Gastroesophageal Reflux
Conditions
Keywords
Esophageal Reflux, Gastro-Esophageal Reflux, Gastroesophageal Reflux Disease, GERD, Regurgitation, Gastric, Heartburn, Drug Therapy, Adolescent
Brief summary
The purpose of this study is to asses the pharmacokinetics and safety of dexlansoprazole modified release (MR), once daily (QD), in adolescent subjects (age 12-17 years old) with Symptomatic Gastroesophageal Reflux Disease.
Detailed description
Gastroesophageal reflux disease is a condition of multifactorial etiology resulting in the reflux of gastric contents into the esophagus through the lower esophageal sphincter. The prevalence of Gastroesophageal reflux disease in the pediatric population is becoming increasingly recognized and documented. It is a chronic disease that can persist through adulthood with symptoms in older children and adolescents being similar to those seen in adults. The prevalence of gastroesophageal reflux disease increases with age, from 2.5% of children between the ages of 3 and 9 years, to 8.5% of those between the ages of 10 and 17 years. Younger children generally present with extra-esophageal manifestations, regurgitation, and epigastric pain, while older children and adolescents typically present with adult-type gastroesophageal reflux disease symptoms of heartburn and regurgitation. Treatment for gastroesophageal reflux disease is aimed at alleviating symptoms and healing the esophageal inflammation. This study evaluated the pharmacokinetics and safety of dexlansoprazole MR in the pediatric population (ages 12-17) and determined if the pharmacokinetic profile is similar to that in adults given the same dose.
Interventions
Dexlansoprazole MR 30 mg, capsules, orally, once daily for up to 7 days.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Body weight is greater than or equal to 30 kg. * Females of childbearing potential who are sexually active must agree to use an acceptable form of contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. * Must have an estimated creatinine clearance greater than or equal to 80 mL/minute as determined from the Cockcroft-Gault formula. * Participants who take prescription or non-prescription proton pump inhibitors, histamine receptor antagonists (except cimetidine), sucralfate, or antacids on a regular or as required basis must agree to discontinue usage throughout the study. * Must have a history of gastroesophageal reflux disease symptoms, as documented by a physician, for at least 2 months prior to Screening or is currently symptomatic. * Must be able to swallow study drug capsule or must be able to ingest study drug granules sprinkled on 1 tablespoon of applesauce.
Exclusion criteria
* Has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic, renal, or metabolic dysfunction, serious allergy, asthma, or allergic skin rash. * Has any finding in his/her medical history, physical examination, or safety clinical laboratory tests giving reasonable suspicion of a disease that might interfere with the conduct of the trial or that would contraindicate taking dexlansoprazole MR or a similar drug in the same class. * Has a known hypersensitivity to any proton pump inhibitors or any component of the formulation of dexlansoprazole MR (see most current version of the Investigator Brochures). * Has a history of malignant disease. * Has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody. * Has a known history of infection with the human immunodeficiency virus. * Has donated or lost greater than or equal to 300 mL blood volume, undergone plasmapheresis, or has had a transfusion of any blood product within 90 days prior to the first dose of study drug. * Is required to take or intends to continue taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication. * Has consumed grapefruit or grapefruit juice within 14 days prior to the first dose of study drug or is unwilling to agree to abstain from grapefruit or grapefruit juice while participating in the study. * Has a history of alcohol abuse or illegal drug use or drug abuse in the past, or tests positive for alcohol or drugs of abuse at the initial Screening Visit or Day -1 or is unwilling to agree to abstain from alcohol and drugs throughout the study. * Has used a product containing nicotine within 90 days prior to the first dose of study drug or has a positive cotinine screen at the initial Screening Visit or Day -1 or is unwilling to agree to abstain throughout the study. * Has participated in a study of an investigational agent (including dosing or follow up) within 30 days prior to first dose of study drug. * Has an initial Screening Visit or Day -1 laboratory value that the principal investigator considers to be clinically significant. * Participant is determined to be a CYP2C19 isozyme poor metabolizer (ie, genotyped homozygous non-wild type). * Is unlikely to comply with the protocol or is unsuitable for any other reason per the opinion of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) Pharmacokinetic Parameter | After 7 days of dosing. | Tmax: Time to reach the Maximum Plasma Concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 7. |
| Cmax: Maximum Observed Plasma Concentration Pharmacokinetic Parameter. | After 7 days of dosing. | Maximum Observed Plasma Concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration Pharmacokinetic Parameter. | After 7 days of dosing. | Area Under the Plasma Concentration Versus Time Curve (AUC(0-tlqc)) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]). |
| AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose Pharmacokinetic Parameter. | After 7 days of dosing. | AUC(0-24) is measure of Area Under the Curve over the dosing interval (tau) (AUC(0-tau\]), where tau is the length of the dosing interval - 24 hours in this study). |
| Terminal Phase Elimination Half-life (T1/2) Pharmacokinetic Parameter. | After 7 days of dosing. | Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. |
| Oral Clearance (CL/F) Pharmacokinetic Parameter. | After 7 days of dosing. | CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-24), expressed in L/hr. |
| Terminal Elimination Rate Constant (λz) Pharmacokinetic Parameter. | After 7 days of dosing. | Terminal elimination rate constant (λz) is the rate at which drugs are eliminated from the body. |
| Apparent Volume of Distribution (Vz/F) Pharmacokinetic Parameter. | After 7 days of dosing. | Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as CL/F divided by λz. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 3 investigative sites in the United States from 31 May 2009 to 10 September 2009.
