Healthy
Conditions
Brief summary
Bioequivalence of two 12.5 mg empagliflozin/500 mg metformin fixed dose combination tablets compared to the free combination of empagliflozin 25 mg and metformin 1000 mg in healthy male and female volunteers under fed conditions
Interventions
DRUGEmpagliflozin
Test Therapy - fixed dose combination of 2 tablets of 12.5 mg Empagliflozin and 500 mg Metformin
DRUGMetformin
Test Therapy - fixed dose combination of 2 tablets of 12.5 mg Empagliflozin and 500 mg Metformin
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female subjects aged 18 to 45 years and BMI 18.50 to 24.99 kg/m2 by Quetelet * Signed informed consent prior to admission to the study * Subjects must be able to undergo all trial related requests and procedures and follow any trial related restrictions on concomitant medications, diet and life style * Subjects must be never-smokers or ex-smokers who stopped smoking prior to enrolment (Visit 1) * Male or female subjects using adequate contraception from at least 30 days before the first study drug administration and until 30 days after trial completion
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) deviating from normal and any laboratory value outside the reference range * Positive results of blood tests for infections (HIV, Syphilis, Hepatitis B or C), urine drug screening test and alcohol breath test * Any evidence of a concomitant disease judged clinically relevant by the investigator and presence of cardiovascular, respiratory, nervous, endocrine, reproductive, hematopoietic, immune system disorders; gastrointestinal, hepatic, urinary tract, hepatobiliary disorder, mental disturbance * Surgery of the gastrointestinal tract that could interfere with kinetics of the study drugs (except appendectomy) * History of relevant orthostatic hypotension, fainting spells, or blackouts * Relevant chronic or aAcute infections/ acute diseases occurred within 4 weeks before inclusion into the study * History of relevant allergy/hypersensitivity (including allergy to the trial medication or its excipients) * Regular use of medicinal products less than 2 weeks before investigational drug administration * Intake of systemic inhibitors or inductors of microsomal hepatic enzymes in less than 30 days before investigational drug administration * 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 * Use of drugs which might reasonably influence the results of the trial based on current knowledge within 14 days prior to drug administration or during the trial * Participation in another trial with investigational drug administration within 3 months prior to administration of trial medication * Alcohol intake = 10 units of alcohol per week (1 unit of alcohol equals one 50 ml single measure of distilled alcoholic beverages/spirits (ABV 40%), or 0.5 litre of beer (ABV 5%), or 200 ml glass or red wine (ABV 12%) or history of alcohol abuse, narcomania, or other drug abuse. * Drug abuse * Blood donation (more than 100 mL within 30 days prior to administration of trial medication or intended during the trial) * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen as per protocol and per protocol procedures * 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 * Intake of xanthine-containing drinks or foods and alcohol from 72 h before screening and second treatment period * Intake of drinks or foods containing grapefruits, Chinese grapefruits, Seville oranges for female subjects: * Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after study completion * Breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration. | Area under the concentration-time curve of the Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis. |
| Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration. | Area under the concentration-time curve of the Metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis. |
| Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) | PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration. | Maximum measured concentration of the Empagliflozin in plasma (Cmax). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis. |
| Maximum Measured Concentration of the Metformin in Plasma (Cmax) | PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration. | Maximum measured concentration of the Metformin in plasma (Cmax). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration. | Area under the concentration-time curve of the Empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-infinity observed). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis. |
| Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration. | Area under the concentration-time curve of the Metformin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-infinity observed). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis. |
Countries
Russia
Participant flow
Recruitment details
Actual number of subjects enrolled in fact represents entered / randomized subjects due to the study set up.
Participants by arm
| Arm | Count |
|---|---|
| Fixed Dose Combination (FDC) / Empagliflozin + Metformin Participants first received 2 film-coated tablets of 12.5 milligram (mg) Empagliflozin and 500 mg Metformin as a single dose in a fixed dose combination (FDC), then they received free combination of 1 film-coated tablet of 25 mg Empagliflozin and 1 film-coated tablet of 1000 mg Metformin (brand name: Glucophage) as a single dose. The study medication was administered orally in the morning with 200 mL of water after intake of a high-fat, high-caloric meal. Single dose in each treatment period was separated by a washout phase of at least 5 days between drug administrations. | 12 |
| Empagliflozin + Metformin / Fixed Dose Combination (FDC) Participants first received free combination of 1 film-coated tablet of 25 mg Empagliflozin and 1 film-coated tablet of 1000 mg Metformin (brand name: Glucophage) as a single dose, then they received 2 film-coated tablets of 12.5 milligram (mg) Empagliflozin and 500 mg Metformin as a single dose in a fixed dose combination (FDC). The study medication was administered orally in the morning with 200 mL of water after intake of a high-fat, high-caloric meal. Single dose in each treatment period was separated by a washout phase of at least 5 days between drug administrations. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 (4 Days) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Fixed Dose Combination (FDC) / Empagliflozin + Metformin | Empagliflozin + Metformin / Fixed Dose Combination (FDC) | Total |
|---|---|---|---|
| Age, Continuous | 24.7 Years STANDARD_DEVIATION 3.6 | 30.4 Years STANDARD_DEVIATION 7.8 | 27.6 Years STANDARD_DEVIATION 6.7 |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 24 | 0 / 25 |
| serious Total, serious adverse events | 0 / 24 | 0 / 25 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of the Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis.
