Gastroesophageal Reflux
Conditions
Keywords
Gastroesophageal Reflux, Erosive Esophagitis, Pharmacokinetics, Pediatrics, Drug Therapy
Brief summary
The purpose of this study is to assess the pharmacokinetics and safety of dexlansoprazole, once daily (QD), in pediatric subjects with symptomatic Gastroesophageal Reflux Disease.
Detailed description
Gastroesophageal Reflux Disease (GERD) is a condition of several causes resulting in the backward flow of gastric contents into the esophagus through the lower esophageal sphincter. The prevalence of GERD in the pediatric population is increasingly becoming recognized and documented. It is a disease that may persist through adulthood, with symptoms in older children and adolescents similar to those seen in adults. Younger children generally present with extra-esophageal manifestations, regurgitation, and epigastric pain, while older children and adolescents typically present with adult-type GERD symptoms of heartburn and regurgitation. Treatment for GERD is aimed at improving symptoms and healing esophageal inflammation. Takeda Global Research & Development Center, Inc. (TGRD) developed dexlansoprazole delayed release capsules as a new therapy for treating acid related disorders including symptomatic non-erosive GERD, healing of erosive esophagitis (EE) and maintenance of healed EE. Dexlansoprazole delayed release capsules have not been studied in subjects younger than 12 years of age. This study is designed to evaluate the safety of dexlansoprazole delayed release capsules in the pediatric population (1 to 11 years old) and to determine if the PK profile of dexlansoprazole in subjects 1 to 11 years of age is similar to that in adults given a similar dose. Subjects who satisfy the screening evaluation and Inclusion/Exclusion Criteria may be enrolled in the study. Eligible subjects will be assigned to one of three treatment groups. Attempts will be made to enroll an equal number of male and female subjects in each treatment group.
Interventions
DRUGDexlansoprazole
Dexlansoprazole 15 mg, delayed release capsules, orally, once daily for up to 7 days.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Must have a body weight within the 5th through 95th percentile by age, inclusive, as determined by the National Center for Health Statistics . * Females of childbearing potential must not be nursing, must have a negative serum pregnancy test at the Screening Visit and on Day -1, and if sexually active agree to routinely use adequate contraception from Screening and throughout the duration of the study. * Subjects who take prescription or non-prescription proton pump inhibitors (PPI), histamine receptor antagonists (except cimetidine), sucralfate, or antacids on a regular or as required basis must agree to discontinue usage on Day -1 and agree to discontinue use throughout the study. * Must have a history of GERD symptoms for at least 2 months prior to Screening or is currently symptomatic, as determined by the investigator. * 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, pulmonary, endocrine disease, hepatic, hematopoietic, renal, or metabolic dysfunction, serious allergy, asthma, or allergic skin rash. * Has a known hypersensitivity to any PPI or any component of the formulation of dexlansoprazole capsules. * Is taking any other prescription (except birth control) or nonprescription medication (including cimetidine), vitamins, or dietary supplements within 10 days prior to Day 1, or has taken herbal over-the-counter medications within 28 days prior to Day 1. * Has a positive test result for hepatitis B surface antigen or hepatitis C virus antibody. * Has donated or lost greater than 10% of the total blood volume, undergone plasmapheresis, or has had a transfusion of any blood product within 90 days prior to the first dose of study drug. * 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. * Is determined to be a Cytochrome P450 2C19 poor metabolizer (ie, genotyped homozygous non-wild-type).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach the Peak Plasma Concentration (Tmax) | Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules. | Time to reach the maximum plasma concentration (Cmax) of Dexlansoprazole, equal to time (hours) to Cmax, as observed on Day 7. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole. |
| The Peak Plasma Concentration (Cmax) | Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules. | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole. |
| Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)) | Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules. | AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (tlqc), calculated using the linear trapezoidal rule. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole. |
| Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)) | Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules. | AUC(0-24) is measure of area under the curve over the dosing interval (tau), where tau is the length of the dosing interval (24 hours), calculated using the linear trapezoidal rule. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)/Dose) | Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules. | AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (tlqc), calculated using the linear trapezoidal rule, and normalized by dose. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole. |
| Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)/Dose) | Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules. | AUC(0-24) is measure of area under the curve over the dosing interval (tau), where tau is the length of the dosing interval (24 hours), calculated using the linear trapezoidal rule and normalized by dose. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole. |
| Dose-normalized Peak Plasma Concentration (Cmax/Dose) | Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules. | Maximum observed plasma concentration (the peak plasma concentration of a drug after administration), normalized by dose. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole. |
Countries
United States
Participant flow
Recruitment details
Participants took part in this study at 3 investigative sites in the United States from 04 March 2010 to 09 February 2011.
Pre-assignment details
36 participants with gastroesophageal reflux disease were assigned to 1 of 3 once daily (QD) treatment regimens (15 mg, 30 mg or 60 mg dexlansoprazole) based on baseline body weight.