Pre-assignment details
Participants were enrolled in one of two, dexlansoprazole modified release (MR), once-daily (QD) treatment groups. 100% of participants randomized completed this study.
Participants by arm
| Arm | Count |
|---|---|
| Dexlansoprazole MR 30 mg QD Dexlansoprazole MR 30 mg, capsules, orally, once daily for up to 7 days. | 18 |
| Dexlansoprazole MR 60 mg QD Dexlansoprazole MR 60 mg, capsules, orally, once daily for up to 7 days. | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | Dexlansoprazole MR 30 mg QD | Dexlansoprazole MR 60 mg QD | Total |
|---|---|---|---|
| Age Continuous | 14.6 years STANDARD_DEVIATION 1.65 | 14.6 years STANDARD_DEVIATION 1.89 | 14.6 years STANDARD_DEVIATION 1.75 |
| Region of Enrollment United States | 18 participants | 18 participants | 36 participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 18 | 5 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Apparent Volume of Distribution (Vz/F) Pharmacokinetic Parameter.
Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as CL/F divided by λz.
Time frame: After 7 days of dosing.
Population: All participants who had Vz/F estimated were included in the analysis for this parameter. One participant in the 30 mg group was excluded from the PK analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. There was no imputation for missing values. No statistical tests were performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | Apparent Volume of Distribution (Vz/F) Pharmacokinetic Parameter. | 28.90 L | Standard Deviation 21.208 |
| Dexlansoprazole MR 60 mg QD | Apparent Volume of Distribution (Vz/F) Pharmacokinetic Parameter. | 58.50 L | Standard Deviation 46.1 |
Primary
AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose Pharmacokinetic Parameter.
AUC(0-24) is measure of Area Under the Curve over the dosing interval (tau) (AUC(0-tau\]), where tau is the length of the dosing interval - 24 hours in this study).
Time frame: After 7 days of dosing.
Population: All participants who had AUC(0-24) estimated were included in the analysis for this parameter. One participant in the 30 mg group was excluded from the PK analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. There was no imputation for missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose Pharmacokinetic Parameter. | 2886.26 ng*hr/mL/mg | Standard Deviation 1355.182 |
| Dexlansoprazole MR 60 mg QD | AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose Pharmacokinetic Parameter. | 5119.81 ng*hr/mL/mg | Standard Deviation 2986.453 |
Comparison: This study was not powered for any hypothesis testing. For Tmax, an ANOVA model was fitted that included fixed effect of age group (12-14 years and 15 17 years), regimen and interaction of age group and regimen. If the interaction term was not statistically significant, it was not included in the final model. The site effect was also tested in the model, and was not included in the final model if it was not statistically significant (P\>0.05). Pairwise comparisons between regimens were conducted.p-value: 0.38890% CI: [0.864, 1.579]ANOVA
Primary
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration Pharmacokinetic Parameter.
Area Under the Plasma Concentration Versus Time Curve (AUC(0-tlqc)) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).
Time frame: After 7 days of dosing.
Population: All participants who had AUC(0-tlqc) estimated were included in the analysis for this parameter. One participant in the 30 mg group was excluded from the PK analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. There was no imputation for missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration Pharmacokinetic Parameter. | 2842.32 ng*hr/mL/mg | Standard Deviation 1313.827 |
| Dexlansoprazole MR 60 mg QD | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration Pharmacokinetic Parameter. | 5113.72 ng*hr/mL/mg | Standard Deviation 2987.508 |
Comparison: This study was not powered for any hypothesis testing. For Tmax, an ANOVA model was fitted that included fixed effect of age group (12-14 years and 15 17 years), regimen and interaction of age group and regimen. If the interaction term was not statistically significant, it was not included in the final model. The site effect was also tested in the model, and was not included in the final model if it was not statistically significant (P\>0.05). Pairwise comparisons between regimens were conducted.p-value: 0.40290% CI: [0.864, 1.551]ANOVA
Primary
Cmax: Maximum Observed Plasma Concentration Pharmacokinetic Parameter.
