibility form and enter it into a secure internet web form 
created by IT/Bioinformatics at the Duke Office of Clinical Research. The randomization 
sequence will be stratified by clinical center in permuted blocks sizes with assignment ratios of 
1:1. The treatment assignment number given to the participant will be associated with a specific 
drug kit. The study pharmacist at Duke will then make up the drug kit in a just-in-time fashion 
and provide a 30-day supply which will be rapid-shipped to the family.

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The randomization visit must capture and document:  
 
Confirmation of participant’s eligibility for randomization  
 
Confirmation of participant’s legal consent 
Completion of the randomization eligibility form by trained staff 
Documentation in REDCap of a body weight 
Documentation in REDCap of a valid and best address to overnight-ship study drug. 
 
If a participant is randomized but does not receive study drug, that participant will not count 
towards total sample size and will be replaced by a new participant who, in turn, will be 
assigned a new identification number and receive treatment corresponding to the new 
identification number. The reason for not dosing the participant will be noted on the CRF. 
 
Randomization: will occur at the end of the run-in period at Visit 2 and will occur roughly 14 
days following visit 1.  The range can be between 10 – 17 days.  The purpose of this visit will 
be to evaluate the participant’s adherence to study procedures, establish that the participant 
continues to be interested in participating in the study, establish that the patient meets all 
inclusion and exclusion criteria for randomization, undergo randomization, undergo further 
training on study procedures (e-diary, spirometry, study drug handling, study drug dosing, 
follow-up planning) and give monetary compensation. Randomization: trained research staff 
will complete a randomization checklist to confirm the participant meets criteria for 
randomization. These will include adherence to the e-diary, desire to remain in the study, no 
new health-related conditions exclusionary to randomization, confirmation that the family plans 
to remains in the area for study duration, no exacerbations of asthma and no significant 
changes in GER symptoms during run-in. Once study staff has confirmed that the participant is 
eligible for randomization, the research staff will sign-in to REDCap to look up and write down 
the participant’s randomization drug code ID and metabolizer phenotype on the randomization 
form. All randomization drug code IDs will have 5-6 digits. The randomization drug code will 
correspond to the drug kits that will be shipped to the home. 
 
Communication Procedures 
Metabolizer phenotype determination: based on CYP2C19 genotyping procedures performed 
at Nemours Jacksonville, each participant will be assigned a metabolizer phenotype: 
Each participant will have a metabolizer phenotype assigned by Dr. Mougey by 5 business 
days following visit 1.  The metabolizer phenotype will be entered by Dr. Mougey or assistant 
into the HIPAA-compliant GenARA REDCap-based study database (116). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4: phenotypes 
UM (5) 
Ultra-rapid 
EM (4) 
Extensive 
NM (3) 
Normal 
IM (2) 
Intermediate 
PM (1) 
Poor 

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5.3.3. 
Masking Procedures 
 
Participants, their families, and the study team will be blinded to the treatment assignment of 
PPI vs. placebo. Placebo will include the same suspension plus an inert corn-starch to 
maintain similar taste and consistency. Both active commercially available Lansoprazole and 
placebo liquid will be manufactured and supplied by Cutis Pharma, Inc. The pharmacy at the 
Duke site will prepare and dispense the study drug into a 30-day supply and will include a pre- 
marked syringe showing the appropriate individualized dosing. 

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5.3.4. 
Reasons for Participant Withdrawal 
The study clinician may choose to suspend study drug dosing for up to 48 hours for any 
reason. 
 
The investigator will withdraw a participant from receiving further study interventions if: 
Any clinically significant adverse event (AE) is deemed by the principal investigator to 
require discontinuation of study drug. 
Unmasking of the participant is performed. All intentional unmasking events should be 
recorded on a protocol deviation form in REDCap within 24 hours of the unmasking. The 
decision to unmask will be made in consultation with the Study PI if possible. The 
unmasked participant will be followed for safety for 7 days after the last dose and 
complete all remaining follow up assessments unless consent has been withdrawn. 
Requested by the FDA, Sponsor or DMC. 
 
Before discontinuing a participant from the study drug, the local investigator must contact the 
Study PI except in emergency situations. 
 
The participant’s parent or guardian may withdraw voluntarily from participation in the study at 
any time. The participant’s parent or guardian is not obligated to state the reason for 
withdrawal. The reasons for withdrawal, or failure to provide a reason, must be documented by 
the study team on an event report form. 
 
If a participant withdraws from treatment for any reason, we will attempt to continue them in the 
remaining study procedures (visits and all subsequent testing and follow-up). This is voluntary 
and will not occur if the participant withdraws consent. 
 
Unmasking Procedure: Contact information: call the 24/7 number (Duke PI) at 919-717-9960 
for ALL emergency unmasking requests.  . 
 
5.3.5. 
Termination of Study 
This study may be terminated at any time by FDA or the Investigational New Drug Application 
(IND) sponsor under advisement of the Data Monitoring Committee (DMC). 

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6. Study Procedures 
 
6.1. Summary of Procedures 
 
Table 5: Summary of Procedures 
Visit 
V1 
V2 
P1 
TH
V3 
P2 
TH 
V4 
P3 
TH 
V5 
Time (weeks)*** 
0 
2 
6 
10 
14 
18 
22 
26 
Consent/(assent) 
x 
Screening 
x 
Baseline Hx 
x 
Saliva for genotyping 
x 
Lifestyle counseling1 
x 
x 
Urine pregnancy testing* 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
x 
Physical exam 
x 
 
 
 
 
 
E-Diary training (or retraining) 
x 
x 
x 
x 
Spirometry 
x 
x 
xa 
xa 
xa 
E-Diary adherence assessment 
x 
x 
x 
x 
Health history2 
x 
x 
x 
x 
x 
x 
x 
Med adherence 
x 
x 
x 
x 
x 
x 
Con meds 
x 
x 
x 
x 
x 
Asthma Questionnaires3 
x 
x 
x 
x 
x 
x 
x 
x 
GSAS 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
Reimbursement 
x 
x 
x 
x 
x 
Discharge 
x 
1 – asthma and GERD counseling 
2 – clinical evaluation with physical examination can be performed as needed at the discretion of the site PI 
to evaluate adverse events or problems with asthma or reflux symptoms 
3 – ACQ6, ASUI, Duke Asthma Score 
GSAS=GERD symptom assessment Score 
*-for females of childbearing potential.  
*** optimal visit windows are +/- 5 days; window can be extended at the discretion of the PI 
a- home spirometry  
TH – telehealth visits over Maestro 
 
 
6.2. Screening 
Participants will be recruited through IRB approved methods including flyers, paid advertisements, 
clinic visits and telephone calls to established patients. 
 
6.2.1. 
Run-in 
The run-in period will begin following the end of visit 1 if the participant meets all criteria for 
inclusion into the study. The run-in period will be planned for 2 weeks. During this time the 
participant will continue his/her daily asthma medications as prescribed by his/her treating 
physician. The participant will begin completing daily diary cards to monitor asthma symptoms 
and to ensure that asthma control is reasonably stable. The participant and caregiver will be 
advised to call the study team in the event of any health problems. The participant will be 
advised to complete diary cards on daily basis and to not complete them all at once, or to 
complete them days at a time. Participants will not be able to be randomized if diary card 

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completion is not satisfactory.  Less than 75% completion of daily diary for asthma symptoms, 

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SABA use and ICS medication adherence during the run-in period will prompt an extension of 
the run-in for an additional 1-2 weeks at the discretion of the investigator. Participants will 
also be asked to perform spirometry utilizing the VitalFlo spirometer and app daily. 
 
 
 
6.3. Baseline Assessments and Training 
6.3.1. 
Baseline Assessments: Visit 1 
i. the study physician or nurse practitioner will complete the baseline physical exam 
form. 
ii. the RC will complete ATS-approved spirometry. Spirometry data can be 
abstracted from participant record if already conducted on day of Visit 1. 
iii. Baseline Asthma and Medical Directed Interview (with concomitant medications). 
iv. Saliva Collection for Genotyping 
v. Questionnaires directed by trained research coordinators. 
1. Asthma Control Questionnaire (ACQ) 
2. Asthma Symptom Utility Index (ASUI) 
3. Duke Asthma Score (DAS) 
4. GERD Symptom Assessment Score (GSAS) 
vi. VitalFlo Mobile App training (with spirometry training) 
 
 

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Figure 5. Study schema. 26-week randomized blinded placebo controlled intervention trial. A 2-week run-in will 
ensure adherence to study procedures prior to randomization. All participants will receive their first month supply of 
study medication (and all subsequent month supplies) by mail. All participants will receive basic asthma education and 
evidence-based GERD lifestyle counseling at V1.  

