Healthy
Conditions
Brief summary
The primary objective of this trial is to establish bioequivalence of two fixed dose combination (FDC) tablets (containing medium dose empagliflozin/500 mg metformin \[Test 1\] and low dose empagliflozin/500 mg metformin \[Test 2\]) and of the single tablets (medium dose empagliflozin tablets + Glucophage® 500 mg tablet \[Reference 1\] and low dose empagliflozin tablet + Glucophage® 500 mg tablet \[Reference 2\]) when administered together after a high fat, high caloric meal. The assessment of safety and tolerability will be an additional objective of this trial.
Interventions
DRUGempagliflozin
single tablet empagliflozin
DRUGmetformin (Glucophage®)
single tablet metformin
DRUGempagliflozin and metformin
FDC tablet empagliflozin and metformin
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 2. Subjects must be able to understand and comply with study requirements 3. Age 18 to 50 years 4. Body mass index (BMI) 18.5 to 29.9 kg/m2
Exclusion criteria
1\. Any relevant deviation from healthy conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-∞ for Empagliflozin | 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake | AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin |
| AUC0-∞ for Metformin | 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake | AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin |
| Cmax for Empagliflozin | 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake | Cmax (maximum measured concentration of the analyte in plasma) for Empagliflozin |
| Cmax for Metformin | 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake | Cmax (maximum measured concentration of the analyte in plasma) for Metformin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz for Empagliflozin | 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake | 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 |
| AUC0-tz for Metformin | 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake | 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 |
|---|---|
| FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500 Participants first received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets).
Oral administration. | 6 |
| Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5 Participants first received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC).
Oral administration. | 6 |
| FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500 Participants first received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets)Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration. | 6 |
| Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5 Participants first received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). Oral administration. | 6 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500 | Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5 | FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500 | Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 8.6 | 30.8 years STANDARD_DEVIATION 7.6 | 35.8 years STANDARD_DEVIATION 10.5 | 37.5 years STANDARD_DEVIATION 9 | 35.6 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 4 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 2 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 21 | 6 / 23 | 3 / 23 | 2 / 20 |
| serious Total, serious adverse events | 0 / 21 | 0 / 23 | 0 / 23 | 0 / 20 |
Outcome results
Primary
AUC0-∞ for Empagliflozin
AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin
Time frame: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake
Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12.5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-∞ for Empagliflozin | 2780 nmol*h/L | Geometric Coefficient of Variation 16.1 |
| 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-∞ for Empagliflozin | 2870 nmol*h/L | Geometric Coefficient of Variation 17.3 |
| 5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-∞ for Empagliflozin | 1110 nmol*h/L | Geometric Coefficient of Variation 15.7 |
| 5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-∞ for Empagliflozin | 1070 nmol*h/L | Geometric Coefficient of Variation 19.2 |
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.p-value: 090% CI: [93.529, 102.52]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.p-value: <0.000190% CI: [93.57, 102.65]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500 , PK set AUCinfpred \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.p-value: 090% CI: [99.077, 106.633]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 (T2) : Empa5 + Met500 (R2), PK set AUCinfpred \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: <0.000190% CI: [98.78, 106.36]ANOVA
Primary
AUC0-∞ for Metformin
AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin
Time frame: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake
Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12.5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-∞ for Metformin | 5590 ng*h/mL | Geometric Coefficient of Variation 19 |
| 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-∞ for Metformin | 5820 ng*h/mL | Geometric Coefficient of Variation 21.8 |
| 5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-∞ for Metformin | 5960 ng*h/mL | Geometric Coefficient of Variation 18 |
| 5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-∞ for Metformin | 6190 ng*h/mL | Geometric Coefficient of Variation 19.5 |