Maximum Observed Plasma Concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: After 7 days of dosing.
Population: All participants who had Cmax estimated were included in the analysis for this parameter. One participant in the 30 mg group was excluded from the PK analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. There was no imputation for missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | Cmax: Maximum Observed Plasma Concentration Pharmacokinetic Parameter. | 691 ng/mL | Standard Deviation 367.5 |
| Dexlansoprazole MR 60 mg QD | Cmax: Maximum Observed Plasma Concentration Pharmacokinetic Parameter. | 1136 ng/mL | Standard Deviation 582.2 |
Comparison: This study was not powered for any hypothesis testing. For natural logarithm of dose-normalized Cmax, an ANOVA model was fitted that included fixed effect of age group, regimen and interaction of age group and regimen. If the interaction term was not statistically significant, it was not included in the final model. Site effect was tested in the model, and was not included in the final model if not statistically significant (P\>0.05). Pairwise comparisons between regimens were conducted.p-value: 0.28990% CI: [0.897, 1.63]ANOVA
Primary
Oral Clearance (CL/F) Pharmacokinetic Parameter.
CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-24), expressed in L/hr.
Time frame: After 7 days of dosing.
Population: All participants who had CL/F estimated were included in the analysis. One participant in the 30 mg group was excluded from the PK analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. There was no imputation for missing values. No statistical tests were performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | Oral Clearance (CL/F) Pharmacokinetic Parameter. | 12.81 liter/hr | Standard Deviation 6.092 |
| Dexlansoprazole MR 60 mg QD | Oral Clearance (CL/F) Pharmacokinetic Parameter. | 15.29 liter/hr | Standard Deviation 7.524 |
Primary
Terminal Elimination Rate Constant (λz) Pharmacokinetic Parameter.
Terminal elimination rate constant (λz) is the rate at which drugs are eliminated from the body.
Time frame: After 7 days of dosing.
Population: All participants who had λz estimated were included in the analysis. One participant in the 30 mg group was excluded from the PK analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. There was no imputation for missing values. No statistical tests were performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | Terminal Elimination Rate Constant (λz) Pharmacokinetic Parameter. | 0.5264 1/hr | Standard Deviation 0.25425 |
| Dexlansoprazole MR 60 mg QD | Terminal Elimination Rate Constant (λz) Pharmacokinetic Parameter. | 0.3404 1/hr | Standard Deviation 0.17406 |
Primary
Terminal Phase Elimination Half-life (T1/2) Pharmacokinetic Parameter.
Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time frame: After 7 days of dosing.
Population: All participants who had T1/2 estimated were included in the analysis for this parameter. One participant in the 30 mg group was excluded from the PK analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. No statistical tests were performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | Terminal Phase Elimination Half-life (T1/2) Pharmacokinetic Parameter. | 1.66 hours | Standard Deviation 0.871 |
| Dexlansoprazole MR 60 mg QD | Terminal Phase Elimination Half-life (T1/2) Pharmacokinetic Parameter. | 2.59 hours | Standard Deviation 1.379 |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) Pharmacokinetic Parameter
Tmax: Time to reach the Maximum Plasma Concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 7.
Time frame: After 7 days of dosing.
Population: All participants who had Tmax estimated were included in the analysis for this parameter. One participant in the 30 mg group was excluded from the pharmacokinetic (PK) analysis because most of the PK samples were not collected, and hence no PK parameters were estimable. There was no imputation for missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole MR 30 mg QD | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) Pharmacokinetic Parameter | 4.65 hours | Standard Deviation 2.909 |
| Dexlansoprazole MR 60 mg QD | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) Pharmacokinetic Parameter | 3.31 hours | Standard Deviation 1.519 |
Comparison: This study was not powered for any hypothesis testing. For Tmax, an analysis of variance (ANOVA) model was fitted that included fixed effect of age group, regimen and interaction of age group and regimen. If the interaction term was not statistically significant, it was not included in the final model. The site effect was also tested in the model, and was not included in the final model if it was not statistically significant (P\>0.05). Pairwise comparisons between regimens were conducted.p-value: 0.095ANOVA