Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to demonstrate bioequivalence (BE) of a 5 mg saxagliptin/1000 mg metformin extended release (XR) fixed-dose combination (FDC) tablet (manufactured in Mt Vernon, Indiana) relative to a coadministered 5 mg Onglyza tablet (saxagliptin, manufactured in Mt Vernon, Indiana) and two 500 mg Glucophage XR tablets (metformin XR, manufactured in Evansville, Indiana) in the fed state in healthy subjects.
Detailed description
This study is designed to evaluate if the FDC tablet of 5 mg saxagliptin/1000 mg metformin extended release (manufactured in Mt Vernon, Indiana) is bioequivalent to the coadministered 5 mg saxagliptin tablet plus 2 x 500 mg Glucophage XR tablets (manufactured in Evansville, Indiana)
Interventions
DRUGsaxagliptin
Tablets, Oral, 5 mg, once daily, Single dose
DRUGGlucophage XR
Tablets, Oral, 500 mg, once daily, Single dose
Tablet, Oral, (saxagliptin 5 mg)(metformin XR 1000 mg), once daily, 4 days
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female subjects as determined by no clinically significant deviation from normal in medical history, physical examination, ECGs, and clinical laboratory determinations * Body Mass Index (BMI) of 18 to 32 kg/m², inclusive * Ages 18 to 55, inclusive
Exclusion criteria
* Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations beyond what is consistent with the target population * Major surgical procedure within 4 weeks prior to randomization * Positive serology test for HIV, HBV or HCV * Clinically significant history or presence of any of the following conditions: heart, liver, or kidney disease, neurologic or psychiatric disease * History of gastrointestinal disease within the past 3 months * Any clinically significant medical condition that could potentially affect your participation in the study and/or personal well-being, as judged by the investigator * Donated blood or blood products to a blood bank, blood transfusion or participated in a clinical study (except a screening visit) requiring withdrawal of blood within 4 weeks prior to randomization * Unable to tolerate oral and/or intravenous (IV) medications * Unable to tolerate the puncturing of veins for drawing of blood * Known allergy or hypersensitivity to any component of the study medication * History of any significant drug allergies (such as anaphylaxis or hepatotoxicity) * Used any prescription drugs or over the counter products to control acid (for example, Prevacid, Mylanta or Rolaids) within 4 weeks prior to randomization * Used any other drugs including over the counter medications and herbal preparations within 1 week prior to randomization * Taken any investigational drug or placebo (inactive drug) within 4 weeks prior to randomization
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) | Periods 1 and 2: pre-dosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours post-dosing. |
| Saxagliptin Observed Maximum Plasma Concentration (Cmax) | Periods 1 & 2: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 & 48 hrs post-dosing. Period 3: predosing on Days 2 & 3; predosing, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hrs postdosing on Day 4 |
| Metformin AUC(0-inf) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. |
| Metformin Cmax | Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Saxagliptin Degree of Fluctuation Over the Dosing Interval (Fluctuation %) | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| Saxagliptin Terminal Half-life (T1/2) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| Saxagliptin Fraction of AUC(0-inf) Contributed by AUC(0-t) (AUC[0-t]/AUC[0-inf]) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| Saxagliptin Time to Achieve the Observed Maximum Plasma Concentration (Tmax) | Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4. | — |
| 5-hydroxy Saxagliptin AUC(0-inf) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| 5-hydroxy Saxagliptin AUC(0-t) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| 5-hydroxy Saxagliptin AUC(0-tau) | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| 5-hydroxy Saxagliptin Cmax | Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4. | — |
| 5-hydroxy Saxagliptin Cmin | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| 5-hydroxy Saxagliptin Cavg | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| 5-hydroxy Saxagliptin Fluctuation % | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| 5-hydroxy Saxagliptin T1/2 | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours post-dosing. | — |
| Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) | Periods 1 and 2: pre-dosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours post-dosing. | — |
| 5-hydroxy Saxagliptin Tmax | Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4. | — |
| Metformin AUC(0-t) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| Metformin AUC(0-tau) | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| Metformin Cmin | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| Metformin Cavg | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| Metformin Fluctuation % | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| Metformin T1/2 | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| Metformin AUC(0-inf) Contributed by AUC(0-t)(AUC[0-t]/AUC[0-inf]) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| Metformin Tmax | Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4. | — |
| Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | AEs: from initiation of study drug administration on morning of Day 1/Period 1 through study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or participation in study if last scheduled visit occurred later. | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. |
| Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | From Day 1 of Period 1 to Day 3 of Period 2 for participants in Treatment Sequence BA and Day 5 of Period 3 for participants in Treatment Sequence ABC | Abnormalities considered clinically significant and/or reported as an AE by the investigator. |
| 5-hydroxy Saxagliptin AUC(0-t)/AUC(0-inf) | Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing. | — |
| Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUC[0-tau]) | Period 3: pre-dosing on Days 2 and 3; pre-dosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours post-dosing on Day 4. | Dosing interval = 24 hours. |
| Saxagliptin Trough (Predose) Plasma Concentration (Cmin) | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
| Saxagliptin Average Plasma Concentration Over the Dosing Period (Cavg) | Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4. | — |
Countries
United States
Participant flow
Pre-assignment details
Participants underwent screening evaluations to determine eligibility within 21 days before dosing, and were admitted to the clinical facility the evening before dosing (Day -1). On Day 1 of Period 1, a total of 30 participants who met all of the inclusion and none of the exclusion criteria were randomly assigned to 1 of 2 treatment sequences.
