Healthy
Conditions
Brief summary
Bioequivalence of an empagliflozin/metformin (FDC) tablet compared with single tablets of two strength of empagliflozin and metformin (Part I) under fasted and under fed conditions and bioequivalence of empagliflozin/metformin (FDC) tablet compared with single tablets empagliflozin and metformin under fed conditions (Part II).
Interventions
DRUGEmpagliflozin
medium dose oral administration
DRUGMetformin
oral administration
low dose of Empagliflozin
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1\. Healthy male and female subjects
Exclusion criteria
1\. Any relevant deviation from healthy conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin | 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | AUC0-inf: area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for Empagliflozin |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin | 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | AUC0-inf: area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for Metformin |
| Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin | 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Cmax: maximum measured concentration of the analyte in plasma for Empagliflozin |
| Maximum Measured Concentration of the Analyte in Plasma, Metformin | 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Cmax: maximum measured concentration of the analyte in plasma for Metformin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin | 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | AUC0-tz: area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point for Empagliflozin |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin | 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | AUC0-tz: area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point for Metformin |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Emp/Met Fasted / Emp+Met Fasted / Emp/Met Fed / Emp+Met Fed fixed-dose-combination (FDC) tablet under fasted conditions first; then free dose combination tablets under fasted conditions; then FDC tablet under fed conditions; then free dose combination tablets under fed conditions
Empagliflozin (Emp): 12.5 mg; Metformin (Met): 1000 mg (oral with 240 ml water) | 6 |
| Emp/Met Fed / Emp+Met Fed / Emp/Met Fasted / Emp+Met Fasted fixed-dose-combination (FDC) tablet under fed conditions first; then free dose combination tablets under fed conditions; then FDC tablet under fasted conditions; then free dose combination tablets under fasted conditions
Empagliflozin (Emp): 12.5 mg; Metformin (Met): 1000 mg (oral with 240 ml water) | 6 |
| Emp+Met Fasted / Emp/Met Fasted / Emp+Met Fed / Emp/Met Fed free dose combination tablets under fasted conditions first; then fixed-dose-combination (FDC) tablet under fasted conditions; then free dose combination tablets under fed conditions; then FDC tablet under fed conditions
Empagliflozin (Emp): 12.5 mg; Metformin (Met): 1000 mg (oral with 240 ml water) | 6 |
| Emp+Met Fed / Emp/Met Fed / Emp+Met Fasted / Emp/Met Fasted free dose combination tablets under fed conditions first; then FDC tablet under fed conditions; then free dose combination tablets under fasted conditions; then fixed-dose-combination (FDC) tablet under fasted conditions
Empagliflozin (Emp): 12.5 mg; Metformin (Met): 1000 mg (oral with 240 ml water) | 6 |
| Low Dose Emp: Emp/Met / Emp+Met fixed-dose-combination tablet under fed conditions first; then free dose combination tablets under fed conditions
Empagliflozin (Emp): 5 mg; Metformin (Met): 1000 mg (oral with 240 ml water) | 12 |
| Low Dose Emp: Emp+Met / Emp/Met free dose combination tablets under fed conditions first; then fixed-dose-combination tablet under fed conditions
Empagliflozin (Emp): 5 mg; Metformin (Met): 1000 mg (oral with 240 ml water) | 12 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Emp/Met Fasted / Emp+Met Fasted / Emp/Met Fed / Emp+Met Fed | Emp/Met Fed / Emp+Met Fed / Emp/Met Fasted / Emp+Met Fasted | Emp+Met Fasted / Emp/Met Fasted / Emp+Met Fed / Emp/Met Fed | Emp+Met Fed / Emp/Met Fed / Emp+Met Fasted / Emp/Met Fasted | Low Dose Emp: Emp/Met / Emp+Met | Low Dose Emp: Emp+Met / Emp/Met | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 33.5 years STANDARD_DEVIATION 6.7 | 26.5 years STANDARD_DEVIATION 9.7 | 28.5 years STANDARD_DEVIATION 9.5 | 33.2 years STANDARD_DEVIATION 7.1 | 32.8 years STANDARD_DEVIATION 9.8 | 32.3 years STANDARD_DEVIATION 9.6 | 31.5 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 1 Participants | 4 Participants | 7 Participants | 7 Participants | 25 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 5 Participants | 2 Participants | 5 Participants | 5 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 23 | 6 / 24 | 4 / 24 | 6 / 24 | 9 / 23 | 10 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 23 | 0 / 23 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin