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Saliva collection for DNA isolation: Saliva will be collected into a special saliva kit called the 
Oragene•DISCOVER (OGR-500) (2 ml sample volume) 
 
 
See Appendix for procedure and handling (Oragene Saliva Collection Appendix). Briefly, the 
procedure to collect saliva goes as follows: (1) explain the procedure to the participant.  (2) 
the participant holds the funnel close to the mouth and carefully spits saliva into the funnel 
until the amount of liquid (not including bubbles) reaches the fill line on the funnel, (3) make 
sure the funnel stays upright and use one hand to stabilize the funnel, while the other hand 
carefully folds the lid closed. With closure the lid will snap into place. With closure, the liquid 
in the lid will mix with the saliva. Make sure the lid is closed tightly, (4) keep the tube upright 
and unscrew the funnel from the tube, (5) use the small cap to close the tube tightly, (6) 
make sure the cap is on tight before shaking vigorously for 5 seconds. All saliva samples 
from Duke and Jacksonville will be processed in the Jacksonville-based Nemours 
Pharmacogenomics Center.  The saliva sample in the Oragene collection tube is stable 
for >12 months at room temperature. Drs. Mougey and Lima will oversee final 
determination of the metabolizer phenotype for each participant. 
 
Genotyping.  We will identify common gain-of-function and loss- of-function SNPs for 
CYP2C19. Samples will be interrogated, and study personnel will be informed using the secure 
REDCap database. We have used this method previously (3) and reported the allele 
frequencies for the *2, *3, *8. *9, and *17 in pediatric and adult populations with asthma. These 
frequencies are shown above in table 1 and are similar to that reported in the literature (59, 60, 
117). Briefly, CYP2C19 SNPs will be interrogated using commercially available Taq-Man 
assays run in a 384 well ViiA 7 real-time qPCR instrument (both from Life Technologies, 
Carlsbad California).  The 5 µL TaqMan assay contains 2.5 µL of 2X TaqMan genotyping 
master mix, 0.13 µL of 40X TaqMan probe, and 10 ng of genomic DNA. The cycle program 
used is a modified version of the manufactures recommended cycling program that involves: 
Stage 1, 60ºC for 30 seconds; Stage 2, 95ºC for 10 minutes; Stage 3, 70 cycles of 96ºC for 15 
seconds, then 60ºC for 1 minute; Stage 4, 60ºC for 30 seconds). ABCB1 SNPs: C3435T 
(rs1045642), T1654C (rs1128503) (silent) and T2677G/A (rs2032582) will be genotyped using 
TaqMan and Hardy-Weinberg Equilibrium will be evaluated. 
Figure 6: Samples will be sent by over- 
night shipping to Nemours-Jacksonville: 
Care of: 
Edward B. Mougey, Ph.D. 
Nemours Pharmacogenetics Center 
Nemours Children's Clinic 
807 Children's Way 
Jacksonville, FL 32207 
Office:  904.697.3781 
Cell: 
904.803.9011 
Email 1: emougey@nemours.org 
Email 
2: emougey@vzw.blackberry.net 

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Data Entry: During the run-in period, the research coordinator or trained support staff will enter 
all demographic questionnaire and V1 PFT data into REDCap. REDCap forms will notify which 
forms need to be entered in real time. It is very important for each clinical site to enter the 
address that the participant wants to receive the study drug.  This address must be entered 
prior to randomization so that the Duke Investigational Drug Service can prepare and send the 
first month’s supply of study drug. Daily home PFT data and daily e-diary data will be 
automatically captured.  
 
Baseline Training: Visit 1 VitalFlo spirometry and App: At visit 1, after the participant has 
been determined to meet eligibility for entering the run-in the participant and guardian will be 
trained on how to download and use the vitalflo mobile app for recording daily study drug 
adherence, recording daily respiratory symptoms, and recording exacerbation events. They will 
also be taught how to use the Bluetooth connected home spirometer.  
 
  
                       VitalFlo Spirometer 
 
The VitalFlo spirometer is a compact, portable, home-based spirometer approximately the 
size of an inhaler that pairs with a smartphone app. The device uses an energy conserving 
turbine. Exhaled air flow causes the turbine to rotate, generating a voltage analogous to the 
rate of air flow across the turbine. The spirometer measures Forced expiratory volume in 1 
second (FEV1), or the volume of air that is exhaled in the first second. The device prompts 
the user to perform a minimum of three expiratory maneuvers in and records the best of the 
three maneuvers. The information generated is collected on a microprocessor and then 
transmitted by a low power Bluetooth radio to the VitalFlo App (password protected) on the 
user's iPhone. The user is alerted, by the App, if their expiratory effort is inadequate (such 
as early termination of exhalation) and is provided coaching for proper technique. The data 
is then transmitted to a HIPAA-compliant cloud database. Participants will receive a survey 
after each time they measure lung function to gather information about any asthma 
symptoms they are experiencing. Investigators will ask that they use the VitalFlo spirometer 
prior to using albuterol for symptoms if possible. VitalFlo will also track, via cloud 
databases, outdoor temperature, humidity, air quality, and pollen counts: all environmental 
factors that can influence asthma symptoms. Routine calibration is not needed. The 
eventual goal of VitalFlo use is to identify drops in lung function preceding asthma 
symptoms to allow persons with asthma to intervene with rescue medications early in 
hopes of preventing progression to a more serious exacerbation of asthma ("red zone") 
requiring healthcare utilization, such as emergency care or hospitalization. 
 
Participants will be given the VitalFlo spirometer after receiving instruction on proper use of 
the device. Participants will be asked to use the VitalFlo spirometer three times a week 
either in the morning or in the evening time. Investigators will use the morning and evening 
measurements to calculate the mean FEV1 for the day. After performing the spirometry 
maneuver, the user will be prompted to answer questions about their asthma symptoms. 
The lung function measurements and responses to the questions will be transmitted to a 
cloud-based HIPAA-compliant database and will be available for the investigators to 
download. Changes in lung function will be matched to subject-reported asthma symptoms 
and/or albuterol use. 
 
 

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                     Daily E-diary Questions Sent via the VitalFlo App 
 
 
 
During the run-in period between Visit 1 and Visit 2, participants will be expected to complete 
spirometry and e-diary questions each day. The vitalFlo mobile app will signal when the diary 
questions are ready and will prompt the participant to complete three forced expiratory 
maneuvers. 
 
6.3.2. 
Baseline Assessments: Visit 2 
i. The RC will complete ATS-approved spirometry 
ii. Randomization eligibility form 
iii. Questionnaires directed by trained research coordinators. 
a. Asthma Control Questionnaire (ACQ) 
b. Asthma Symptom Utility Index (ASUI) 
c. Duke Asthma Score (DAS) 
iv. Randomize (if eligible) (see randomization procedure above) 
v. Confirm appropriate mailing address  
 
 
 
Baseline Training: Visit 2 
Duke GenARA Daily E-Questionnaire 
1. Did you take your GenARA medication today? 
 
Yes 
 
No 
2. Do you have cold or respiratory infection symptoms? 
 
Yes 
 
If yes, proceed to Q2A 
 
No 
 
If no, proceed to Q3 
2A. Which of the following symptoms do you have? (Choose all that apply) 
 
Runny/stuffy nose 
 
Sore or itchy throat 
 
Headache 
 
Fever 
 
Cough 
3. Did you have any daytime or nighttime asthma symptoms in the last 24 hours? 
 