Time frame: PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration.
Population: Pharmacokinetic analysis set (PKS): all subjects from treated set (TS) who provided at least 1 primary or secondary Pharmacokinetic (PK) endpoint value that was judged as PK evaluable and was not affected by protocol violations relevant to the statistical evaluation. Subject was included, even if he/she contributed only 1 PK value for one period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin / Metformin (FDC) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 6147 nanomol (nmol)* hours (h) / Litre (L) | Geometric Coefficient of Variation 5.4 |
| Empagliflozin + Metformin Free Combination | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 6141 nanomol (nmol)* hours (h) / Litre (L) | Geometric Coefficient of Variation 5.4 |
Comparison: Empagliflozin / Metformin (FDC) vs. Empagliflozin + Metformin free combination90% CI: [97.466, 102.804]ANOVA
Primary
Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of the Metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis.
Time frame: PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration.
Population: Pharmacokinetic analysis set (PKS): all subjects from the TS who provided at least 1 primary or secondary Pharmacokinetic (PK) endpoint value that was judged as PK evaluable and was not affected by protocol violations relevant to the statistical evaluation. Thus, subject was included, even if he/she contributed only 1 PK value for one period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin / Metformin (FDC) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 11912 nanogram (ng)*h /millilitre (mL) | Geometric Coefficient of Variation 13.6 |
| Empagliflozin + Metformin Free Combination | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 12472 nanogram (ng)*h /millilitre (mL) | Geometric Coefficient of Variation 13.6 |
Comparison: Empagliflozin / Metformin (FDC) vs. Empagliflozin + Metformin free combination90% CI: [89.29, 102.16]ANOVA
Primary
Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)
Maximum measured concentration of the Empagliflozin in plasma (Cmax). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis.
Time frame: PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration.
Population: Pharmacokinetic analysis set (PKS): all subjects from the TS who provided at least 1 primary or secondary Pharmacokinetic (PK) endpoint value that was judged as PK evaluable and was not affected by protocol violations relevant to the statistical evaluation. Thus, subject was included, even if he/she contributed only 1 PK value for one period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin / Metformin (FDC) | Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) | 660 nmol/L | Geometric Coefficient of Variation 10.9 |
| Empagliflozin + Metformin Free Combination | Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) | 642 nmol/L | Geometric Coefficient of Variation 10.9 |
Comparison: Empagliflozin / Metformin (FDC) vs. Empagliflozin + Metformin free combination90% CI: [97.309, 108.413]ANOVA
Primary
Maximum Measured Concentration of the Metformin in Plasma (Cmax)
Maximum measured concentration of the Metformin in plasma (Cmax). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis.
Time frame: PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration.
Population: Pharmacokinetic analysis set (PKS): all subjects from the TS who provided at least 1 primary or secondary Pharmacokinetic (PK) endpoint value that was judged as PK evaluable and was not affected by protocol violations relevant to the statistical evaluation. Thus, subject was included, even if he/she contributed only 1 PK value for one period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin / Metformin (FDC) | Maximum Measured Concentration of the Metformin in Plasma (Cmax) | 1452 ng/mL | Geometric Coefficient of Variation 11.3 |
| Empagliflozin + Metformin Free Combination | Maximum Measured Concentration of the Metformin in Plasma (Cmax) | 1437 ng/mL | Geometric Coefficient of Variation 11.3 |
Comparison: Empagliflozin / Metformin (FDC) vs. Empagliflozin + Metformin free combination90% CI: [95.565, 106.902]ANOVA
Secondary
Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity)
Area under the concentration-time curve of the Empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-infinity observed). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis.
Time frame: PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration.
Population: Pharmacokinetic analysis set (PKS): all subjects from the TS who provided at least 1 primary or secondary Pharmacokinetic (PK) endpoint value that was judged as PK evaluable and was not affected by protocol violations relevant to the statistical evaluation. Thus, subject was included, even if he/she contributed only 1 PK value for one period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin / Metformin (FDC) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | 6280 nmol*h/L | Geometric Coefficient of Variation 5.7 |
| Empagliflozin + Metformin Free Combination | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | 6261 nmol*h/L | Geometric Coefficient of Variation 5.7 |
Comparison: Empagliflozin / Metformin (FDC) vs. Empagliflozin + Metformin free combination90% CI: [97.532, 103.149]ANOVA
Secondary
Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity)
Area under the concentration-time curve of the Metformin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-infinity observed). Geometric means (gMeans) represent adjusted gMeans and geometric coefficient of variation (gCV) reflects the intra-individual gCV (%) from the mixed model analysis.
Time frame: PK plasma samples were taken at: 2 hours (h) before drug administration and 20 minutes, 40 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration.
Population: Pharmacokinetic analysis set (PKS): all subjects from the TS who provided at least 1 primary or secondary Pharmacokinetic (PK) endpoint value that was judged as PK evaluable and was not affected by protocol violations relevant to the statistical evaluation. Thus, subject was included, even if he/she contributed only 1 PK value for one period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin / Metformin (FDC) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | 12428 ng*h/mL | Geometric Coefficient of Variation 24.8 |
| Empagliflozin + Metformin Free Combination | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | 13285 ng*h/mL | Geometric Coefficient of Variation 24.8 |
Comparison: Empagliflozin / Metformin (FDC) vs. Empagliflozin + Metformin free combination90% CI: [82.86, 105.61]ANOVA