AUC0-inf: area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for Empagliflozin
Time frame: 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: Pharmacokinetic set (PKS): included all subjects of the TS who provided at least one observation for at least one primary PK endpoint and who did not have a protocol violation relevant to the evaluation of Pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin | 2810 nmol*h/L | Geometric Coefficient of Variation 19.3 |
| 2 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin | 2580 nmol*h/L | Geometric Coefficient of Variation 20.4 |
| 3 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin | 2760 nmol*h/L | Geometric Coefficient of Variation 20 |
| 4 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin | 2570 nmol*h/L | Geometric Coefficient of Variation 20.7 |
| 5 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin | 988 nmol*h/L | Geometric Coefficient of Variation 16.2 |
| 6 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Empagliflozin | 927 nmol*h/L | Geometric Coefficient of Variation 18 |
p-value: <0.000190% CI: [99.531, 105.653]ANOVA
p-value: <0.000190% CI: [94.879, 103.059]ANOVA
p-value: <0.000190% CI: [102.728, 109.386]ANOVA
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin
AUC0-inf: area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for Metformin
Time frame: 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS: included all subjects of the TS who provided at least one observation for at least one primary PK endpoint and who did not have a protocol violation relevant to the evaluation of Pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin | 10400 ng*h/mL | Geometric Coefficient of Variation 23 |
| 2 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin | 9220 ng*h/mL | Geometric Coefficient of Variation 26.4 |
| 3 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin | 11000 ng*h/mL | Geometric Coefficient of Variation 26.8 |
| 4 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin | 9140 ng*h/mL | Geometric Coefficient of Variation 22.9 |
| 5 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin | 9080 ng*h/mL | Geometric Coefficient of Variation 32.7 |
| 6 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Metformin | 9060 ng*h/mL | Geometric Coefficient of Variation 26.7 |
p-value: <0.000190% CI: [91.25, 101.26]ANOVA
p-value: <0.000190% CI: [92.56, 106.62]ANOVA
p-value: <0.000190% CI: [95.74, 106.14]ANOVA
Primary
Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin
Cmax: maximum measured concentration of the analyte in plasma for Empagliflozin
Time frame: 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS: included all subjects of the TS who provided at least one observation for at least one primary PK endpoint and who did not have a protocol violation relevant to the evaluation of Pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1 Empagliflozin/Metformin (T) | Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin | 379 nmol/L | Geometric Coefficient of Variation 23.7 |
| 2 Empagliflozin/Metformin (T) | Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin | 276 nmol/L | Geometric Coefficient of Variation 24.8 |
| 3 Empagliflozin + Metformin (R) | Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin | 375 nmol/L | Geometric Coefficient of Variation 27.3 |
| 4 Empagliflozin + Metformin (R) | Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin | 258 nmol/L | Geometric Coefficient of Variation 28.5 |
| 5 Empagliflozin/Metformin (T) | Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin | 108 nmol/L | Geometric Coefficient of Variation 16.9 |
| 6 Empagliflozin + Metformin (R) | Maximum Measured Concentration of the Analyte in Plasma, Empagliflozin | 103 nmol/L | Geometric Coefficient of Variation 14.5 |