Yes 
 
If yes, proceed to Q3A 
 
No 
 
If no, proceed to Q4 
 
3A. Which of the following asthma symptoms do you have? (Choose all that apply) 
 
Shortness of breath 
 
Wheezing/whistling in the chest 
 
Coughing 
 
Chest tightness 
 
I needed albuterol 
4. Since the last time you took the survey, did you experience any of the following? (Choose all that apply) 
 
Used an oral steroid for asthma 
 
Went to my doctor for asthma 
 
Went to the Emergency Room for asthma 
 
None of the above 
 

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VitalFlo spirometry and App: At visit 2, the research staff will review the daily adherence data 
from during the run-in period to determine if the participant is eligible for randomization. The 
participant and guardian will be given a brief refresher training on how to use the vitalflo mobile 
app for recording daily study drug adherence, recording daily respiratory symptoms, and 
recording exacerbation events.  
After randomization at Visit 2, participants will be expected to complete the e-diary questions 
each day. The vitalFlo mobile app will signal when the diary questions are ready and will 
prompt the participant to complete spirometry (three forced expiratory maneuvers) once per 
week. 
If a participant fails to complete more than 2 of 7 surveys in a week, they will be contacted by 
phone to attempt to recover missing data from that week.  They will be asked about genara 
medication adherence, SABA use, presence of asthma symptoms, need for systemic 
corticosteroids and any need for urgent healthcare for asthma.  
 
6.3.3. 
Follow-up Procedures 
Will occur according to the procedures table 5 and figure 5. See below (section 6.5) for 
details of testing procedures. 

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a. Follow up Telehealth/videoVisits (week 10, 18, 24) 
i. Home Spirometry witnessed by video (week 10, 18, 26) 
ii. 
Concomitant medications 
iii. Adherence assessment and counseling 
iv. Questionnaires directed by trained research coordinators. 
a. Asthma Control Questionnaire (ACQ) 
b. Asthma Symptom Utility Index (ASUI) 
c. Duke Asthma Score (DAS) 
d. GERD Symptom Assessment Score (GSAS) 
e. Adverse Events 
f. 
Premature Withdrawal: We will request that the participant voluntarily 
return for a final termination phone visit. This visit will aim to be similar 
to the study completion phone visit (visit 5). The purpose of this visit 
will also be to evaluate general health and Asthma and GERD 
symptoms, and to ascertain any problems related to the request for 
withdrawal. Adverse event reporting will occur per protocol. We will 
recommend that the participant follow up in a timely manner with 
his/her primary care physician and asthma provider. If significant 
problems are present the PI/Study physician will facilitate the 
appropriate care – if needed, in consultation with the Genara Pediatric 
Gastroenterologist. We will also request that the participant return any 
unused study drug for appropriate destruction.  The study physician/PI 
will also ensure that the participant has access to their normal 
controller and rescue asthma medications. 
 
 
b. Interim Phone visits (weeks 6, 14, and 22) 
i. Asthma Control Questionnaire6 (ACQ6) 
ii. DAS interview 
iii. Asthma Symptom Utility Index (ASUI) 
iv. Concomitant medications 
c. Final Visit. Study completion 
i. End of Study procedures: preparation and mailing of un-blinding envelope to 
participant. Participants will receive a letter from the site PI and IND Sponsor (JL) 
regarding the participant’s genotype with information and resources. The participant 
will be encouraged to share the letter with his/her doctor. Dispense monetary 
compensation. 
 
 

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7. Study Intervention/Product Description 
All participants will have the intervention of lifestyle modification counseling which have been 
recommended in the pediatric GERD expert guidelines (97, 98). Participants will be randomized to 
receive either genotype-tailored once daily lansoprazole dosing or matched placebo according to table 
6. The active lansoprazole and placebo will be provided by CutisPharma, Inc (Wilmington, MA). Each 5 
FL OZ lansoprazole Compounding Kit is comprised of 0.45 grams of lansoprazole powder USP and 150 
ml of PPI suspension containing artificial strawberry flavor. A research pharmacist will prepare blinded 
drug kits with individual dosing instructions (as shown here (https://www.youtube.com/watch?v=ANr_oZ- 
Bu6M). Premixed containers last for 30 days and will be shipped to participants between study visits. 
When compounded, the final product provides a homogeneous suspension containing 3mg/mL of 
lansoprazole in PPI Suspension comparable to the active ingredient contained in Simplified 
Lansoprazole Suspension (SLS). A matching placebo suspension with indistinguishable taste, color and 
viscosity will also be supplied by CutisPharma (see letter of support from CutisPharma, Inc.). The 
research pharmacist and trained research coordinator will instruct the caregiver on the exact daily 
volume amount.  This approach will allow for genotype-tailored dosing. 
 
 
7.1. Drug Administration 
7.1.1. Drug will be given Once daily 
Briefly, the compounding instructions are: (1) remove the cap from the bottle containing 
lansoprazole powder. Loosen powder inside. (2) Shake First PPI suspension for several 
seconds and then open bottle to pour out roughly 50% of the contents into the lansoprazole 
powder bottle. Make sure you are pouring liquid into solid. Re-cap the mixture and shake 
vigorously for 60 seconds. (3) Pour the remaining suspension into the lansoprazole powder 
bottle and shake again for 60 seconds.  Make sure bottle is tightly capped. 
 
7.1.2. 
Study Drug Delivery 
Study drug will be sent from the Duke Investigational Drug Service (IDS) to the family’s home 
address. The correct home address must be entered into REDCap prior to the randomization 
date. The pre-compounded study drug (either active drug or placebo) will be sent to each 
participant in a refrigerated container. Study drug will be sent to the family each 30 days. If 
there is a change in address, the individual clinical site coordinator is responsible for changing 
the preferred address in REDCap along with a notice by e-mail to GenARATeam@duke.edu). 
 
7.1.3. Confirmation of Study Drug Receipt  
Within 3 days of randomization, the 
participant’s study coordinator should 
establish confirmation of receipt of study drug 
with the family. Once established, the 
coordinator will review with the participant and 
caregiver the proper dosing of the study drug. 
The study drug will come in a large bottle with 
instructions and a pre-marked syringe. Once 
there is confirmation that the participant has 
received the study drug and the coordinator 
has reviewed proper dosing instructions, the 
coordinator will enter confirmation of this into 
REDCap (in the study drug receipt field for 
visit 2). 
 
Table 6: Genotype-guided Dosing Adjustments(1) 
 
Daily Dosing (and volume) 
phenotype %change <30kg 
≥30kg 
UM 
100% ↑ 
30mg 
(10ml) 
60mg 
(20ml) 
EM 
50% ↑ 
22.5mg 
(7.5ml) 
45mg 
(15ml) 
NM 
0% 
15mg 
(5ml) 
30mg 
(10ml) 
IM 
30% ↓ 
10.5mg 
(3.5ml) 
21mg 
(7ml) 
PM 
60% ↓ 
6mg 
(2ml) 
12mg 
(4ml) 

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7.2. Investigational New Drug (IND): commercially available lansoprazole 
Chemistry, Manufacturing, and Control Information (Drug/Active Ingredients, Pharmaceutical Class, 
Structural Formula, Formulation, Route of Administration). The drug to be used is a commercially 
available lansoprazole suspension under the Compounding Quality Act provided by a state licensed 
physician and compounded by a state licensed pharmacist. Drug/Active Ingredients: Each FIRST® - 
Lansoprazole Compounding Kit (5 FL OZ) is comprised of 0.45 grams of lansoprazole powder USP and 
150 mL of FIRST® PPI (Proton Pump Inhibitor) suspension containing artificial strawberry flavor, benzyl 
alcohol, FD&C red# 40, hydroxyethylcellulose, purified water, saccharin sodium, simethicone emulsion, 
sodium bicarbonate, sodium citrate (dihydrate), sorbitol solution, and sucralose. This product contains 
ingredients that are derived from corn. When compounded, the final product provides a homogeneous 
suspension containing 3 mg per mL of lansoprazole in FIRST® PPI Suspension comparable to the 
active ingredient contained in Simplified Lansoprazole Suspension (SLS). First® Lansoprazole is 
marketed by CutisPharma, Inc, (Wilmington, MA). 
 
Figure 7 
Size 
5 FL OZ 
NDC# 
65628-080-05 
Lansoprazole Powder 
0.45 g 
FIRST – PPI Suspension 
150 mL 
PubChem CID 
3883 
Molecular Formula 
C16H14F3N3O2S 
Molecular Weight 
369.36147 g/mol 
IUPAC Name: 
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2- 
yl]methylsulfinyl]-1H-benzimidazole 
 
 
Structure: 
 
 
Proton Pump Inhibitor for oral administration: Labeling of Drug Product. For ages 6-17 years: 
Each label will provide the instructions: “Swallow directed dose once daily. Take at least 30 minutes 
before meal”. Also, all participants will be advised that study drug should be taken before eating. All 
labels also will include (1) subject identifier, (2) study identification, (3) instructions for administration, 
and (4) expiration date. Each study drug labels will consist of a 2-part tear off label. WARNING: 
ADAPTER CAP IS NOT CHILD-RESISTANT. 
 
