Asthma, Gastroesophageal Reflux
Conditions
Keywords
Personalized Medicine, CYP2C19, Lansoprazole, Pharmacokinetics
Brief summary
This study will evaluate the effect of CYP2C19 and ABCB1 genes on pharmacokinetics of lansoprazole in children with mild gastroesophageal reflux (GER) and uncontrolled asthma. It will determine if genotype-guided lansoprazole dosing of lansoprazole improves GER and asthma control.
Detailed description
BACKGROUND: Poorly controlled asthma especially in children remains a major public health problem. Many children with poor asthma control experience gastroesophageal reflux (GERD). The effect of mild GERD on asthma remains controversial despite studies involving proton-pump inhibitors (PPIs) assessing their effect on asthma. Past inconsistent findings regarding the effect of PPIs on asthma control may have resulted from ineffective dosing strategies of proton-pump inhibitors employed in these studies. Drug levels and efficacy vary widely in the population and depend on genetics. Dosing in children which adjusts for the gene CYP2C19 may improve efficacy and reduce side-effects leading to improved asthma control. HYPOTHESIS: #1: The investigators hypothesize that genotype-tailored lansoprazole dosing will reduce asthma symptoms in children with mild symptoms of GERD compared to placebo. #2: CYP2C19 and ABCB1 genetic variants influence the pharmacokinetics (drug levels) of lansoprazole as determined by population pharmacokinetic modeling. METHODS: The investigators will conduct a 6-month randomized controlled trial comparing genotype-tailored lansoprazole dosing versus matched placebo in the control of asthma symptoms in 6-17 year olds with asthma and mild reflux. All participants will have baseline pharmacokinetics analysis following a single genotype-tailored dose to assess the effects of CYP2C19 and ABCB1. IMPACT: These results would be a major advance in the science of safe dosing of proton-pump inhibitors in children and for the management of the millions of children struggling with reflux and asthma.
Interventions
DRUGcommercially available lansoprazole
these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily lansoprazole for 24 weeks
DRUGmatched placebo
these participants will receive a one-time dose of lansoprazole followed by PK analysis and then once daily placebo for 24 weeks
Sponsors
Thrasher Research Fund
Nemours Children's Clinic
Jason Lang, M.D., M.P.H.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Age: 6-17 year olds with documented clinician-diagnosed asthma * Evidence of recent uncontrolled asthma (must meet at least one of the following). This convention for defining poorly-controlled asthma has been successfully used in a large pediatric trial. * ACQ \> 1.2 * Use of short-acting beta-agonist for asthma symptoms twice/week or more on average over the past month * Nocturnal awakenings with asthma symptoms more than once per week on average over the last month * Two or more emergency department visits, unscheduled provider visits, prednisone courses or hospitalizations for asthma in the past 12 months * Currently on stable dose of daily inhaled corticosteroid medication (ICS) for asthma control equivalent to 88mcg of fluticasone or greater for at least 6 weeks from the time of enrollment. Participant must be on National Asthma Education and Prevention Program (NAEPP) controller step 2, 3 or 4. * Currently with mild GERD symptoms reported at V1 defined by a score on the Pediatric GERD Symptom Assessment Score greater than 15 and less than 80. GSAS ranges from 0 to \>440.