Participants by arm
| Arm | Count |
|---|---|
| Dexlansoprazole 15 mg QD Dexlansoprazole 15 mg, delayed release capsules, orally, once daily for up to 7 days. | 12 |
| Dexlansoprazole 30 mg QD Dexlansoprazole 30 mg, delayed release capsules, orally, once daily for up to 7 days | 12 |
| Dexlansoprazole 60 mg QD Dexlansoprazole 60 mg, delayed release capsules, orally, once daily for up to 7 days | 12 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Dexlansoprazole 15 mg QD | Dexlansoprazole 30 mg QD | Dexlansoprazole 60 mg QD | Total |
|---|---|---|---|---|
| Age Continuous | 3.3 years STANDARD_DEVIATION 1.97 | 7.8 years STANDARD_DEVIATION 2.89 | 10.2 years STANDARD_DEVIATION 0.72 | 7.1 years STANDARD_DEVIATION 3.5 |
| Body Mass Index (BMI) | 22.3 kg/m^2 STANDARD_DEVIATION 20.08 | 16.4 kg/m^2 STANDARD_DEVIATION 3.09 | 19.0 kg/m^2 STANDARD_DEVIATION 2.56 | 19.2 kg/m^2 STANDARD_DEVIATION 11.73 |
| Mean height | 92.5 cm STANDARD_DEVIATION 24.16 | 131.9 cm STANDARD_DEVIATION 18.8 | 146.3 cm STANDARD_DEVIATION 8.73 | 123.6 cm STANDARD_DEVIATION 29.17 |
| Mean Weight per Weight Group 12.7 kg - < 25.4 kg | 19.0 kg STANDARD_DEVIATION 4.76 | 20.3 kg STANDARD_DEVIATION 3.67 | NA kg | 19.6 kg STANDARD_DEVIATION 4.17 |
| Mean Weight per Weight Group ≥ 25.4 kg | NA kg | 39.1 kg STANDARD_DEVIATION 9.19 | 41.0 kg STANDARD_DEVIATION 8.5 | 40.3 kg STANDARD_DEVIATION 8.51 |
| Mean Weight per Weight Group 8.6 kg - < 12.7 kg | 11.1 kg STANDARD_DEVIATION 1.05 | NA kg | NA kg | 11.1 kg STANDARD_DEVIATION 1.05 |
| Number of Participants per Weight Group 12.7 kg - < 25.4 kg | 7 participants | 6 participants | 0 participants | 13 participants |
| Number of Participants per Weight Group ≥ 25.4 kg | 0 participants | 6 participants | 12 participants | 18 participants |
| Number of Participants per Weight Group 8.6 kg - < 12.7 kg | 5 participants | 0 participants | 0 participants | 5 participants |
| Overall Mean Weight | 15.7 kg STANDARD_DEVIATION 5.43 | 29.7 kg STANDARD_DEVIATION 11.86 | 41.0 kg STANDARD_DEVIATION 8.5 | 28.8 kg STANDARD_DEVIATION 13.64 |
| Race/Ethnicity, Customized Black or African American | 2 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 participants | 8 participants | 8 participants | 22 participants |
| Race/Ethnicity, Customized Multiracial | 2 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 6 participants | 4 participants | 4 participants | 14 participants |
| Race/Ethnicity, Customized White | 8 participants | 12 participants | 12 participants | 32 participants |
| Region of Enrollment United States | 12 participants | 12 participants | 12 participants | 36 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 7 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 12 | 2 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 1 / 12 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24))
AUC(0-24) is measure of area under the curve over the dosing interval (tau), where tau is the length of the dosing interval (24 hours), calculated using the linear trapezoidal rule. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole.
Time frame: Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules.
Population: Pharmacokinetic set included all participants with at least one estimable PK parameter for dexlansoprazole on Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole 15 mg QD | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)) | 2149 ng*hr/mL | Standard Deviation 563.7 |
| Dexlansoprazole 30 mg QD | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)) | 2628 ng*hr/mL | Standard Deviation 1383.2 |
| Dexlansoprazole 60 mg QD | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)) | 3330 ng*hr/mL | Standard Deviation 1883.3 |
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc))
AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (tlqc), calculated using the linear trapezoidal rule. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole.
Time frame: Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules.
Population: Pharmacokinetic set included all participants with at least one estimable PK parameter for dexlansoprazole on Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole 15 mg QD | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)) | 1914 ng*hr/mL | Standard Deviation 631.8 |
| Dexlansoprazole 30 mg QD | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)) | 2892 ng*hr/mL | Standard Deviation 1668.6 |
| Dexlansoprazole 60 mg QD | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)) | 3747 ng*hr/mL | Standard Deviation 2795.6 |
Primary
The Peak Plasma Concentration (Cmax)
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole.
Time frame: Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules.
Population: Pharmacokinetic set included all participants with at least one estimable PK parameter for dexlansoprazole on Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole 15 mg QD | The Peak Plasma Concentration (Cmax) | 559 ng/mL | Standard Deviation 225.3 |
| Dexlansoprazole 30 mg QD | The Peak Plasma Concentration (Cmax) | 1005 ng/mL | Standard Deviation 748.1 |
| Dexlansoprazole 60 mg QD | The Peak Plasma Concentration (Cmax) | 964 ng/mL | Standard Deviation 519 |
Primary
Time to Reach the Peak Plasma Concentration (Tmax)
Time to reach the maximum plasma concentration (Cmax) of Dexlansoprazole, equal to time (hours) to Cmax, as observed on Day 7. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole.