Handling of Study drug: FIRST®- Lansoprazole Compounding Kit components (un-mixed) have a 
two-year expiration date. Prior to compounding, store FIRST®- Lansoprazole Compounding Kit at room 
temperature 15°- 30°C (59°- 86°F). Based on real time temperature and humidity testing, compounded 
(mixed) FIRST®- Lansoprazole product is stable for at least 30 days at refrigerated temperature 2°-8°C 
(36° -46°F).  Store the final compounded formulation at refrigerated temperature 2°-8°C (36°-46°F). For 

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oral use only. Avoid contact with eyes. Keep container tightly closed. Keep out of the reach of children. 
Protect from light. Protect from freezing. When compounded and stored according to instructions, acid 
neutralizing capacity is maintained for at least 30 days. The beyond-use date of the compounded 
product, as dispensed, when stored at refrigerated temperature is not later than 30 days. 
 
7.3. Pharmacology and Toxicology Information 
Mechanism of Action:  Lansoprazole belongs to a class of antisecretory compounds, the 
substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+/K+)- 
ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme 
system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been 
characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This 
effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion 
irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 
antagonist activity. 
 
Pharmacodynamics: 
 
Antisecretory Activity: After oral administration, lansoprazole was shown to significantly decrease the 
basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH 
was greater than 3 and greater than 4. Lansoprazole also significantly reduced meal-stimulated 
gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients 
with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated 
gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and 
acid output induced by insulin. After the initial dose in that study, increased gastric pH was seen 
within 1 to 2 hours with 30 mg of lansoprazole and 2 to 3 hours with 15 mg of lansoprazole. After 
multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of 
lansoprazole and within 1 to 2 hours post-dosing with 15 mg of lansoprazole. Acid suppression may 
enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of 
time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of PREVACID given 
daily, twice daily and three times daily. The inhibition of gastric acid secretion as measured by 
intragastric pH gradually returned to normal over two to four days after multiple doses. There was no 
indication of rebound gastric acidity. 
 
Enterochromaffin-like (ECL) Cell Effects. During lifetime exposure of rats with up to 150 mg/kg/day 
of lansoprazole dosed seven days per week, marked hypergastrinemia was observed followed by 
ECL cell proliferation and formation of carcinoid tumors, especially in female rats. Gastric biopsy 
specimens from the body of the stomach from approximately 150 patients treated continuously with 
lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in 
rat studies. Longer term data are needed to rule out the possibility of an increased risk of the 
development of gastric tumors in patients receiving long-term therapy with lansoprazole. 
 
Other Gastric Effects in Humans. Lansoprazole did not significantly affect mucosal blood flow in the 
fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid 
secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was 
seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole 
increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in 
response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, 
increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of 
nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in 
nitrosamine concentrations was observed. 

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Serum Gastrin Effects. In over 2100 patients, median fasting serum gastrin levels increased 50% to 
100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral 
lansoprazole. These elevations reached a plateau within two months of therapy and returned to 
pretreatment levels within four weeks after discontinuation of therapy. 
 
Endocrine Effects. Human studies for up to one year have not detected any clinically significant 
effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), 
follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone 
sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid 
stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). 
Lansoprazole in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on 
sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for two to eight weeks had no 
clinically significant effect on thyroid function. In 24-month carcinogenicity studies in Sprague- 
Dawley rats with daily lansoprazole dosages up to 150 mg/kg, proliferative changes in the Leydig 
cells of the testes, including benign neoplasm, were increased compared to control rats. 
 
 
Other Effects. No systemic effects of lansoprazole on the central nervous system, lymphoid, 
hematopoietic, renal, hepatic, cardiovascular, or respiratory systems have been found in humans. 
Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed 
after lansoprazole treatment (up to 180 mg/day) for up to 58 months. After lifetime lansoprazole 
exposure in rats, focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and 
spontaneous retinal atrophy were seen. Microbiology: Lansoprazole, clarithromycin and/or 
amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in 
clinical infections as described in the INDICATIONS AND USAGE section of the product label. 
Helicobacter pylori Pretreatment Resistance. Clarithromycin pretreatment resistance (≥2.0 mcg/mL) 
was 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy 
clinical trials (M93-125, M93-130, M93-131, M95-392, and M95- 399). 
 
Adverse Effects. There have been no reported cases of drug dependence or abuse involving proton 
pump inhibitors including Lansoprazole. There are also no radioactivity concerns. Adverse 
Reactions:  Most commonly reported adverse reactions (≥1%): diarrhea, abdominal pain, nausea 
and constipation. Warnings & Precautions: Symptomatic response with Lansoprazole does not 
preclude the presence of gastric malignancy. PPI therapy may be associated with increased risk of 
Clostridium difficile associated diarrhea. Bone Fracture: Long-term and multiple daily dose PPI 
therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist 
or spine.  Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. 
 
 
Risk or Seriousness Anticipated: The possible risks and side effects observed in asthmatics 
treated with FIRST®Lansoprazole include the following: WARNINGS AND PRECAUTIONS: Bone 
fractures. People who are taking multiple daily doses of proton pump inhibitors for a long period of 
time may have an increased risk of fractures of the hip, wrist, or spine. Low magnesium levels in the 
body. This problem can be serious. Low magnesium can happen in some people who take proton 
pump inhibitors for at least 3 months. If low magnesium levels happen, it is usually after a year of 
treatment. Clostridium difficile-associated diarrhea. Long-term use of proton pump inhibitors may 
increase the risk of diarrhea caused by Clostridium difficile, especially in hospitalized patients. 
 
 
Table 7: Drug Interactions 
Atazanavir 
Do not co-administer with atazanavir. 

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Warfarin 
Concomitant warfarin use may require monitoring for increases in INR and 
prothrombin time. 
Tacrolimus 
Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. 
Theophylline 
Titration of theophylline dosage may be required when concomitant PREVACID 
use is started or stopped. 
Methotrexate 
FIRST Lansoprazole may increase serum levels of methotrexate. 
 
 
 
8. Safety Procedures 
 
8.1. Methods and Timing for Assessing, Recording and Analyzing Safety Parameters 
Safety will be assessed from the initial study procedure at visit 1 through to the completion visit 
which will span roughly 26 weeks. Safety will be assessed by frequency and incidence of AEs and 
SAEs. A safety data monitoring committee (DMC) will be convened by Drs. Lang and Sorkness to 
review data and safety information from study participants throughout the study. A DMC charter will 
outline in detail the policies and procedures of the DMC (see Appendix). 
 
8.2. Adverse Event 
An adverse event (AE) is any untoward medical occurrence in humans, whether or not considered 
drug-related, which occurs during the conduct of a clinical trial. (Any change in clinical status, 
routine labs, x-rays, physical examinations, etc.), that is considered clinically significant by the study 
investigator is considered an AE. 
 
8.3. Unexpected Adverse Event 
This is defined as any adverse event, the specificity or severity of which is not consistent with the 
package insert, underlying disease processes or investigational plan. 
 
8.4. Events of Special Interest 
Unscheduled medical visit primarily for asthma, Acute Care/ED care for asthma, systemic steroids 
for asthma, hospitalization for asthma, Strep throat, pneumonia, ear infection, sinus infection, sore 
throat, acute RTI (any), upper respiratory tract infection (cold), diarrhea, gastroenteritis, fractures, 
and vomiting. 
 
8.5. Guidelines for Determining Causality 
The investigator will use the following question when assessing causality of an adverse event 
to study drug, where an affirmative answer designates the event as a suspected adverse 
reaction: Is there a reasonable possibility that the drug caused the event? ‘‘Reasonable 
possibility’’ means that there is evidence to suggest a causal relationship between the drug and 
the adverse event. Therefore, suspected adverse reaction is any adverse event for which it 
appears more likely than not that the drug caused the adverse event. Adverse reaction is any 
adverse event caused by the drug. In cases where there is uncertainty, the site PI should seek 
council from the IND PI and DMC chair to determine. 
 
