Healthy
Conditions
Brief summary
The trial is being conducted to establish the bioequivalence of emp/met (12.5mg/500mg) fixed dose combination tablets compared to tablets administered together in healthy male and female volunteers under fed conditions.
Interventions
DRUGEmpagliflozin 10 mg
Empagliflozin 10 mg tablet
DRUGMetformin 500 mg
Metformin 500 mg tablet
DRUGEmpagliflozin 2.5 mg
Empagliflozin 2.5 mg tablet
DRUGEmpagliflozin/Metformin FDC
12.5 mg Empagliflozin / 500 mg Metformin
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males or females according to the investigator's assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG and clinical laboratory tests. 2. Age 18 to 50 years (inclusive) 3. BMI 18.5 to 29.9 kg/m2 (inclusive) 4. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation.
Exclusion criteria
1. Any finding in the medical examination (Including blood pressure \[BP\], pulse rate \[PR\], or electrocardiogram \[ECG\]) deviating from normal and judged clinically relevant by the investigator. 2. Any evidence of a concomitant disease judged clinically relevant by the investigator. 3. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders. 4. Surgery of the gastrointestinal tract that could interfere with kinetics of the study drug(s) 5. Diseases of the central nervous system (such as epilepsy), other neurological disorders or psychiatric disorders. 6. History of relevant orthostatic hypotension, fainting spells, or blackouts. 7. Chronic or relevant acute infections 8. History of relevant allergy/hypersensitivity (including allergy to the trial medication or it's excipients) 9. Intake of drugs with a long half-life (\>24 hours) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication. 10. Within 14 days prior to the administration of trial medication, use of drugs that might reasonably influence the results of the trial, based on current knowledge 11. Participation in another trial with investigational drug administration within 60 days prior to administration of trial medication. 12. Smoker (has used tobacco or nicotine-containing products within 6 months prior to administration of trial medication) 13. Inability to refrain from smoking on specified trial days 14. Alcohol abuse (consumption of more than 20g/day in females and 30g/day in males or \> 7 alcohol-containing drinks per week) 15. Drug abuse or positive drug screen 16. Blood donation (more than 100 ml wihtin 30 days prior to administration of trial medication or intended during the trial) 17. Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial 18. Inability to comply with dietary regimen of trial site 19. Subject is assessed by the investigator as unsuitable for inclusion, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study. For female subjects: 20. Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after study completion. 21. No adequate contraception during the study and until 1 month after study completion, i.e. not any of the following: implants, injectables, combined oral contraceptives, IUD (intrauterine device), sexual abstinence for at least 1 month prior to enrolment, vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who do not have a vasectomised partner, are not sexually abstinent, surgically sterile, or post menopausal will be asked to use an additional barrier method (e.g. condom, diaphragm with spermicide). Post-menopausal is defined as at least 1 year of spontaneous amenorrhea and deemed post menopausal by a physician based on screening clinical laboratory tests (follicle stimulating hormone and luteinizing hormone). 22. Lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-tz) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | AUC (0-tz) (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 Metformin in Plasma) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Cmax (maximum measured concentration of metformin in plasma) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-infinity) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | AUC (0-infinity) (Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity) |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fixed Dose Combination vs. Separate Tablets 12.5 mg Empagliflozin / 500mg metformin fixed dose combination vs. free combination of 2.5 mg tablet Empagliflozin, 10 mg tablet Empagliflozin and 500 mg tablet Metformin | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 2 | Non compliant with protocol | 1 | 0 |
| Treatment Period 2 | Reason other than those specified above | 1 | 0 |
Baseline characteristics
| Characteristic | Fixed Dose Combination vs. Separate Tablets |
|---|---|
| Age, Continuous | 36.1 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 32 | 5 / 30 |
| serious Total, serious adverse events | 0 / 32 | 0 / 30 |
Outcome results
Primary
AUC (0-tz) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point)
AUC (0-tz) (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 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: Pharmacokinetic set (PKS): includes all subjects of the TS who provided at least 1 observation for at least 1 primary pharmacokinetic endpoint, and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination (FDC) | AUC (0-tz) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 6260 ng*h/mL | Geometric Coefficient of Variation 20.4 |
| Separate Tablets | AUC (0-tz) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 6360 ng*h/mL | Geometric Coefficient of Variation 21.8 |
p-value: 090% CI: [94.662, 102.639]ANOVA
Comparison: Analysis with fixed effects for all termsp-value: <0.000190% CI: [94.783, 102.796]ANOVA
Primary
Cmax (Maximum Measured Concentration of Metformin in Plasma)
Cmax (maximum measured concentration of metformin in plasma)
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS: includes all subjects of the TS who provided at least 1 observation for at least 1 primary pharmacokinetic endpoint, and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination (FDC) | Cmax (Maximum Measured Concentration of Metformin in Plasma) | 746 ng/mL | Geometric Coefficient of Variation 21.3 |
| Separate Tablets | Cmax (Maximum Measured Concentration of Metformin in Plasma) | 754 ng/mL | Geometric Coefficient of Variation 23.3 |
p-value: 090% CI: [95.856, 102.107]ANOVA
Comparison: Analysis with fixed effects for all termsp-value: <0.000190% CI: [95.877, 102.15]ANOVA
Secondary
AUC (0-infinity) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
AUC (0-infinity) (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 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS: includes all subjects of the TS who provided at least 1 observation for at least 1 primary pharmacokinetic endpoint, and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination (FDC) | AUC (0-infinity) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 6410 ng*h/mL | Geometric Coefficient of Variation 20.9 |
| Separate Tablets | AUC (0-infinity) (Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 6520 ng*h/mL | Geometric Coefficient of Variation 22.5 |
p-value: 090% CI: [94.549, 102.156]ANOVA
Comparison: Analysis with fixed effects for all termsp-value: <0.000190% CI: [94.603, 102.252]ANOVA