Healthy
Conditions
Brief summary
The purpose of this trial is to demonstrate the relative bioavailability of 2 newly developed fixed dose combinations (FDC) tablets containing empagliflozin & metformin XR and the single tablets of empagliflozin and metformin XR when administered singularly
Interventions
Active Comparator: 1 x Empagliflozin/2x Metformin XR tablets
DRUG10 mg Empagliflozin/1000 mg Metformin XR
Experimental: high dose Empagliflozin/Metformin XR, FDC tablet
DRUG1 tablet 10 mg Empagliflozin/3 tablets Metformin XR
Active Comparator: 1 x Empagliflozin/3 x Metformin XR tablets
DRUG2 tablets 5 mg Empagliflozin/750 Metformin XR
Experimental:2 x low dose Empagliflozin/Metformin XR FDC 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 |
|---|---|---|
| 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 | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 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 empagliflozin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). |
| 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 | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 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 metformin in plasma over the time interval from 0 to the last quantifiable data point |
| Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | Maximum measured concentration of empagliflozin in plasma (Cmax). |
| Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration | Maximum measured concentration of metformin in plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Empagliflozin | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 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 empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity). |
| AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 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 metformin in plasma over the time interval from 0 extrapolated to infinity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1000mg, Fasted Patients orally administered either 1 x 10 mg Empagliflozin/1000 mg metformin (Met) XR FDC or 1 x 10 mg Empagliflozin + 2 x 500 mg Glumetza® XR. Both treatments were taken with 240 mL of water after an overnight fast of at least 10 hours (h). | 24 |
| 1000mg, Fed Patients orally administered either 1 x 10 mg Empagliflozin/1000 mg Metformin XR FDC or 1 x 10 mg Empagliflozin + 2 x 500 mg Glumetza® XR. Both treatments were taken with 240 mL of water after a high-fat, high-caloric meal | 24 |
| 1500mg, Fasted Patients orally administered either 2 x 5 mg Empagliflozin/750 mg Metformin XR FDC or 1 x 10 mg Empagliflozin + 3 x 500 mg Glumetza® XR. Both treatments were taken with 240 mL of water after an overnight fast of at least 10 h | 24 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 1000mg, Fasted | 1000mg, Fed | 1500mg, Fasted | Total |
|---|---|---|---|---|
| Age, Continuous | 28.5 years STANDARD_DEVIATION 8.7 | 32.4 years STANDARD_DEVIATION 9.1 | 31.3 years STANDARD_DEVIATION 8.7 | 30.7 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 16 Participants | 48 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 24 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 / 24 | 5 / 24 | 4 / 24 | 4 / 24 | 6 / 24 | 7 / 23 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 23 |
Outcome results
Primary
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 empagliflozin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz).
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set (PKS) which included all subjects of the treated set who provided at least one observation for at least one primary PK endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa/1000 mg Glumetza® (Fasted) | 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 | 2630 nmol*h/L | Geometric Coefficient of Variation 18.9 |
| Empa/ 1000 mg Met FDC (Fasted) | 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 | 2710 nmol*h/L | Geometric Coefficient of Variation 18.3 |
| Empa/1000 mg Glumetza ® (Fed) | 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 | 2720 nmol*h/L | Geometric Coefficient of Variation 20.5 |
| Empa/ 1000 mg Met FDC (Fed) | 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 | 2710 nmol*h/L | Geometric Coefficient of Variation 19.9 |
| Empa/ 1500 mg Glumetza® (Fasted) | 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 | 2790 nmol*h/L | Geometric Coefficient of Variation 17.3 |
| Empa/ 1500 mg Met FDC (Fasted) | 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 | 2680 nmol*h/L | Geometric Coefficient of Variation 18.7 |
p-value: <0.000190% CI: [100.505, 105.514]ANOVA
p-value: <0.000190% CI: [96.809, 103.823]ANOVA
p-value: <0.000190% CI: [93.507, 98.721]ANOVA
Primary
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
Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set (PKS) which included all subjects of the treated set who provided at least one observation for at least one primary PK endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa/1000 mg Glumetza® (Fasted) | 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 | 7020 ng*h/mL | Geometric Coefficient of Variation 35.2 |
| Empa/ 1000 mg Met FDC (Fasted) | 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 | 7170 ng*h/mL | Geometric Coefficient of Variation 36.2 |
| Empa/1000 mg Glumetza ® (Fed) | 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 | 13500 ng*h/mL | Geometric Coefficient of Variation 19.1 |
| Empa/ 1000 mg Met FDC (Fed) | 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 | 13200 ng*h/mL | Geometric Coefficient of Variation 18.8 |
| Empa/ 1500 mg Glumetza® (Fasted) | 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 | 9860 ng*h/mL | Geometric Coefficient of Variation 26.4 |
| Empa/ 1500 mg Met FDC (Fasted) | 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 | 10100 ng*h/mL | Geometric Coefficient of Variation 25.6 |
p-value: 0.001190% CI: [92.3, 112.81]ANOVA
p-value: <0.000190% CI: [95.45, 102.53]ANOVA
p-value: 0.000290% CI: [93.59, 110.52]ANOVA
Primary
Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin
Maximum measured concentration of empagliflozin in plasma (Cmax).