8.5.1. 
Serious adverse event 
or serious suspected adverse reaction or serious adverse reaction as determined by the 
investigator or the sponsor is any event that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction 
as it occurred and required immediate intervention) 

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• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Important medical event that may not result in one of the above outcomes, but in 
the judgement of the site PI may jeopardize the health of the study participant or 
require medical or surgical intervention to prevent one of the outcomes listed in 
the above definition of serious event 
 
Any serious adverse event entered in the safety database will should elicit the 
research coordinator to notify the IND sponsor/PI by e-mail. The IND sponsor/PI will 
review all SAEs at the time that they are reported. Site Investigators must also 
submit safety reports locally as required by their local IRB. 
 
8.6. Guidelines for Assessing Intensity of an Adverse Event 
The investigator should use the following definitions when assessing intensity of an adverse 
event: 
MILD: Participant is aware of symptoms or has minor findings but tolerates them 
well, and no or minimal intervention required 
MODERATE: Participant experiences enough symptoms or findings to require 
intervention 
SEVERE: Participant experiences symptoms or findings that require significant 
intervention 
 
Table 8: Definitions of Events for use in Genara Study 
Adverse Event 
untoward medical occurrence in humans, whether or not considered 
drug/intervention-related 
Unexpected 
This is defined as any adverse event, the specificity or severity of which is not 
consistent with the package insert or investigational plan 
Reaction 
Drug/intervention caused the adverse event 
Suspected – means there is a reasonable possibility 
Serious 
Event with death, that was life-threatening, or associated with persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life 
functions (can be related (reaction) or un-related (event) to intervention/drug) 
8.7. Identification of Events and Timeframe for Reporting 
As all participants in this study will have pre-existing medical conditions, those pre-existing 
conditions will not be considered as adverse events. New events that occur or pre-existing 
conditions that worsen in terms of frequency or intensity will be reported as adverse events. All 
reportable events as defined above, determined to be an AE based on physical examination, 
laboratory findings, or other means, will be reported in the hard copy and electronic case report 
form (REDCap). The investigator will provide the date of onset and resolution, intensity, frequency, 
action(s) taken, changes in study drug dosing, relationship to study drug, and outcome. 
 
8.8. Follow-up of Adverse Events 
All events (study-related or not) must be followed until resolution, or if ongoing at the time of last 
safety contact, will be followed up to adequately evaluate the participant’s safety or until the event 
stabilizes. All serious suspected adverse reactions and serious adverse reactions will be followed 
until resolution or until the patient is medically stable. All other events that cannot be resolved by 30 
days after the safety monitoring period will be considered resolved by convention and entered in the 
electronic data capture (REDCap) system as such. Any event beginning more than 7 days after the 
last dose of study drug will not be captured. 
 
8.9. Discontinuation of a Participant Due to Adverse Events 

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Participants may be withdrawn from the study at any time due to concerns about subject safety. 
Participants withdrawn from the study due to an AE (whether or not event was thought to be caused 
by intervention), whether serious or non-serious, must be followed by the investigator until the 
clinical outcome from the AE is determined. Any participant who experiences an AE may be 
withdrawn at any time from the study at the discretion of the investigator. The IND/protocol PI will 
seek input from DMC chair if needed. The AE(s) should be noted on the appropriate CRFs, and the 
participant’s progress should be followed until the AE is resolved or considered stable. The IRB and 
DMC must be notified. If the AE may relate to overdose of study treatment, the package insert 
should be consulted for details of any specific actions to be taken. 
 
8.10. 
Reporting Procedures 
All adverse events will be entered into the safety data system within 7 days of identification 
(REDCap). Serious events will be entered into the data system within 48 hours of identification and 
reported to the IND/protocol PI. If there are any technical difficulties, the SAE will be reported by 
direct communication to the study PI. The study PI will notify the Chair of the DMC. Reporting to 
the Duke IRB: 
 
Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or 
Others and Adverse Events (http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm). Any event that: 
(1) involves harm, or an increased potential for harm, to one or more participant(s), or others, 
AND (2) is unexpected, AND (3) is related, or probably related, to study procedures will be 
reported to the Duke IRB within 5 days of discovery, or within 24 hours if an unforeseen death. 
 
Study staff can find reporting requirements and criteria for reporting on the Genara REDCap 
site. 
 
8.10.1. Regulatory Reporting 
Any event that requires expedited reporting based on federal regulations will be forwarded to 
the DMC. The IND sponsor will submit expedited safety reports (e.g. IND safety reports) to the 
regulatory agencies (FDA, DMC, IRB) as necessary, and will inform the sub-investigators of 
such regulatory reports. Site investigators must submit safety reports as required by their IRB. 
Documentation of the submission and receipt by the IRB must be retained for each expedited 
safety report. All serious events irrespective of their designation as “related” (reactions) or “not 
related” (events) to study product(s) will be reported to the FDA at least annually in a summary 
format. 
 
8.10.2. Safety Oversight 
The DMC will review written serious adverse events on a quarterly basis. In addition, a qualified 
and experienced pediatric pulmonologist (IND Sponsor/PI) and gastroenterologist (Co-I) will 
serve as clinical monitors. The IND sponsor/PI will review all SAEs at the time they are 
reported. If safety concerns are identified, the PI may request a meeting of the DMC to review 
safety data. At a minimum, PI will comment on the outcomes of the SAE and causal 
relationship of the SAE to the study product. If no SAEs prompt review at an earlier time point, 
the DMC will review AEs and SAEs at the regularly scheduled annual meeting. Additionally, 
DMC will periodically review interim safety analyses. The DMC will convene and make 
recommendations on termination of the study based on review of safety reports and halting 
rules. The safety data will be compiled by the REDCap study support team. Based on the 
recommendations of the DMC, the IND sponsor will make a decision to terminate or continue 
the study. 
 
8.11. 
Justification for PPI placebo/GERD Safety Plan 

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For patients with mild GERD and some persisting degree of asthma symptoms, there exists 
reasonable equipoise regarding the role of long-term PPI use, and thus use of a placebo-control 
with safety monitoring in place is justifiable.   Current guidelines from the NAEPP and    
NASPGHAN recommend that clinicians consider use of a PPI in this setting. However, the FDA has 
published warnings about the chronic use of PPIs citing various side effects that appear to be 
higher in patients taking higher doses or for prolonged periods.  The FDA has advised clinicians 
that longer use (>8-12 weeks) should be approached with caution. The FDA advises providers to 
consider a lower dose (than the conventional) or a shorter duration if possible. Currently, 
lansoprazole is not approved for treatment of GERD beyond the duration of 8 weeks (beyond 12 
weeks in children 1-11 years). For patients with serious acid-related disorders, the risk-to-benefit 
ratio is often favorable, however the risk-benefit analysis for patients with mild GER and asthma is 
more difficult to determine and thus requires study.  The first management strategy recommended 
in the recent NASPGHAN expert guidelines for pediatric GERD includes very specific evidence- 
based modifications to diet and lifestyle (97, 98). Thus, all participants in the trial (regardless of 
randomization) will receive the intervention of education about diet and lifestyle   modifications. 
These therapies are outlined in the patient handout: GERD in Children and Adolescents,  
published jointly by the NASPGHAN and the American Academy of Pediatrics, which will be given 
to all subjects (see Appendix). Participants will also be monitored closely throughout the study for 
worsening of GERD symptoms. A GERD rescue plan has been developed with consultation from 
the study pediatric gastroenterologist (see Appendix: GERD Safety Plan). 
 
8.12. 
Asthma Safety Parameters 
8.12.1. Assessment and Documentation of Asthma Action Plan at Visit 1 
 
8.12.2. Daily e-Diary documentation of medication adherence 
 
8.12.3. Phone study visits and interim phone contacts to monitor asthma control 
 
8.12.4. Plans for asthma worsening 
Since all participants have asthma, it is expected that some exacerbations will occur over the 6- 
month intervention. During the study, participants will be able to seek care from their normal 
asthma physician. However, the study PI will be available 24/7 by cell phone for asthma 
problems and other clinical care questions. Trained research staff will review basic asthma 
education with each family which will include signs and symptoms of asthma.  They will be 
given an asthma educational packet that will include directions on self-management of asthma 
symptoms and the indications for calling study staff right away for management (see Appendix 
for Asthma safety plan). Participants will be educated on how to complete daily diary cards to 
closely monitor for changes in asthma and educated on the indications for taking rescue 
albuterol. Participants will also be monitored by 4 clinic visits and 3 telephone visits during the 
trial. Phone visits will assess study adherence and will monitor for asthma symptoms. Pre- 
specified threshold criteria for starting oral steroids for an asthma exacerbation will also be in 
place consistent with past NIH-funded pediatric asthma trials. 
 