Exclusion criteria
* Taking daily CYP2C19 substrates, inducers or inhibitors medication * Past or current history of moderate-severe GERD or related disorders (erosive esophagitis, peptic ulcer disease, eosinophilic esophagitis) which in the opinion of the pediatric gastroenterology safety specialist/study physician requires treatment with acid-blocking agents; * Daily use of a PPI for more than 4 consecutive weeks in the past 6 months; * previous intubation for asthma, * admission to intensive care unit for more than 24 hours for asthma in the past year, * Previous surgery involving the esophagus or stomach (anti-reflux surgery, peptic ulcer surgery, trachea-esophageal fistula repair); * Forced expiratory volume in 1 second (FEV1) \< 60% of predicted at enrollment; * Any major chronic illness that would interfere with participation in the intervention or completion of the study procedures; * History of phenylketonuria (PKU); * Medication use: treatment of GERD symptoms with over-the-counter antacids 4 days/week or more on average over past month; * Theophylline preparations, azoles, anti-coagulants, insulin for Type 1 diabetes, digitalis, oral iron supplements when administered for iron deficiency within 1 month; * Any investigational drugs within the past 2 months; * Drug Allergies: previous allergic reaction from lansoprazole or other proton pump inhibitor medication or adverse reaction to aspartame; * Inability to complete baseline measurements in a satisfactory manner according to the judgment of the research coordinator or site PI; * Less than 75% completion of daily diary for asthma symptoms, SABA use and ICS medication adherence during the run-in period; * Plan for family to move from study location within the next 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Asthma Control Questionnaire (ACQ) From Screening Through Week 26 | Week 0 (baseline) to week 26 | The ACQ considers a broad set of common indicators of asthma control including use of bronchodilators, cough, nocturnal symptoms, level of activity, and pulmonary function. Scores range between 0 (totally controlled) and 6 (severely uncontrolled). Reported is the change from week 0 to week 26; a negative change value indicates an improvement in asthma control. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Asthma Symptom Utility Index (ASUI) From Screening Through Week 26 | Week 0 (baseline) to week 26 | Questionnaire measures changes in asthma control. Each of the 11 items are scored on a 4-point Likert scale to assess frequency (not at all, 1 to 3 days, 4 to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate, and severe). The adjusted overall score ranges from 0 (worst possible symptoms) to 1 (no symptoms). Reported is the change from week 0 to week 26. |
| Annualized Rate of Asthma Exacerbations | Up to week 26 | An exacerbation will be defined per the recommendations of the NIH Asthma Exacerbation Taskforce and will be defined as a worsening of asthma requiring the use of a systemic corticosteroid (at least 3 days of prednisolone/ prednisone or ≥1 days of dexamethasone) to prevent asthma worsening. |
| Change in GERD (Gastroesophageal Reflux Disease) Symptom Assessment Questionnaire Score (GSAS) From Screening Through Week 26 | Week 0 (baseline) to week 26 | A 10-item tool that has been validated in children in the assessment of gastroesophageal reflux disease related symptoms such as chest/abdominal pain, pain/choking with eating, swallowing dysfunction, regurgitation and nausea. It assesses symptom frequency and severity from the previous 7-days on an 8-point scale with 0 and 7 indicating the least and greatest severity, respectively. The total score ranges from 0 to 70, where a higher score indicates greater GERD symptom severity. Reported is the change from week 0 to week 26. |
| Annualized Rate of Respiratory Tract Infection (RTI) | Up to week 26 | Participants/Caregivers will be asked to report diagnoses of RTI that occurred during the treatment period using interval reporting. RTI will include: (1) bronchitis, (2) otitis, (3) pneumonia. |
| Change in Lung Function Testing From Screening Through Week 26 | Week -2 (screening) to week 26 | Forced Expiratory Volume in 1 Second (FEV1) measurement (mean change in FEV1 percent predicted from screening). |
| Annualized Rate of Episodes of Poor Asthma Control (EPAC) | Up to week 26 | A study EPAC will be present if the participant meets any of the following criteria, (1) addition of systemic corticosteroid medication for asthma or (2) any unscheduled encounter to a non-study related health care provider (phone contact, ED, urgent care, hospital) for asthma symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants will receive oral blinded matched placebo once daily. | 17 |
| Genotype-guided Lansoprazole Participants will receive oral blinded commercially available lansoprazole once daily with a dose appropriate for the participant's metabolizer phenotype. | 18 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 5 |
Baseline characteristics
| Characteristic | Placebo | Total | Genotype-guided Lansoprazole |
|---|---|---|---|
| Age, Continuous | 9.8 years STANDARD_DEVIATION 3.6 | 10.3 years STANDARD_DEVIATION 3.5 | 10.8 years STANDARD_DEVIATION 3.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 29 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 20 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 10 Participants | 4 Participants |
| Region of Enrollment United States | 17 Participants | 35 Participants | 18 Participants |
| Sex: Female, Male Female | 6 Participants | 17 Participants | 11 Participants |
| Sex: Female, Male Male | 11 Participants | 18 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 13 / 17 | 15 / 18 |
| serious Total, serious adverse events | 0 / 17 | 0 / 18 |
Outcome results
Primary
Change in Asthma Control Questionnaire (ACQ) From Screening Through Week 26
The ACQ considers a broad set of common indicators of asthma control including use of bronchodilators, cough, nocturnal symptoms, level of activity, and pulmonary function. Scores range between 0 (totally controlled) and 6 (severely uncontrolled). Reported is the change from week 0 to week 26; a negative change value indicates an improvement in asthma control.