Time frame: Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules.
Population: Pharmacokinetic (PK) set included all participants with at least one estimable PK parameter for dexlansoprazole on Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole 15 mg QD | Time to Reach the Peak Plasma Concentration (Tmax) | 4.4 hours | Standard Deviation 3.18 |
| Dexlansoprazole 30 mg QD | Time to Reach the Peak Plasma Concentration (Tmax) | 4.1 hours | Standard Deviation 2.34 |
| Dexlansoprazole 60 mg QD | Time to Reach the Peak Plasma Concentration (Tmax) | 4.1 hours | Standard Deviation 3.59 |
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An analysis of variance with covariates (ANCOVA) model with weight as a covariate and regimen as a factor were fitted to Tmax. Pairwise comparisons between regimens were conducted.p-value: 0.809ANCOVA
Other Pre-specified
Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)/Dose)
AUC(0-24) is measure of area under the curve over the dosing interval (tau), where tau is the length of the dosing interval (24 hours), calculated using the linear trapezoidal rule and normalized by dose. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole.
Time frame: Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules.
Population: Pharmacokinetic set included all participants with at least one estimable PK parameter for dexlansoprazole on Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole 15 mg QD | Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)/Dose) | 143.2 ng*hr/mL/mg | Standard Deviation 37.58 |
| Dexlansoprazole 30 mg QD | Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)/Dose) | 87.6 ng*hr/mL/mg | Standard Deviation 46.11 |
| Dexlansoprazole 60 mg QD | Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC(0-24)/Dose) | 55.5 ng*hr/mL/mg | Standard Deviation 31.39 |
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized AUC\[0-24\]. Pairwise comparisons between regimens were conducted.90% CI: [0.692, 1.636]ANCOVA
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized AUC\[0-24\]. Pairwise comparisons between regimens were conducted.90% CI: [0.691, 2.314]ANCOVA
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized AUC\[0-24\]. Pairwise comparisons between regimens were conducted.95% CI: [0.777, 1.817]ANCOVA
Other Pre-specified
Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)/Dose)
AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (tlqc), calculated using the linear trapezoidal rule, and normalized by dose. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole.
Time frame: Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules.
Population: Pharmacokinetic set included all participants with at least one estimable PK parameter for dexlansoprazole on Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole 15 mg QD | Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)/Dose) | 128 ng*hr/mL/mg | Standard Deviation 42.1 |
| Dexlansoprazole 30 mg QD | Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)/Dose) | 96 ng*hr/mL/mg | Standard Deviation 55.6 |
| Dexlansoprazole 60 mg QD | Dose-normalized Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC(0-tlqc)/Dose) | 62 ng*hr/mL/mg | Standard Deviation 46.6 |
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized AUC\[0-tlqc\]. Pairwise comparisons between regimens were conducted.90% CI: [0.693, 1.848]ANCOVA
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized AUC\[0-tlqc\]. Pairwise comparisons between regimens were conducted.90% CI: [0.584, 2.276]ANCOVA
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized AUC\[0-tlqc\]. Pairwise comparisons between regimens were conducted.90% CI: [0.632, 1.642]ANCOVA
Other Pre-specified
Dose-normalized Peak Plasma Concentration (Cmax/Dose)
Maximum observed plasma concentration (the peak plasma concentration of a drug after administration), normalized by dose. Pharmacokinetic parameters were derived using noncompartmental methods from the plasma concentrations of dexlansoprazole.
Time frame: Day 7 after 7 days of dosing with dexlansoprazole delayed release capsules.
Population: Pharmacokinetic set included all participants with at least one estimable PK parameter for dexlansoprazole on Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexlansoprazole 15 mg QD | Dose-normalized Peak Plasma Concentration (Cmax/Dose) | 37.3 ng/mL/mg | Standard Deviation 15.02 |
| Dexlansoprazole 30 mg QD | Dose-normalized Peak Plasma Concentration (Cmax/Dose) | 33.5 ng/mL/mg | Standard Deviation 24.94 |
| Dexlansoprazole 60 mg QD | Dose-normalized Peak Plasma Concentration (Cmax/Dose) | 16.1 ng/mL/mg | Standard Deviation 8.65 |
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized Cmax. Pairwise comparisons between regimens were conducted.90% CI: [0.66, 2.183]ANCOVA
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized Cmax. Pairwise comparisons between regimens were conducted.90% CI: [0.463, 2.427]ANCOVA
Comparison: Sample size of 12 participants per dose group, along with the intense PK sampling in each regimen was needed for characterization of the PK profile. An ANCOVA model with weight as a covariate and regimen as a factor were fitted to dose-normalized Cmax. Pairwise comparisons between regimens were conducted.90% CI: [0.493, 1.579]ANCOVA