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled and Treated Participants | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | left prematurely (while on treatment B) | 0 | 1 |
| Period 3 | family emergency | 1 | 0 |
Baseline characteristics
| Characteristic | All Enrolled and Treated Participants |
|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 7.76 |
| Body Mass Index | 25.69 kg/m^2 STANDARD_DEVIATION 2.7 |
| Height | 166.85 cm STANDARD_DEVIATION 9.02 |
| Race/Ethnicity, Customized Black or African American | 8 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 17 participants |
| Race/Ethnicity, Customized White | 22 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 13 Participants |
| Weight | 71.56 kg STANDARD_DEVIATION 9.39 |
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 | 3 / 29 | 3 / 30 | 4 / 14 |
| serious Total, serious adverse events | 0 / 29 | 0 / 30 | 0 / 14 |
Outcome results
Primary
Metformin AUC(0-inf)
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to end of study. 2 participants in Treatment A \& 1 in Treatment B were excluded due to the inability to estimate with acceptable accuracy a terminal slope for terminal phase concentration data. Treatment C administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Metformin AUC(0-inf) | 10336.18 ng*hr/mL | Standard Deviation 3066.13 |
| Treatment B | Metformin AUC(0-inf) | 9211.29 ng*hr/mL | Standard Deviation 3364.24 |
Comparison: If there was no difference between the bioavailabilities of metformin from the FDC tablet versus metformin from coadministration of a 5-mg saxagliptin tablet plus two 500-mg metformin XR tablets under fed conditions, then 24 subjects would have provided 99% power to conclude BE with respect to Cmax and AUC0-inf. If there was a 5% difference, then 24 subjects would have provided at least 99% power to conclude BE with respect to Cmax and AUC0-inf.90% CI: [0.833, 0.959]
Comparison: Geometric least squares mean for Treatment B
Comparison: Geometric least squares mean for Treatment A
Primary
Metformin Cmax
Time frame: Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Metformin Cmax | 1184.07 ng/mL | Standard Deviation 276.12 |
| Treatment B | Metformin Cmax | 1078.67 ng/mL | Standard Deviation 221.72 |
| Treatment C | Metformin Cmax | 979.93 ng/mL | Standard Deviation 267.58 |
Comparison: If there was no difference between the bioavailabilities of metformin from the FDC tablet versus metformin from coadministration of a 5-mg saxagliptin tablet plus two 500-mg metformin XR tablets under fed conditions, then 24 subjects would have provided 99% power to conclude BE with respect to Cmax and AUC0-inf. If there was a 5% difference, then 24 subjects would have provided at least 99% power to conclude BE with respect to Cmax and AUC0-inf.90% CI: [0.859, 0.98]
Comparison: Geometric least squares means for Treatment B
Comparison: Geometric least squares means for Treatment A
Primary
Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])
Time frame: Periods 1 and 2: pre-dosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours post-dosing.