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set (PKS) which included all subjects of the treated set who provided at least one observation for at least one primary PK endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa/1000 mg Glumetza® (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin | 377 nmol/L | Geometric Coefficient of Variation 22.5 |
| Empa/ 1000 mg Met FDC (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin | 395 nmol/L | Geometric Coefficient of Variation 24.6 |
| Empa/1000 mg Glumetza ® (Fed) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin | 273 nmol/L | Geometric Coefficient of Variation 27.6 |
| Empa/ 1000 mg Met FDC (Fed) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin | 277 nmol/L | Geometric Coefficient of Variation 31 |
| Empa/ 1500 mg Glumetza® (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin | 396 nmol/L | Geometric Coefficient of Variation 21.9 |
| Empa/ 1500 mg Met FDC (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Empagliflozin | 381 nmol/L | Geometric Coefficient of Variation 22 |
p-value: <0.000190% CI: [99.522, 110.412]ANOVA
p-value: <0.000190% CI: [95.03, 109.134]ANOVA
p-value: <0.000190% CI: [90.217, 102.211]ANOVA
Primary
Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin
Maximum measured concentration of metformin in plasma
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set (PKS) which included all subjects of the treated set who provided at least one observation for at least one primary PK endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa/1000 mg Glumetza® (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin | 975 ng/mL | Geometric Coefficient of Variation 37.2 |
| Empa/ 1000 mg Met FDC (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin | 964 ng/mL | Geometric Coefficient of Variation 39.9 |
| Empa/1000 mg Glumetza ® (Fed) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin | 1110 ng/mL | Geometric Coefficient of Variation 21.2 |
| Empa/ 1000 mg Met FDC (Fed) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin | 1200 ng/mL | Geometric Coefficient of Variation 22.7 |
| Empa/ 1500 mg Glumetza® (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin | 1220 ng/mL | Geometric Coefficient of Variation 32.8 |
| Empa/ 1500 mg Met FDC (Fasted) | Cmax (Maximum Measured Concentration of the Analyte in Plasma, for Metformin | 1270 ng/mL | Geometric Coefficient of Variation 34.7 |
p-value: 0.002790% CI: [87.925, 111.329]ANOVA
p-value: <0.000190% CI: [102.792, 113.859]ANOVA
p-value: 0.00690% CI: [92.116, 116.559]ANOVA
Secondary
AUC0-infinity (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 empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity).
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set (PKS) which included all subjects of the treated set who provided at least one observation for at least one primary PK endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa/1000 mg Glumetza® (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Empagliflozin | 2680 nmol*h/L | Geometric Coefficient of Variation 18.7 |
| Empa/ 1000 mg Met FDC (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Empagliflozin | 2760 nmol*h/L | Geometric Coefficient of Variation 17.9 |
| Empa/1000 mg Glumetza ® (Fed) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Empagliflozin | 2790 nmol*h/L | Geometric Coefficient of Variation 21.3 |
| Empa/ 1000 mg Met FDC (Fed) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Empagliflozin | 2770 nmol*h/L | Geometric Coefficient of Variation 20.2 |
| Empa/ 1500 mg Glumetza® (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Empagliflozin | 2840 nmol*h/L | Geometric Coefficient of Variation 17.4 |
| Empa/ 1500 mg Met FDC (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Empagliflozin | 2740 nmol*h/L | Geometric Coefficient of Variation 19.5 |
p-value: <0.000190% CI: [100.446, 105.373]ANOVA
p-value: <0.000190% CI: [96.448, 103.738]ANOVA
p-value: <0.000190% CI: [93.758, 99.311]ANOVA
Secondary
AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin
Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set (PKS) which included all subjects of the treated set who provided at least one observation for at least one primary PK endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa/1000 mg Glumetza® (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin | 7480 ng*h/mL | Geometric Coefficient of Variation 37.4 |
| Empa/ 1000 mg Met FDC (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin | 7360 ng*h/mL | Geometric Coefficient of Variation 36.7 |
| Empa/1000 mg Glumetza ® (Fed) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin | 13900 ng*h/mL | Geometric Coefficient of Variation 20.7 |
| Empa/ 1000 mg Met FDC (Fed) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin | 13600 ng*h/mL | Geometric Coefficient of Variation 20.4 |
| Empa/ 1500 mg Glumetza® (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin | 10500 ng*h/mL | Geometric Coefficient of Variation 28.5 |
| Empa/ 1500 mg Met FDC (Fasted) | AUC0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity), for Metformin | 10900 ng*h/mL | Geometric Coefficient of Variation 28.7 |
p-value: 0.000890% CI: [89.13, 108.47]ANOVA
p-value: <0.000190% CI: [94.77, 102.8]ANOVA
p-value: 0.002190% CI: [94.09, 114.74]ANOVA