Time frame: Week 0 (baseline) to week 26
Population: Participants with data collected at both timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Asthma Control Questionnaire (ACQ) From Screening Through Week 26 | -0.5 score on a scale | Standard Deviation 0.5 |
| Genotype-guided Lansoprazole | Change in Asthma Control Questionnaire (ACQ) From Screening Through Week 26 | -0.6 score on a scale | Standard Deviation 0.9 |
p-value: 0.8716Wilcoxon (Mann-Whitney)
Secondary
Annualized Rate of Asthma Exacerbations
An exacerbation will be defined per the recommendations of the NIH Asthma Exacerbation Taskforce and will be defined as a worsening of asthma requiring the use of a systemic corticosteroid (at least 3 days of prednisolone/ prednisone or ≥1 days of dexamethasone) to prevent asthma worsening.
Time frame: Up to week 26
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Annualized Rate of Asthma Exacerbations | 0 exacerbations per participant per year |
| Genotype-guided Lansoprazole | Annualized Rate of Asthma Exacerbations | 0 exacerbations per participant per year |
p-value: 0.2765Wilcoxon (Mann-Whitney)
Secondary
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 or (2) any unscheduled encounter to a non-study related health care provider (phone contact, ED, urgent care, hospital) for asthma symptoms.
Time frame: Up to week 26
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Annualized Rate of Episodes of Poor Asthma Control (EPAC) | 0 episodes per participant per year |
| Genotype-guided Lansoprazole | Annualized Rate of Episodes of Poor Asthma Control (EPAC) | 0 episodes per participant per year |
p-value: 0.19195% CI: [0.66, 8.2]Negative binomial regression
Secondary
Annualized Rate of Respiratory Tract Infection (RTI)
Participants/Caregivers will be asked to report diagnoses of RTI that occurred during the treatment period using interval reporting. RTI will include: (1) bronchitis, (2) otitis, (3) pneumonia.
Time frame: Up to week 26
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Annualized Rate of Respiratory Tract Infection (RTI) | 4.16 RTIs per participant per year |
| Genotype-guided Lansoprazole | Annualized Rate of Respiratory Tract Infection (RTI) | 4.0 RTIs per participant per year |
p-value: 0.043595% CI: [0.29, 0.98]Negative binomial regression
Secondary
Change in Asthma Symptom Utility Index (ASUI) From Screening Through Week 26
Questionnaire measures changes in asthma control. Each of the 11 items are scored on a 4-point Likert scale to assess frequency (not at all, 1 to 3 days, 4 to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate, and severe). The adjusted overall score ranges from 0 (worst possible symptoms) to 1 (no symptoms). Reported is the change from week 0 to week 26.
Time frame: Week 0 (baseline) to week 26
Population: Participants with data collected at both timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Asthma Symptom Utility Index (ASUI) From Screening Through Week 26 | 0 score on a scale | Standard Deviation 0.2 |
| Genotype-guided Lansoprazole | Change in Asthma Symptom Utility Index (ASUI) From Screening Through Week 26 | -0.1 score on a scale | Standard Deviation 0.3 |
p-value: 0.039Wilcoxon (Mann-Whitney)
Secondary
Change in GERD (Gastroesophageal Reflux Disease) Symptom Assessment Questionnaire Score (GSAS) From Screening Through Week 26
A 10-item tool that has been validated in children in the assessment of gastroesophageal reflux disease related symptoms such as chest/abdominal pain, pain/choking with eating, swallowing dysfunction, regurgitation and nausea. It assesses symptom frequency and severity from the previous 7-days on an 8-point scale with 0 and 7 indicating the least and greatest severity, respectively. The total score ranges from 0 to 70, where a higher score indicates greater GERD symptom severity. Reported is the change from week 0 to week 26.
Time frame: Week 0 (baseline) to week 26
Population: Participants with data collected at both timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in GERD (Gastroesophageal Reflux Disease) Symptom Assessment Questionnaire Score (GSAS) From Screening Through Week 26 | -32.3 score on a scale | Standard Deviation 18.7 |
| Genotype-guided Lansoprazole | Change in GERD (Gastroesophageal Reflux Disease) Symptom Assessment Questionnaire Score (GSAS) From Screening Through Week 26 | 23.4 score on a scale | Standard Deviation 21.4 |
p-value: 0.2471Wilcoxon (Mann-Whitney)
Secondary
Change in Lung Function Testing From Screening Through Week 26
Forced Expiratory Volume in 1 Second (FEV1) measurement (mean change in FEV1 percent predicted from screening).
Time frame: Week -2 (screening) to week 26
Population: Participants with data collected at both timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Lung Function Testing From Screening Through Week 26 | 4.4 percentage of predicted value | Standard Deviation 16.1 |
| Genotype-guided Lansoprazole | Change in Lung Function Testing From Screening Through Week 26 | -3.7 percentage of predicted value | Standard Deviation 17.6 |
p-value: 0.3808Wilcoxon (Mann-Whitney)