Population: All treated participants not discontinuing prior to the end of study. One participant in Treatment A was excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for the terminal phase concentration data. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) | 99.45 ng*hr/mL | Standard Deviation 18.34 |
| Treatment B | Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) | 105.28 ng*hr/mL | Standard Deviation 23.14 |
Comparison: If there was no difference between the bioavailabilities of saxagliptin from the FDC tablet versus saxagliptin from coadministration of a 5-mg saxagliptin tablet plus two 500-mg metformin XR tablets under fed conditions, then 24 subjects would have provided 99% power to conclude bioequivalence (BE) with respect to Cmax and AUC0-inf. If there was a 5% difference, then 24 subjects would have provided 94% and 99% power to conclude BE with respect to Cmax and AUC0-inf.90% CI: [1.025, 1.065]
Comparison: Geometric least squares means for Treatment B
Comparison: Geometric least squares means for Treatment A
Primary
Saxagliptin Observed Maximum Plasma Concentration (Cmax)
Time frame: Periods 1 & 2: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 & 48 hrs post-dosing. Period 3: predosing on Days 2 & 3; predosing, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hrs postdosing on Day 4
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin Observed Maximum Plasma Concentration (Cmax) | 25.28 ng/mL | Standard Deviation 6.4 |
| Treatment B | Saxagliptin Observed Maximum Plasma Concentration (Cmax) | 25.75 ng/mL | Standard Deviation 6.92 |
| Treatment C | Saxagliptin Observed Maximum Plasma Concentration (Cmax) | 25.75 ng/mL | Standard Deviation 7.13 |
Comparison: If there was no difference between the bioavailabilities of saxagliptin from the FDC tablet versus saxagliptin from coadministration of a 5-mg saxagliptin tablet plus two 500-mg metformin XR tablets under fed conditions, then 24 subjects would have provided 99% power to conclude bioequivalence (BE) with respect to Cmax and AUC0-inf. If there was a 5% difference, then 24 subjects would have provided 94% and 99% power to conclude BE with respect to Cmax and AUC0-inf.90% CI: [0.948, 1.053]
Comparison: Geometric least squares means for Treatment B
Comparison: Geometric least squares means for Treatment A
Secondary
5-hydroxy Saxagliptin AUC(0-inf)
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to the end of study. One participant in Treatment A was excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for the terminal phase concentration data. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | 5-hydroxy Saxagliptin AUC(0-inf) | 298.80 ng*hr/mL | Standard Deviation 69.32 |
| Treatment B | 5-hydroxy Saxagliptin AUC(0-inf) | 296.99 ng*hr/mL | Standard Deviation 69.35 |
Secondary
5-hydroxy Saxagliptin AUC(0-t)
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to end of study. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | 5-hydroxy Saxagliptin AUC(0-t) | 293.06 ng*hr/mL | Standard Deviation 68.28 |
| Treatment B | 5-hydroxy Saxagliptin AUC(0-t) | 289.37 ng*hr/mL | Standard Deviation 68.72 |
Secondary
5-hydroxy Saxagliptin AUC(0-tau)
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | 5-hydroxy Saxagliptin AUC(0-tau) | 318.47 ng*hr/mL | Standard Deviation 54.95 |
Secondary
5-hydroxy Saxagliptin AUC(0-t)/AUC(0-inf)
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to the end of study. One participant in Treatment A was excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for the terminal phase concentration data. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | 5-hydroxy Saxagliptin AUC(0-t)/AUC(0-inf) | 0.975 ratio | Standard Deviation 0.009 |
| Treatment B | 5-hydroxy Saxagliptin AUC(0-t)/AUC(0-inf) | 0.973 ratio | Standard Deviation 0.01 |
Secondary
5-hydroxy Saxagliptin Cavg
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | 5-hydroxy Saxagliptin Cavg | 13.27 ng/mL | Standard Deviation 2.29 |
Secondary
5-hydroxy Saxagliptin Cmax
Time frame: Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | 5-hydroxy Saxagliptin Cmax | 54.69 ng/mL | Standard Deviation 17 |
| Treatment B | 5-hydroxy Saxagliptin Cmax | 51.32 ng/mL | Standard Deviation 16.19 |
| Treatment C | 5-hydroxy Saxagliptin Cmax | 59.87 ng/mL | Standard Deviation 13.83 |
Secondary
5-hydroxy Saxagliptin Cmin
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | 5-hydroxy Saxagliptin Cmin | 1.51 ng/mL | Standard Deviation 0.22 |
Secondary
5-hydroxy Saxagliptin Fluctuation %
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | 5-hydroxy Saxagliptin Fluctuation % | 437.09 percentage of fluctuation | Standard Deviation 43.97 |
Secondary
5-hydroxy Saxagliptin T1/2
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours post-dosing.
