Healthy
Conditions
Brief summary
The purpose of this trial is to demonstrate the relative bioavailability of 2 newly developed fixed dose combination (FDC) tablets containing empagliflozin & metformin and the single tablets of empagliflozin and metformin when administered singularly.
Interventions
DRUGEmpagliflozin/Metformin XR, FDC
Experimental: high dose empagliflozin/metformin XR, FDC tablet
DRUGEmpagliflozin/Metformin XR FDC
Experimental: low dose empagliflozin/metformin XR, FDC tablet
DRUG25 mg Empagliflozin/1000 mg Metformin XR, FDC
Experimental, high dose Empagliflozin/Metformin XR,FDC Tablet
Active Comparator: 1x empagliflozin/2x metformin XR tablets
DRUG1 tablet Empagliflozin/3 tablets Metformin XR
Active Comparator: 1x empagliflozin/3x metformin XR tablets
Sponsors
Eli Lilly and Company
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 males or females 2. Age 18-50 years (incl) 3. Body Mass Index (BMI) 18.5 to 29.9 kg/m2 (incl) 4. Subjects must be able to understand and comply with study requirements
Exclusion criteria
Any deviation from healthy condition
Design outcomes
Primary
| 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 (AUC 0-tz); Empagliflozin | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | Area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz); Empagliflozin |
| AUC 0-tz (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 drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | AUC 0-tz (area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point); Metformin |
| Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | Cmax (maximum measured concentration of the analyte in plasma); Empagliflozin |
| Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | Cmax (maximum measured concentration of the analyte in plasma); Metformin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC 0-infinity (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 drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Empagliflozin |
| AUC 0-infinity (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 drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Metformin |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Dose, Fasted 1 fixed dose combination (FDC) tablet vs. 3 single tablets under fasted conditions:
25 mg Empagliflozin/1000 mg Metformin XR (extended release), FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet;
1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets | 23 |
| High Dose, Fed 1 fixed dose combination (FDC) tablet vs. 3 single tablets under fed conditions:
25 mg Empagliflozin/1000 mg Metformin XR, FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet;
1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets | 24 |
| Low Dose, Fasted 2 fixed low dose combination (FDC) tablets vs. 4 single tablets under fasted conditions:
12.5 mg Empagliflozin / 750 mg Metformin XR FDC tablets: Experimental: low dose Empagliflozin/Metformin XR, 2 FDC tablets;
1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 3x Metformin XR tablets | 24 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Test Period 1 | Not treated | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | High Dose, Fasted | High Dose, Fed | Low Dose, Fasted | Total |
|---|---|---|---|---|
| Age, Continuous | 32.4 years STANDARD_DEVIATION 8.7 | 34.2 years STANDARD_DEVIATION 9.2 | 30.8 years STANDARD_DEVIATION 8.4 | 32.5 years STANDARD_DEVIATION 8.8 |
| Gender Female | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
| Gender Male | 13 Participants | 14 Participants | 14 Participants | 41 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 | 4 / 23 | 1 / 23 | 1 / 24 | 2 / 24 | 4 / 24 | 1 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 |
Outcome results
Primary
Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin
Area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz); Empagliflozin
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic set (PKS): This set includes all subjects of the Treated set (TS) who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of Pharmacokinetic (PK) endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose, Fasted: 1 FDC Tablet | Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin | 6430 nmol*h/L | Geometric Coefficient of Variation 22.3 |
| High Dose, Fasted: 3 Single Tablets | Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin | 6430 nmol*h/L | Geometric Coefficient of Variation 21.7 |
| High Dose, Fed: 1 FDC Tablet | Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin | 5690 nmol*h/L | Geometric Coefficient of Variation 21 |
| High Dose, Fed: 3 Single Tablets | Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin | 5850 nmol*h/L | Geometric Coefficient of Variation 19.6 |
| Low Dose, Fasted: 2 FDC Tablets | Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin | 7160 nmol*h/L | Geometric Coefficient of Variation 19.5 |
| Low Dose, Fasted: 4 Single Tablets | Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin | 7110 nmol*h/L | Geometric Coefficient of Variation 20.5 |
p-value: <0.000190% CI: [97.275, 102.751]ANOVA
p-value: <0.000190% CI: [93.857, 100.436]ANOVA
p-value: <0.000190% CI: [98.28, 103.18]ANOVA
Primary
AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin
AUC 0-tz (area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point); Metformin
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose, Fasted: 1 FDC Tablet | AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin | 6350 ng*h/mL | Geometric Coefficient of Variation 32.8 |