8.13. 
GERD Safety Parameters 
8.13.1. GERD non-pharmacologic management counseling (See Appendix: GERD educational 
handout) 
 
8.13.2. Clinic visit and phone contacts to monitor GERD severity 
 
8.13.3. Plans for GERD worsening 

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Since all participants have mild GERD, it is possible that some will experience worsening of 
symptoms over the 6-month intervention. A detailed GERD management plan has been 
developed. This will allow for management of mild breakthrough symptoms and rapid 
identification and management of more severe symptoms. Families will be given a GERD 
educational packet that will include directions on self-management and the use of over-the- 
counter Calcium Carbonate (OTC-CC) remedies if needed (see GERD safety plan in 
appendix). If GERD worsens, is not managed with the study drug and OTC-CC, and is 
affecting normal functioning, the family will be advised to call the study staff for management 
with Dr. Lang in consultation with the pediatric gastroenterology physician (JF). Pre-specified 
threshold criteria for un-blinding and study termination will be in place to allow prompt 
management. This will include GSAS>150 for 2 consecutive weeks and preference of the 
participant and/or caregiver to drop-out. 
 
8.13.4. Additional protections for children 
Participation in this trial for children with asthma and GERD will provide closer monitoring and 
education on self-management for these conditions than would be provided for non- 
participants. 

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9. Clinical monitoring 
Site monitoring will be conducted to ensure that human subject protection, study procedures, laboratory 
procedures, study intervention administration, and data collection processes are of high quality and 
meet sponsor, GCP/ICH, and regulatory guidelines, and that the study is conducted in accordance with 
the protocol and Duke sponsor standard operating procedures. The IND sponsor/PI will conduct a site- 
monitoring visit after the site has received IRB approval around the time of first enrollment. Additional 
site visits will occur on an ad-hoc basis. Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, CRFs, informed consent forms, medical and laboratory reports, 
and protocol compliance. Study monitors will meet with investigators to discuss any problems and 
actions to be taken and document visit findings and discussions. 

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Table 9: Sample Size Calculations 
 
 
Analysis: 
A priori: Compute required sample size 
Effect size d 
α err prob 
Power (1-β err prob) 
=  0.7142857 
=  0.05 
=  .9 
Allocation ratio N2/N1 
=  1 
Output: 
Noncentrality parameter δ=3.3120065 
Critical t 
Df 
Sample size group 1 
Sample size group 2 
Total sample size 
=  1.9886097 
=  84 
=  43 
=  43 
=  86 
 
10. Data Analysis & Statistical Considerations 
10.1. 
Analyses for Lansoprazole treatment effect 
Descriptive data summaries of key outcomes will be performed throughout the study for safety 
monitoring and identification of outliers. We will employ means, ranges, and measures of variance 
by treatment group; box-plots by treatment group; and time plots of diary data by treatment group. 
The primary outcome will be the change from baseline in ACQ during the treatment period. The 
means during the baseline and treatment period are calculated from ACQ completed by each 
individual. A mid-point analysis will be completed on efficacy and safety outcomes (GSAS, RTI, 
AEs) and presented to an independent Data & Safety Monitoring Committee (DMC). We will use a 
multiple regression model to analyze the primary outcome to address the specific hypotheses of the 
study.  Secondary analyses will include evaluation of the hypotheses outlined in the specific aims 
for other outcomes such as rate of exacerbations and EPACs, rate of RTI, GSAS score, and FEV1. 
The same analytic approach as outlined for the primary outcome will be used for the analysis of 
other outcomes. In addition, secondary analyses will explore other contrasts that are of interest, 
such as the effect of obesity status, age, and sex, though this will only be of secondary importance 
as we are not powering the study for these interactive effects. We will test for effect modification of 
outcomes by patient characteristics stated above by adding additional terms to the model and 
testing for significance of the coefficients and interactions with main effects. A preliminary analysis 
will be performed on all outcome measures to assess distribution and normality assumptions, 
identify outliers, and check for unusual patterns of longitudinal data.  We will use transformations, 
as appropriate. Continuous measures that are not normally distributed or amenable to 
transformation will be analyzed as ranks or categorized and analyzed with logistic regression 
models for binary, ordered or multinomial outcomes using likelihood ratio tests and the same 
indicator variables and contrast as outlined above. All pre-specified outcomes will be analyzed by 
data analysts (JEL) to confirm that accuracy of data filters and coding routines. Data filtering 
routines analysis programs will be archived to allow future replication of our results. We will use the 
latest version of SAS 9.3 (SAS Institute, Inc, Cary NC). 
 
10.2. 
Analyses of genotype/haplotype associations 
Associations between lansoprazole and metabolite PK with CYP2C19 genotype will be analyzed by 
additive, dominant or recessive models as previously described by our laboratory (118) using SAS 
9.3 (Cary, NC). Associations between lansoprazole and metabolite PK with ABCB1 SNPs (C3435T 
(rs1045642), T1654C (rs1128503) (silent) and T2677G/A (rs2032582)) and the 1236/2677/3435 
haplotype will be analyzed similarly.  General linear modeling will be performed and adjusted for 
age, race gender and CYP2C19 diplotype. These analyses will complement the pop PK association 
analyses with genetic variation. 
 
10.3. 
Sample size and Power 
calculations 
The primary outcome for 
evaluation of power is change 
from baseline of ACQ. Based on 
our preliminary data in this exact 
patient population, we anticipate 
the mean ACQ at entry will be 
around 1.2, and a standard 
deviation of roughly 0.7 (based 
on Lang JE, Thorax, 2016) (45). 
Based on the differences in ACQ 
we saw between children without 
GERD symptoms and those with 

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mild GERD symptoms, we aim to detect an AQC change of 0.5.  By using the ACQ (instead of 
ASUI) and assuming a two-tailed type 1 error rate of 5%, we will have improved power compared to 
using ASUI. Maintaining the goal of 110 randomizations, we can have an attrition rate of 20% (88 
complete) and have a power of 90.6%.  This assumes an intention to treat paradigm to the 
statistical analysis. Calculations were performed based on t-tests of independent means using 
G*Power Version 3.1.9.2 (Universitat Kiel, Germany). 

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11. Privacy, Data Storage & Confidentiality 
The principal investigator will ensure that the use and disclosure of protected health information 
obtained during a research study complies with the HIPAA Privacy Rule. The rule provides U.S. federal 
protection for the privacy of protected health information by implementing standards to protect and 
guard against the misuse of individually identifiable health information of participants participating in 
clinical trials. Authorization is required from each research participant (i.e., specific permission granted 
by an individual to a covered entity for the use or disclosure of an individual’s protected health 
information). A valid authorization must meet the implementation specifications under the HIPAA Privacy 
Rule. Authorization will be combined in the informed consent document (approved by the IRB). 
 
11.1. 
Participant confidentiality 
Participant confidentiality is held strictly in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples 
and genetic tests, in addition to the clinical information relating to participating participants. The 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. The study monitor or other authorized 
representatives of the sponsor may inspect all documents and records required to be maintained by 
the investigator. This documentation includes, but is not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. Clinical study sites will permit 
access to such records. The principal investigator will ensure that the use and disclosure of 
personal health information obtained during this research study complies with the Federal Privacy 
Regulation. In the U.S., the Health Insurance and Portability and Accountability (HIPAA) Privacy 
Rule applies. The rule provides U.S. federal protection for the privacy of protected health 
information sent to or collected in the U.S. for the purposes of this research by implementing 
standards to protect and guard against the misuse of individually identifiable health information of 
participants participating in clinical trials. “Authorization” is required from each research participant 
(i.e., specific permission granted by an individual to a covered entity for the use or disclosure of an 
individual’s protected health information). A valid authorization must meet the implementation 
specifications under the applicable Federal Privacy Regulations. The relevant privacy authorization 
will be combined in the informed consent document (approved by the IRB). 