Population: All treated participants not discontinuing prior to the end of study. One participant in Treatment A was excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for the terminal phase concentration data. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | 5-hydroxy Saxagliptin T1/2 | 13.48 ng*hr/mL | Standard Deviation 1.78 |
| Treatment B | 5-hydroxy Saxagliptin T1/2 | 13.82 ng*hr/mL | Standard Deviation 2.52 |
Secondary
5-hydroxy Saxagliptin Tmax
Time frame: Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | 5-hydroxy Saxagliptin Tmax | 2.69 hour | Standard Deviation 0.8 |
| Treatment B | 5-hydroxy Saxagliptin Tmax | 2.27 hour | Standard Deviation 0.84 |
| Treatment C | 5-hydroxy Saxagliptin Tmax | 2.05 hour | Standard Deviation 0.57 |
Secondary
Metformin AUC(0-inf) Contributed by AUC(0-t)(AUC[0-t]/AUC[0-inf])
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to end of study. 2 participants in Treatment A \& 1 in Treatment B were excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for terminal phase concentration data. Treatment C was administered only during Period 3, \& this measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Metformin AUC(0-inf) Contributed by AUC(0-t)(AUC[0-t]/AUC[0-inf]) | 0.967 ratio | Standard Deviation 0.029 |
| Treatment B | Metformin AUC(0-inf) Contributed by AUC(0-t)(AUC[0-t]/AUC[0-inf]) | 0.963 ratio | Standard Deviation 0.034 |
Secondary
Metformin AUC(0-t)
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to end of study. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Metformin AUC(0-t) | 9734.38 ng*hr/mL | Standard Deviation 3123.76 |
| Treatment B | Metformin AUC(0-t) | 8846.36 ng*hr/mL | Standard Deviation 3304.75 |
90% CI: [0.848, 0.968]
Comparison: Geometric least squares means for Treatment B
Comparison: Geometric least squares mean for Treatment A
Secondary
Metformin AUC(0-tau)
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Metformin AUC(0-tau) | 9501.81 ng*hr/mL | Standard Deviation 4001 |
Secondary
Metformin Cavg
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Metformin Cavg | 395.91 ng/mL | Standard Deviation 166.71 |
Secondary
Metformin Cmin
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Metformin Cmin | 105.04 ng/mL | Standard Deviation 88.09 |
Secondary
Metformin Fluctuation %
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Metformin Fluctuation % | 240.06 percentage of fluctuation | Standard Deviation 73.54 |
Secondary
Metformin T1/2
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to the end of study. One participant in Treatment A was excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for the terminal phase concentration data. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Metformin T1/2 | 13.02 ng*hr/mL | Standard Deviation 6.15 |
| Treatment B | Metformin T1/2 | 12.94 ng*hr/mL | Standard Deviation 6.74 |
Secondary
Metformin Tmax
Time frame: Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Metformin Tmax | 4.38 hour | Standard Deviation 0.73 |
| Treatment B | Metformin Tmax | 4.84 hour | Standard Deviation 0.91 |
| Treatment C | Metformin Tmax | 5.00 hour | Standard Deviation 1.3 |
Secondary
Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs)
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.
Time frame: AEs: from initiation of study drug administration on morning of Day 1/Period 1 through study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or participation in study if last scheduled visit occurred later.
Population: All subjects who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Deaths | 0 participants |
| Treatment A | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | SAEs | 0 participants |
| Treatment A | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Discontinuation Due to AE | 0 participants |
| Treatment A | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Number of Participants With At Least 1 AE | 3 participants |
| Treatment B | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Number of Participants With At Least 1 AE | 3 participants |
| Treatment B | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Discontinuation Due to AE | 0 participants |
| Treatment B | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | SAEs | 0 participants |
| Treatment B | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Deaths | 0 participants |
| Treatment C | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | SAEs | 0 participants |
| Treatment C | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Number of Participants With At Least 1 AE | 4 participants |
| Treatment C | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Discontinuation Due to AE | 0 participants |
| Treatment C | Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | Deaths | 0 participants |
Secondary
Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities
Abnormalities considered clinically significant and/or reported as an AE by the investigator.