| High Dose, Fasted: 3 Single Tablets | AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin | 6700 ng*h/mL | Geometric Coefficient of Variation 28.9 |
| High Dose, Fed: 1 FDC Tablet | AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin | 13000 ng*h/mL | Geometric Coefficient of Variation 23.6 |
| High Dose, Fed: 3 Single Tablets | AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin | 13100 ng*h/mL | Geometric Coefficient of Variation 21.1 |
| Low Dose, Fasted: 2 FDC Tablets | AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin | 10200 ng*h/mL | Geometric Coefficient of Variation 38.5 |
| Low Dose, Fasted: 4 Single Tablets | AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin | 10300 ng*h/mL | Geometric Coefficient of Variation 38.3 |
p-value: 0.025690% CI: [82.29, 108.88]ANOVA
p-value: <0.000190% CI: [96.25, 103.26]ANOVA
p-value: 0.00290% CI: [88.65, 112.27]ANOVA
Primary
Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin
Cmax (maximum measured concentration of the analyte in plasma); Empagliflozin
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose, Fasted: 1 FDC Tablet | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin | 886 nmol/L | Geometric Coefficient of Variation 27.3 |
| High Dose, Fasted: 3 Single Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin | 810 nmol/L | Geometric Coefficient of Variation 28.1 |
| High Dose, Fed: 1 FDC Tablet | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin | 559 nmol/L | Geometric Coefficient of Variation 29 |
| High Dose, Fed: 3 Single Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin | 601 nmol/L | Geometric Coefficient of Variation 25 |
| Low Dose, Fasted: 2 FDC Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin | 1010 nmol/L | Geometric Coefficient of Variation 27 |
| Low Dose, Fasted: 4 Single Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin | 963 nmol/L | Geometric Coefficient of Variation 29.7 |
p-value: 0.007290% CI: [99.892, 119.1]ANOVA
p-value: 0.000490% CI: [86.781, 98.428]ANOVA
p-value: 0.001490% CI: [96.6, 114.942]ANOVA
Primary
Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin
Cmax (maximum measured concentration of the analyte in plasma); Metformin
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose, Fasted: 1 FDC Tablet | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin | 822 ng/mL | Geometric Coefficient of Variation 37.4 |
| High Dose, Fasted: 3 Single Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin | 851 ng/mL | Geometric Coefficient of Variation 28.8 |
| High Dose, Fed: 1 FDC Tablet | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin | 1180 ng/mL | Geometric Coefficient of Variation 27.4 |
| High Dose, Fed: 3 Single Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin | 1070 ng/mL | Geometric Coefficient of Variation 22.8 |
| Low Dose, Fasted: 2 FDC Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin | 1300 ng/mL | Geometric Coefficient of Variation 34.4 |
| Low Dose, Fasted: 4 Single Tablets | Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin | 1330 ng/mL | Geometric Coefficient of Variation 41.3 |
p-value: 0.019890% CI: [83.337, 112.079]ANOVA
p-value: 0.000790% CI: [103.809, 116.926]ANOVA
p-value: 0.003790% CI: [86.942, 109.734]ANOVA
Secondary
AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin
AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Empagliflozin
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose, Fasted: 1 FDC Tablet | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin | 6510 nmol*h/L | Geometric Coefficient of Variation 22.9 |
| High Dose, Fasted: 3 Single Tablets | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin | 6490 nmol*h/L | Geometric Coefficient of Variation 21.6 |
| High Dose, Fed: 1 FDC Tablet | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin | 5800 nmol*h/L | Geometric Coefficient of Variation 21.8 |
| High Dose, Fed: 3 Single Tablets | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin | 5970 nmol*h/L | Geometric Coefficient of Variation 20.5 |
| Low Dose, Fasted: 2 FDC Tablets | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin | 7240 nmol*h/L | Geometric Coefficient of Variation 19.7 |
| Low Dose, Fasted: 4 Single Tablets | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin | 7180 nmol*h/L | Geometric Coefficient of Variation 20.8 |
p-value: <0.000190% CI: [97.555, 102.719]ANOVA
p-value: <0.000190% CI: [93.622, 100.531]ANOVA
p-value: <0.000190% CI: [98.36, 103.27]ANOVA
Secondary
AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin
AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Metformin
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose, Fasted: 1 FDC Tablet | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin | 6490 ng*h/mL | Geometric Coefficient of Variation 35.2 |
| High Dose, Fasted: 3 Single Tablets | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin | 6790 ng*h/mL | Geometric Coefficient of Variation 29.6 |
| High Dose, Fed: 1 FDC Tablet | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin | 13200 ng*h/mL | Geometric Coefficient of Variation 24 |
| High Dose, Fed: 3 Single Tablets | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin | 13200 ng*h/mL | Geometric Coefficient of Variation 21.6 |
| Low Dose, Fasted: 2 FDC Tablets | AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin | 10500 ng*h/mL | Geometric Coefficient of Variation 41.9 |
| Low Dose, Fasted: 4 Single Tablets | AUC 0-infinity (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 39.9 |
p-value: 0.025490% CI: [82.42, 110.44]ANOVA
p-value: <0.000190% CI: [96.21, 103.17]ANOVA
p-value: 0.002990% CI: [89.7, 113.86]ANOVA