Healthy
Conditions
Brief summary
The primary objective of this trial is to investigate the bioequivalence of one fixed dose combination tablet of empagliflozin/linagliptin (Test, T) compared with the free combination of one empagliflozin tablet and one linagliptin tablet (Reference, R) administered as single dose under fasted conditions.
Interventions
DRUGEmpagliflozin
DRUGLinagliptin
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 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects according to the investigators assessment, based on a complete medical history including a physical examination, vital signs (Blood Pressure \[BP\], Pulse Rate \[PR\]), 12-lead Electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 55 years (incl.) * Body Mass Index (BMI) of 18.5 to 29.9 kg/m2 (incl.) * Signed and dated written informed consent prior to admission to the study in accordance with GCP (Good Clinical Practice) and local legislation * Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and until 30 days after trial completion: * Use of adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral or vaginal contraceptives, intrauterine device * Sexually abstinent * A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) * Surgically sterilised (including hysterectomy) * Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of FSH (Follicle Stimulating Hormone) above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including Blood Pressure \[BP\], Pulse Rate \[PR\] or Electrocardiogram \[ECG\]) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration. | This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point. Time frame description: The time -1:00 hour (h) was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-tz (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point). |
| AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours) | 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration. | This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-72 (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours). |
| Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma) | 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration. | This outcome measure presents maximum measured concentration of Empagliflozin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Empagliflozin analyte in plasma). |
| Cmax (Maximum Measured Concentration of Linagliptin Analyte in Plasma) | 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration. | This outcome measure presents maximum measured concentration of Linagliptin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Linagliptin analyte in plasma). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-infinity (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration. | This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-infinity (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity). |
| AUC0-infinity (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration. | This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FDC/Empagliflozin+Linagliptin The subjects were administered one FDC (Fixed-Dose Combination) film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T) in period 1, followed by one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) administered orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 2.
A wash-out period of at least 35 days was set following the drug administration in each period. | 28 |
| Empagliflozin+Linagliptin/FDC The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 1, followed by one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin administered orally with 240 mL of water after an overnight fast of at least 10 h, as a single dose in the fasted state on Day 1 of Test treatment (T) in period 2.
A wash-out period of at least 35 days was set following the drug administration in each period. | 28 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Wash-out | Other reason | 1 | 0 |
| Wash-out | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | FDC/Empagliflozin+Linagliptin | Empagliflozin+Linagliptin/FDC | Total |
|---|---|---|---|
| Age, Continuous | 39.1 Years STANDARD_DEVIATION 9.7 | 38.9 Years STANDARD_DEVIATION 10.2 | 39.0 Years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 56 | 7 / 54 |
| serious Total, serious adverse events | 0 / 56 | 0 / 54 |
Outcome results
Primary
AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours)
This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-72 (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours).
Time frame: 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
Population: PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC (10 mg Empagliflozin and 5 mg Linagliptin) | AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours) | 281 nmol*h/L | Geometric Coefficient of Variation 22.5 |
| Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets | AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours) | 283 nmol*h/L | Geometric Coefficient of Variation 23.3 |
Comparison: The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.p-value: <0.000190% CI: [95.29, 103.672]ANOVA
Primary
AUC0-tz (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point)
This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point. Time frame description: The time -1:00 hour (h) was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-tz (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point).
Time frame: 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
Population: PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC (10 mg Empagliflozin and 5 mg Linagliptin) | AUC0-tz (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 2550 nmol*h/L | Geometric Coefficient of Variation 18 |
| Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets | AUC0-tz (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 2510 nmol*h/L | Geometric Coefficient of Variation 19.9 |
Comparison: The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.p-value: <0.000190% CI: [99.818, 103.644]ANOVA
Primary
Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma)
This outcome measure presents maximum measured concentration of Empagliflozin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Empagliflozin analyte in plasma).
Time frame: 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
Population: PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC (10 mg Empagliflozin and 5 mg Linagliptin) | Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma) | 370 nmol/L | Geometric Coefficient of Variation 23.9 |
| Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets | Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma) | 365 nmol/L | Geometric Coefficient of Variation 23.9 |
Comparison: The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.p-value: <0.000190% CI: [97.945, 106.91]ANOVA
Primary
Cmax (Maximum Measured Concentration of Linagliptin Analyte in Plasma)
This outcome measure presents maximum measured concentration of Linagliptin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Linagliptin analyte in plasma).
Time frame: 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
Population: PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC (10 mg Empagliflozin and 5 mg Linagliptin) | Cmax (Maximum Measured Concentration of Linagliptin Analyte in Plasma) | 9.33 nmol/L | Geometric Coefficient of Variation 36.2 |
| Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets | Cmax (Maximum Measured Concentration of Linagliptin Analyte in Plasma) | 8.73 nmol/L | Geometric Coefficient of Variation 37.1 |
Comparison: The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.p-value: 0.002790% CI: [98.561, 117.282]ANOVA
Secondary
AUC0-infinity (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-infinity (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity).
Time frame: 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
Population: PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC (10 mg Empagliflozin and 5 mg Linagliptin) | AUC0-infinity (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 2580 nmol*h/L | Geometric Coefficient of Variation 18 |
| Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets | AUC0-infinity (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 2550 nmol*h/L | Geometric Coefficient of Variation 19.8 |
Comparison: The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.90% CI: [99.574, 103.336]ANOVA
Secondary
AUC0-infinity (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity).
Time frame: 1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
Population: PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC (10 mg Empagliflozin and 5 mg Linagliptin) | AUC0-infinity (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 451 nmol*h/L | Geometric Coefficient of Variation 25.9 |
| Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets | AUC0-infinity (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 462 nmol*h/L | Geometric Coefficient of Variation 29.2 |
Comparison: The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.90% CI: [93.456, 103.082]ANOVA