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000690% CI: [88.542, 104.628]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 (T1) : Empa12.5 + Met500 (R1), PK set AUCinfpred \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000490% CI: [89.41, 105.68]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUCinfpred \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: 090% CI: [91.772, 102.093]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUCinfpred \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: <0.000190% CI: [91.79, 102.32]ANOVA
Primary
Cmax for Empagliflozin
Cmax (maximum measured concentration of the analyte in plasma) for Empagliflozin
Time frame: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake
Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12.5 mg Empagliflozin and 500 mg Metformin as FDC | Cmax for Empagliflozin | 294 nmol/L | Geometric Coefficient of Variation 23.7 |
| 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets | Cmax for Empagliflozin | 282 nmol/L | Geometric Coefficient of Variation 27.4 |
| 5 mg Empagliflozin and 500 mg Metformin as FDC | Cmax for Empagliflozin | 109 nmol/L | Geometric Coefficient of Variation 22.8 |
| 5 mg Empagliflozin and 500 mg Metformin as Single Tablets | Cmax for Empagliflozin | 106 nmol/L | Geometric Coefficient of Variation 22.5 |
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax \[nmol/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: 090% CI: [99.882, 109.555]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax \[nmol/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: <0.000190% CI: [99.76, 109.53]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set Cmax \[nmol/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: 090% CI: [97.917, 108.258]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set Cmax \[nmol/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: <0.000190% CI: [97.72, 108.14]ANOVA
Primary
Cmax for Metformin
Cmax (maximum measured concentration of the analyte in plasma) for Metformin
Time frame: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake
Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12.5 mg Empagliflozin and 500 mg Metformin as FDC | Cmax for Metformin | 686 ng/mL | Geometric Coefficient of Variation 14.1 |
| 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets | Cmax for Metformin | 718 ng/mL | Geometric Coefficient of Variation 19.7 |
| 5 mg Empagliflozin and 500 mg Metformin as FDC | Cmax for Metformin | 693 ng/mL | Geometric Coefficient of Variation 12.8 |
| 5 mg Empagliflozin and 500 mg Metformin as Single Tablets | Cmax for Metformin | 743 ng/mL | Geometric Coefficient of Variation 19.6 |
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax \[ng/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000190% CI: [89.056, 100.819]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax \[ng/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000190% CI: [88.64, 100.54]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set Cmax \[ng/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000290% CI: [88.006, 100.034]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set Cmax \[ng/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000390% CI: [87.94, 100.43]ANOVA
Secondary
AUC0-tz for 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: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake
Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12.5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-tz for Empagliflozin | 2740 nmol*h/L | Geometric Coefficient of Variation 16.3 |
| 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-tz for Empagliflozin | 2830 nmol*h/L | Geometric Coefficient of Variation 17.3 |
| 5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-tz for Empagliflozin | 1080 nmol*h/L | Geometric Coefficient of Variation 15.7 |
| 5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-tz for Empagliflozin | 1040 nmol*h/L | Geometric Coefficient of Variation 19.1 |
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: 090% CI: [93.53, 102.686]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: <0.000190% CI: [93.55, 102.81]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUClast \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: 090% CI: [99.146, 106.522]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUClast \[nmol\*h/L\] for EMPAGLIFLOZIN (PLASMA EDTA)p-value: <0.000190% CI: [98.85, 106.25]ANOVA
Secondary
AUC0-tz for 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: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake
Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12.5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-tz for Metformin | 5480 ng*h/mL | Geometric Coefficient of Variation 18.9 |
| 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-tz for Metformin | 5720 ng*h/mL | Geometric Coefficient of Variation 21.2 |
| 5 mg Empagliflozin and 500 mg Metformin as FDC | AUC0-tz for Metformin | 5820 ng*h/mL | Geometric Coefficient of Variation 17.7 |
| 5 mg Empagliflozin and 500 mg Metformin as Single Tablets | AUC0-tz for Metformin | 6110 ng*h/mL | Geometric Coefficient of Variation 19.2 |
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000890% CI: [88, 104.256]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: 0.000690% CI: [88.78, 105.41]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUClast \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: 090% CI: [91.199, 100.934]ANOVA
Comparison: Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUClast \[ng\*h/mL\] for METFORMIN (PLASMA EDTA)p-value: <0.000190% CI: [91.28, 101.19]ANOVA