Time frame: From Day 1 of Period 1 to Day 3 of Period 2 for participants in Treatment Sequence BA and Day 5 of Period 3 for participants in Treatment Sequence ABC
Population: All subjects who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Clinical Laboratory Abnormalities | 0 participants |
| Treatment A | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Vital Sign Abnormalities | 0 participants |
| Treatment A | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Physical Examination Abnormalities | 0 participants |
| Treatment A | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | 12-Lead ECG Abnormalities | 0 participants |
| Treatment B | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | 12-Lead ECG Abnormalities | 0 participants |
| Treatment B | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Clinical Laboratory Abnormalities | 0 participants |
| Treatment B | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Physical Examination Abnormalities | 0 participants |
| Treatment B | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Vital Sign Abnormalities | 0 participants |
| Treatment C | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | 12-Lead ECG Abnormalities | 0 participants |
| Treatment C | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Vital Sign Abnormalities | 0 participants |
| Treatment C | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Physical Examination Abnormalities | 1 participants |
| Treatment C | Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Clinical Laboratory Abnormalities | 0 participants |
Secondary
Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUC[0-tau])
Dosing interval = 24 hours.
Time frame: Period 3: pre-dosing on Days 2 and 3; pre-dosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours post-dosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUC[0-tau]) | 19.20 ng*hr/mL | Standard Deviation 20.68 |
Secondary
Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t])
Time frame: Periods 1 and 2: pre-dosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours post-dosing.
Population: All treated participants not discontinuing prior to end of study. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) | 97.76 ng*hr/mL | Standard Deviation 17.96 |
| Treatment B | Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) | 103.34 ng*hr/mL | Standard Deviation 22.73 |
90% CI: [1.009, 1.062]
Comparison: Geometric least squares means for Treatment B
Comparison: Geometric least squares means for Treatment A
Secondary
Saxagliptin Average Plasma Concentration Over the Dosing Period (Cavg)
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Saxagliptin Average Plasma Concentration Over the Dosing Period (Cavg) | 4.13 ng/mL | Standard Deviation 0.86 |
Secondary
Saxagliptin Degree of Fluctuation Over the Dosing Interval (Fluctuation %)
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Saxagliptin Degree of Fluctuation Over the Dosing Interval (Fluctuation %) | 611.85 percentage of fluctuation | Standard Deviation 107.36 |
Secondary
Saxagliptin Fraction of AUC(0-inf) Contributed by AUC(0-t) (AUC[0-t]/AUC[0-inf])
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to the end of study. One participant in Treatment A was excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for the terminal phase concentration data. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin Fraction of AUC(0-inf) Contributed by AUC(0-t) (AUC[0-t]/AUC[0-inf]) | 0.981 ratio | Standard Deviation 0.01 |
| Treatment B | Saxagliptin Fraction of AUC(0-inf) Contributed by AUC(0-t) (AUC[0-t]/AUC[0-inf]) | 0.982 ratio | Standard Deviation 0.008 |
Secondary
Saxagliptin Terminal Half-life (T1/2)
Time frame: Periods 1 and 2: predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36 and 48 hours postdosing.
Population: All treated participants not discontinuing prior to the end of study. One participant in Treatment A was excluded as a result of the inability to estimate with acceptable accuracy a terminal slope for the terminal phase concentration data. Treatment C was administered only during Period 3, and this outcome measure was analyzed for Periods 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin Terminal Half-life (T1/2) | 8.69 ng*hr/mL | Standard Deviation 3.71 |
| Treatment B | Saxagliptin Terminal Half-life (T1/2) | 8.85 ng*hr/mL | Standard Deviation 4.47 |
Secondary
Saxagliptin Time to Achieve the Observed Maximum Plasma Concentration (Tmax)
Time frame: Periods 1 & 2:predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24, 36, 48 hours postdose. Period 3: predose on Days 2 & 3; predose, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, 24 hours postdose on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin Time to Achieve the Observed Maximum Plasma Concentration (Tmax) | 1.88 hour | Standard Deviation 0.87 |
| Treatment B | Saxagliptin Time to Achieve the Observed Maximum Plasma Concentration (Tmax) | 1.51 hour | Standard Deviation 0.64 |
| Treatment C | Saxagliptin Time to Achieve the Observed Maximum Plasma Concentration (Tmax) | 1.35 hour | Standard Deviation 0.51 |
Secondary
Saxagliptin Trough (Predose) Plasma Concentration (Cmin)
Time frame: Period 3: predosing on Days 2 and 3; predosing, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18, and 24 hours postdosing on Day 4.
Population: All treated participants not discontinuing prior to end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Saxagliptin Trough (Predose) Plasma Concentration (Cmin) | 0.28 ng/mL | Standard Deviation 0.1 |