p-value: <0.000190% CI: [96.255, 108.351]ANOVA
p-value: 0.008290% CI: [95.863, 118.353]ANOVA
p-value: <0.000190% CI: [99.152, 110.224]ANOVA
Primary
Maximum Measured Concentration of the Analyte in Plasma, Metformin
Cmax: maximum measured concentration of the analyte in plasma for Metformin
Time frame: 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS: included all subjects of the TS who provided at least one observation for at least one primary PK endpoint and who did not have a protocol violation relevant to the evaluation of Pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1 Empagliflozin/Metformin (T) | Maximum Measured Concentration of the Analyte in Plasma, Metformin | 1580 ng/mL | Geometric Coefficient of Variation 26.9 |
| 2 Empagliflozin/Metformin (T) | Maximum Measured Concentration of the Analyte in Plasma, Metformin | 1160 ng/mL | Geometric Coefficient of Variation 17.8 |
| 3 Empagliflozin + Metformin (R) | Maximum Measured Concentration of the Analyte in Plasma, Metformin | 1680 ng/mL | Geometric Coefficient of Variation 25.8 |
| 4 Empagliflozin + Metformin (R) | Maximum Measured Concentration of the Analyte in Plasma, Metformin | 1180 ng/mL | Geometric Coefficient of Variation 21.2 |
| 5 Empagliflozin/Metformin (T) | Maximum Measured Concentration of the Analyte in Plasma, Metformin | 1180 ng/mL | Geometric Coefficient of Variation 23.8 |
| 6 Empagliflozin + Metformin (R) | Maximum Measured Concentration of the Analyte in Plasma, Metformin | 1150 ng/mL | Geometric Coefficient of Variation 24.8 |
p-value: 0.000190% CI: [88.931, 101.21]ANOVA
p-value: <0.000190% CI: [92.339, 103.935]ANOVA
p-value: <0.000190% CI: [97.166, 109.082]ANOVA
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin
AUC0-tz: area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point for Empagliflozin
Time frame: 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS: included all subjects of the TS who provided at least one observation for at least one primary PK endpoint and who did not have a protocol violation relevant to the evaluation of Pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin | 2770 nmol*h/L | Geometric Coefficient of Variation 19.2 |
| 2 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin | 2530 nmol*h/L | Geometric Coefficient of Variation 20.1 |
| 3 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin | 2720 nmol*h/L | Geometric Coefficient of Variation 20 |
| 4 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin | 2510 nmol*h/L | Geometric Coefficient of Variation 20.2 |
| 5 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin | 962 nmol*h/L | Geometric Coefficient of Variation 16.3 |
| 6 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Empagliflozin | 903 nmol*h/L | Geometric Coefficient of Variation 18.2 |
p-value: <0.000190% CI: [99.315, 105.43]ANOVA
p-value: <0.000190% CI: [94.784, 103.037]ANOVA
p-value: <0.000190% CI: [102.73, 109.329]ANOVA
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin
AUC0-tz: area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point for Metformin
Time frame: 1 hour (h) before first drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30 min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS: included all subjects of the TS who provided at least one observation for at least one primary PK endpoint and who did not have a protocol violation relevant to the evaluation of Pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin | 10100 ng*h/mL | Geometric Coefficient of Variation 21.3 |
| 2 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin | 8960 ng*h/mL | Geometric Coefficient of Variation 24.5 |
| 3 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin | 10700 ng*h/mL | Geometric Coefficient of Variation 24.1 |
| 4 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin | 8930 ng*h/mL | Geometric Coefficient of Variation 22.5 |
| 5 Empagliflozin/Metformin (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin | 8870 ng*h/mL | Geometric Coefficient of Variation 30.8 |
| 6 Empagliflozin + Metformin (R) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point, Metformin | 8850 ng*h/mL | Geometric Coefficient of Variation 26.3 |
p-value: <0.000190% CI: [89.8, 100.26]ANOVA
p-value: <0.000190% CI: [92.14, 107.03]ANOVA
p-value: <0.000190% CI: [95.77, 105.96]ANOVA