Healthy
Conditions
Brief summary
The purpose of this trial is to investigate bioequivalence of a newly developed fixed dose combination (FDC) tablet containing empagliflozin and metformin extended release compared to the free combination of empagliflozin and metformin extended release under fed conditions.
Interventions
DRUGmetformin
single dose of metformin given as tablets
Single dose empagliflozin/metformin given as fixed-dose combination tablet
DRUGempagliflozin
single dose of empagliflozin given as tablet
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 and female subjects * age of 18 to 55 years * body mass index (BMI) of 18.5 to 29.9 kg/m2 * additional inclusion criteria may apply
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) 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 or 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 * Surgery of the gastrointestinal tract that could interfere with kinetics of the trial medication * Diseases of the central nervous system (including but not limited to any kind of seizures and stroke), and other relevant neurological disorders or psychiatric disorders * additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz of Empagliflozin in Plasma | -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration | Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) |
| AUC0-tz of Metformin in Plasma | -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration | Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) |
| Cmax of Empagliflozin in Plasma | -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration | Maximum measured concentration of the empagliflozin in plasma |
| Cmax of Metformin in Plasma | -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration | Maximum measured concentration of the metformin in plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-infinity of Empagliflozin in Plasma | -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. |
| AUC0-infinity of Metformin in Plasma | -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. |
Countries
Germany
Participant flow
Pre-assignment details
This was an open-label, randomised, 2-way crossover trial with 2 treatments (T and R) and 2 treatment sequences (T\_R and R\_T). Trial drug administrations of the 2 single dose treatments were separated by a washout period of at least 7 days.
Participants by arm
| Arm | Count |
|---|---|
| Fed 10mg+1000mg FDC/Single (TR) Subjects received in period 1 a single dose of 10 mg empagliflozin/1000 mg metformin hydrochloride (HCl) extended release (XR) (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 10 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal. 2 treatments separated by a wash-out period of at least 7 days. | 15 |
| Fed 10mg+1000mg Single/FDC (RT) Subjects received in period 1 a single dose of 10 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal. 2 treatments separated by a wash-out period of at least 7 days. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Fed 10mg+1000mg FDC/Single (TR) | Fed 10mg+1000mg Single/FDC (RT) | Total |
|---|---|---|---|
| Age, Continuous | 33.5 years STANDARD_DEVIATION 8.1 | 33.7 years STANDARD_DEVIATION 10.1 | 33.6 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 30 | 5 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
AUC0-tz of Empagliflozin in Plasma
Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)
Time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Population: Pharmacokinetic set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary endpoint without important protocol violations with respect to the statistical evaluation of the pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fed 10mg+ 1000mg FDC (T) | AUC0-tz of Empagliflozin in Plasma | 2190 nmol*h/L | Geometric Coefficient of Variation 18.1 |
| Fed 10mg+1000mg Single (R) | AUC0-tz of Empagliflozin in Plasma | 2210 nmol*h/L | Geometric Coefficient of Variation 16.3 |
p-value: <0.000190% CI: [96.4, 101.89]ANOVA
Primary
AUC0-tz of Metformin in Plasma
Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)
Time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fed 10mg+ 1000mg FDC (T) | AUC0-tz of Metformin in Plasma | 10800 ng*h/mL | Geometric Coefficient of Variation 20.1 |
| Fed 10mg+1000mg Single (R) | AUC0-tz of Metformin in Plasma | 10700 ng*h/mL | Geometric Coefficient of Variation 22.4 |
p-value: <0.000190% CI: [96.54, 106.19]ANOVA
Primary
Cmax of Empagliflozin in Plasma
Maximum measured concentration of the empagliflozin in plasma
Time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fed 10mg+ 1000mg FDC (T) | Cmax of Empagliflozin in Plasma | 243 nmol/L | Geometric Coefficient of Variation 23.1 |
| Fed 10mg+1000mg Single (R) | Cmax of Empagliflozin in Plasma | 245 nmol/L | Geometric Coefficient of Variation 20.4 |
p-value: <0.000190% CI: [93.69, 104.87]ANOVA
Primary
Cmax of Metformin in Plasma
Maximum measured concentration of the metformin in plasma
Time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fed 10mg+ 1000mg FDC (T) | Cmax of Metformin in Plasma | 1170 ng/mL | Geometric Coefficient of Variation 25.5 |
| Fed 10mg+1000mg Single (R) | Cmax of Metformin in Plasma | 1080 ng/mL | Geometric Coefficient of Variation 25.2 |
p-value: <0.000190% CI: [104.17, 113.17]ANOVA
Secondary
AUC0-infinity of Empagliflozin in Plasma
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fed 10mg+ 1000mg FDC (T) | AUC0-infinity of Empagliflozin in Plasma | 2230 nmol*h/L | Geometric Coefficient of Variation 18 |
| Fed 10mg+1000mg Single (R) | AUC0-infinity of Empagliflozin in Plasma | 2260 nmol*h/L | Geometric Coefficient of Variation 16.3 |
90% CI: [96.18, 101.67]ANOVA
Secondary
AUC0-infinity of Metformin in Plasma
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fed 10mg+ 1000mg FDC (T) | AUC0-infinity of Metformin in Plasma | 11000 ng*h/mL | Geometric Coefficient of Variation 20.8 |
| Fed 10mg+1000mg Single (R) | AUC0-infinity of Metformin in Plasma | 10800 ng*h/mL | Geometric Coefficient of Variation 22.7 |
90% CI: [96.53, 106.45]ANOVA