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12. Quality Control and Quality Assurance 
 
12.1. 
Data handling and record keeping 
The investigator is obligated to conduct this study in accordance with U.S. Federal Regulation 21 
CFR 312.60-69 as specified on the signed form FDA 1572, applicable local laws, and the 
International Conference on Harmonisation: Good Clinical Practice: Consolidation Guideline. The 
investigator is responsible for informing the IRB of any safety issues related to the study and the 
study drug, including reports of serious adverse events, if required, and all expedited safety reports. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. Case report forms will be derived from the eCRFs and provided to the sites to 
record and maintain data for each participant enrolled in the study. All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data. Permanent ink is 
required to ensure clarity of reproduced copies. When making a change or correction, the original 
entry should be crossed out with a single line, and the change should be initialed and dated. Do not 
erase, overwrite, or use correction fluid or tape on the original. Data reported in the eCRF should be 
consistent with the case report form/source documents, or the discrepancies should be 
documented. The sponsor and/or its designee will provide guidance to investigators on making 
corrections to the case report forms and eCRFs. 
 
12.2. 
Data Management Responsibilities 
All case report forms, and laboratory reports must be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. Adverse events must be graded, 
assessed for severity and causality, and reviewed by the site principal investigator or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site principal investigator. During the study, the investigator must maintain complete and accurate 
documentation for the study. Duke for this study will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
 
12.3. 
Data Capture Methods 
Clinical data (including AEs and concomitant medications) will be entered into a 21 CFR Part 11- 
compliant internet data entry system (REDCap) provided by the DCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
case report forms/source documents. 
 
12.4. 
Study Records Retention 
Records and documents pertaining to the conduct of this study, including case report forms, source 
documents, consent forms, laboratory test results, and medication inventory records, must be 
retained by the investigator for at least 10 years after the end of the study or per local/state 
regulations or until participants reach 21 years, or applicable Federal laws, whichever is longer. No 
study records will be destroyed without prior authorization from the sponsor. 
 
12.5. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or manual of 
procedures requirements. The noncompliance may be on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly. 
These practices are consistent with Good Clinical Practice: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf 
4.5. 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1. 
Quality Assurance and Quality Control, section 5.1.1 

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5.2. 
Noncompliance, sections 5.20.1, and 5.20.2 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation or within 5 working days of the scheduled 
protocol-required activity. All deviations must be promptly reported to the site PI and IND sponsor. 
 
All deviations from the protocol must be addressed in study case report forms. A completed copy of 
the protocol deviation form must be maintained in the regulatory file and uploaded into REDCap. 
Protocol deviations must be submitted to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. 

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13. Ethics/Protection of Human Participants 
 
13.1. 
Ethical Standard 
The investigator will ensure that the study will be conducted in accordance with the protocol, the 
ethical principles of Good Clinical Practice (ICH E6) that have their origin in the Declaration of 
Helsinki, and all applicable national and local regulations. The investigator will ensure that the study 
is conducted in accordance with the provisions as stated and will comply with the prevailing local 
laws and customs. 
 
13.2. 
Institutional Review Board 
Prior to enrollment of participants into this trial, the protocol, the informed consent form, and any 
materials or advertisements presented to participants will be reviewed and approved by the 
appropriate IRB/REB. The responsible official for the IRB/REB will sign the IRB letter of approval of 
the protocol prior to the start of this trial, and a copy will be provided to the DCC. Notification of the 
IRB/REB's composition and the institution’s federal-wide assurance number (if applicable) will be 
provided to the DCC. If amendments to the protocol were required, the amendments will be written 
by the sponsor and provided to the investigator for submission and approval to the IRB/REB. 
 
13.3. 
Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continuing throughout the individual’s study participation. Extensive discussion of risks 
and possible benefits of participation in this study will be provided to the participants and their 
families. Consent forms describing in detail the study procedures and risks are given to the 
participant’s legal guardian, and written documentation of informed consent is required prior to 
enrolling in the study. Consent forms will be IRB-approved, and the participant’s legal guardian will 
be asked to read and review the document. Upon reviewing the document, a trained member of the 
study team will explain the research study to the participant’s legal guardian and answer any 
questions that may arise. The participant/participant’s legal guardian will sign the informed consent 
document prior to the conduct of any study procedures. The participant’s legal guardian should 
have the opportunity to think about the study prior to agreeing to participate. The participant’s legal 
guardian may withdraw consent at any time throughout the course of the study. A copy of the 
informed consent document will be given to the participants for their records. The rights and welfare 
of the participants will be protected by emphasizing to their legal guardian that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. For non- 
English speakers, an interpreter will be provided to present the study, accompanied by a short form 
may be used to obtain informed consent. 
The IND sponsor, or designee will provide the investigator, in writing, any new information that 
bears significantly on the participants' risk to receive the investigational product. This new 
information will be communicated by the investigator to participants' legal guardians who consent to 
participate in the trial in accordance with IRB requirements. The informed consent document will be 
updated, and participants’ legal guardians will be re-consented, if necessary. 
Site staff may employ IRB-approved recruitment efforts prior to the participant’s legal guardian 
consenting; however, before any protocol-specific procedures are performed to determine protocol 
eligibility, informed consent must be obtained and properly executed. 
By signing the informed consent form, the participant’s legal guardian agrees that the participant 
will complete all evaluations required by the trial, unless the participant’s legal guardian withdraws 
the participant voluntarily or the participant is withdrawn from the trial for any reason. The family 
will get a signed copy of the informed consent form and will be given contact information that will 
allow them to contact research staff (including coordinator 24-hour pager and PI cell phone) and 
Nemours or Duke IRB staff (as appropriate) at all hours.  
 

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Subject’s Capacity to Give Legally Effective Consent: the GenARA study will include minors 
who cannot independently give legally effective consent. In these cases, inclusion will require 
parental permission/informed consent from a legal guardian.  Assent will be required by children 
age 12 and up. 
 
13.4. 
Recruitment 
Recruitment will occur through IRB approved means. 
 
 
13.5. 
Study Discontinuation 
If the study is discontinued, enrolled participants will continue to be followed for safety 
assessments.  All adverse events must be followed through resolution. 

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Appendix B 
SUBSTUDY: Asthma Medication Dosage 
 
Step 2 
Low Daily Dose 
Low dose ICS 
5-11 yo 
Ages 12+ 
Beclomethasone 
80-160 
80-240 
Qvar 40 
Qvar 80 
2-4 puffs daily 
2-6 puffs daily 
1-2 puffs daily 
1-3 puffs daily 
Budesonide DPI 
180-360 
180-540 
Pulmicort 90 
Pulmicort 180 
2-4 puffs daily 
2-6 puffs daily 
1-2 puffs daily 
1-3 puffs daily 
Ciclesonide MDI 
80-160 
160-320 
Alvesco 80 
Alvesco 160 
1-2 puffs daily 
2-4 puffs daily 
1 puff daily 
1-2 puffs daily 
Flunisolide MDI 
160 
320 
Aerospan 80 
2 puffs daily 
4 puffs daily 
Fluticasone MDI 
88-176 
88-264 
Flovent 44 
Flovent 110 
Flovent 220 
2-4 puffs daily 
2-6 puffs daily 
1 puff daily 
1-2 puffs daily 
1 puff daily 
Fluticasone Diskus 
100-200 
100-300 
Flovent 50 
Flovent 100 
Flovent 250 
2-4 puffs daily 
2-6 puffs daily 
1-2 puffs daily 
1-3 puffs daily 
1 puffs daily 
 
Step 3 
Low Daily Dose/LABA 
Low dose ICS + LABA 
5-11 yo 
Ages 12+ 
Fluticasone MDI 
100-200 
100-300 
Advair 45 
Advair 115 
Advair 230 
2-4 puffs daily 
2-6 puffs 
1 puff daily 
1-2 puffs daily 
1 puff daily 
Fluciasone Diskus 
100-200 
100-300 
Advair 100 
Advair 250 
Advair 500 
1-2 puffs daily 
1-3 puffs daily 
1 puff daily 
Mometasone DPI 
110 
110-220 
Asmanex Twisthaler 110 
Asmanex Twisthaler 220 
1 puff daily 
1 -2 puffs daily 
1 puff daily 

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Mometasone DPI 
110 
110-220 
Dulura 100 
Dulura 200 
1 puff daily 
1 -2 puffs daily 
1 puff daily 
Budesonide DPI 
180-360 
180-540 
Symbicort 80/4.5 
Symbicort 160/4.5 
2-4 puffs 
2-6 puffs daily 
1-2 puffs 
1-3 puffs 
 
Step 3 
Low Daily Dose 
Low dose ICS + Singulair 
5-11 yo 
Ages 12+ 
Beclomethasone 
80-160 
80-240 
Qvar 40 
Qvar 80 
2-4 puffs daily 
2-6 puffs daily 
1 -2 puffs daily 1-3 puffs daily 
Budesonide DPI 
180-360 
180-540 
Pulmicort 90 
Pulmicort 180 
2-4 puffs daily 
2-6 puffs daily 
1-2 puffs daily 
1-3 puffs daily 
Ciclesonide MDI 
80-160 
160-320 
Alvesco 80 
Alvesco 160 
1-2 puffs daily 
2-4 puffs daily 
1 puff daily 
1-2 puffs daily 
Flunisolide MDI 
160 
320 
Aerospan 80 
2 puffs daily 
4 puffs daily 
Fluticasone MDI 
88-176 
88-264 
Flovent 44 
Flovent 110 
Flovent 220 
2-4 puffs daily 
2-6 puffs daily 
1 puff daily 
1-2 puffs daily 
1 puff daily 
Fluticasone Diskus 
100-200 
100-300 
Flovent 50 
Flovent 100 
Flovent 250 
2-4 puffs daily 
2-6 puffs daily 
1-2 puffs daily 
1-3 puffs daily 
1 puff daily 
 
Step 3 
Medium Daily Dose 
High Daily Dose 
Medium/high dose 
ICS 
Ages 5-11 
Ages 12+ 
Ages 5-11 
Ages 12+ 
Beclomethasone 
>160-320 
>240-480 
>320 
>480 
Qvar 40 
Qvar 80 
6-8 puffs 
daily 
8-12 puffs 
daily 
3-4 puffs 
daily 
4-6 puffs daily 
> 6 puffs 
daily 
> 8 puffs daily 
Budesonide DPI 
>360-720 
>540-1080 
>720 
>1080 

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Pulmicort 90 
Pulmicort 180 
6-8 puffs 
daily 
3-4 puffs 
daily 
4-6 puffs daily 
> 6 puffs 
daily 
> 8 puffs daily 
Ciclesonide MDI 
>160-320 
>320-640 
>320 
>640 
Alvesco 80 
Alvesco 160 
3-4 puffs 
daily 
6-8 puffs daily 
> 6 puffs 
daily 
2 puffs daily 
3-4 puffs daily 
> 4 puffs 
daily 
>6 puffs daily 
Flunisolide MDI 
320-480 
>320-640 
>480 
>640 
Aerospan 80 
4-6 puffs 
daily 
6-8 puffs daily 
>8 puffs 
daily 
> 10 puffs 
daily 
Fluticasone MDI 
>176-352 
>264-440 
>352 
>440 
Flovent 44 
Flovent 110 
Flovent 220 
6-8 puffs 
daily 
2-3 puffs 
daily 
3-4 puffs daily 
>4 puffs 
daily 
>6 puffs daily 
1 puff daily 
2 puffs daily 
>2 puffs 
daily 
>4 puffs daily 
Fluticasone Diskus 
>200-400 
>300-500 
>400 
>500 
Flovent 50 
Flovent 100 
Flovent 250 
6-8 puffs 
daily 
3-4 puffs 
daily 
3-4 puffs daily 
> 4 puffs 
daily 
> 6 puffs daily 
1 puff daily 
2 puffs daily 
>2 puffs 
daily 
> 4 puffs daily 
 
Step 4 
Medium Daily Dose/LABA 
Medium dose ICS + LABA 
Ages 5-11 
Ages 12+ 
Fluticasone MDI 
>200-400 
>300-500 
Advair 45 
Advair 115 
Advair 230 
6-8 puffs daily 
2-3 puff daily 
3-4 puffs daily 
1 puff daily 
2 puffs daily 
Fluciasone Diskus 
>200-400 
>300-500 
Advair 100 
Advair 250 
Advair 500 
3-4 puffs daily 
4-5 puffs daily 
1 puff daily 
2 puff daily 
1 puff daily 
Mometasone DPI 
>220-440 
>220-440 
Asmanex Twisthaler 110 
Asmanex Twisthaler 220 
2-4 puffs daily 
2-4 puffs daily 
1-2 puffs daily 
1-2 puffs daily 

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Mometasone DPI 
>220-440 
>220-440 
Dulura 100 
Dulura 200 
2-4 puffs daily 
2-4 puffs daily 
1-2 puffs daily 
1-2 puffs daily 
Budesonide DPI 
>360-720 
>540-1080 
Symbicort 80/4.5 
Symbicort 160/4.5 
6-8 puffs daily 
3-4 puffs 
4-6 puffs daily 
 
Step 4 
Medium Daily Dose 
Medium dose ICS + Singulair 
Ages 5-11 
Ages 12+ 
Beclomethasone 
>160-320 
>240-480 
Qvar 40 
Qvar 80 
6-8 puffs 
daily 
8-12 puffs 
daily 
3-4 puffs 
daily 
4-6 puffs daily 
Budesonide DPI 
>360-720 
>540-1080 
Pulmicort 90 
Pulmicort 180 
6-8 puffs 
daily 
3-4 puffs 
daily 
4-6 puffs daily 
Ciclesonide MDI 
>160-320 
>320-640 
Alvesco 80 
Alvesco 160 
3-4 puffs 
daily 
6-8 puffs daily 
2 puffs daily 
3-4 puffs daily 
Flunisolide MDI 
320-480 
>320-640 
Aerospan 80 
4-6 puffs 
daily 
6-8 puffs daily 
Fluticasone MDI 
>176-352 
>264-440 
Flovent 44 
Flovent 110 
Flovent 220 
6-8 puffs 
daily 
2-3 puffs 
daily 
3-4 puffs daily 
1 puff daily 
2 puffs daily 
Fluticasone Diskus 
>200-400 
>300-500 
Flovent 50 
Flovent 100 
Flovent 250 
6-8 puffs 
daily 
3-4 puffs 
daily 
3-4 puffs daily 
1 puff daily 
2 puffs daily 
Step 5 
High Daily Dose/LABA 

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High dose ICS + LABA 
Ages 5-11 
Ages 12+ 
Fluticasone MDI 
>400 
>500 
Advair 45 
Advair 115 
Advair 230 
>4 puffs daily 
>6 puffs daily 
>2 puffs daily 
>4 puffs daily 
Fluciasone Diskus 
>400 
>500 
Advair 100 
Advair 250 
Advair 500 
> 2 puff daily 
> 2 puffs daily 
> 1 puff daily 
> 2 puff daily 
Mometasone DPI 
>440 
>440 
Asmanex Twisthaler 110 
Asmanex Twisthaler 220 
>2 puffs daily 
>2 puffs daily 
Mometasone DPI 
>440 
>440 
Dulura 100 
Dulura 200 
>2 puffs daily 
>2 puffs daily 
Budesonide DPI 
>720 
>1080 
Symbicort 80/4.5 
Symbicort 160/4.5 
 
 
 
 
Step 5 
High Daily Dose 
High dose ICS + Singulair 
Ages 5-11 
Ages 12+ 
Beclomethasone 
>320 
>480 
Qvar 40 
Qvar 80 
> 6 puffs 
daily 
> 8 puffs daily 
Budesonide DPI 
>720 
>1080 
Pulmicort 90 
Pulmicort 180 
> 6 puffs 
daily 
> 8 puffs daily 
Ciclesonide MDI 
>320 
>640 
Alvesco 80 
Alvesco 160 
> 6 puffs 
daily 
> 4 puffs 
daily 
>6 puffs daily 
Flunisolide MDI 
>480 
>640 
Aerospan 80 
>8 puffs daily 
> 10 puffs daily 

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Fluticasone MDI 
>352 
>440 
Flovent 44 
Flovent 110 
Flovent 220 
>4 puffs daily 
>6 puffs daily 
>2 puffs daily 
>4 puffs daily 
Fluticasone Diskus 
>400 
>500 
Flovent 50 
Flovent 100 
Flovent 250 
> 4 puffs 
daily 
> 6 puffs daily 
>2 puffs daily 
> 4 puffs daily 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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