Demonstrate Bioequivalence of Two 12.5 mg Empagliflozin/500 mg Metformin Fixed Dose Combination Tablets With Free Combination of Empagliflozin 25 mg and Metformin 1000 mg in Healthy Male and Female Volunteers Under Fed Conditions

Study Overview
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Brief Summary
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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

Official Title
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An Open-label, Randomised, Single-dose, Two-way Crossover Study in Healthy Male and Female Subjects to Evaluate the Bioequivalence of Two Fixed Dose Combination Tablets of Empagliflozin 12.5 mg and Metformin 500 mg Compared With the Free Combination of Empagliflozin 25 mg and Metformin 1000 mg Tablets Under Fed Conditions

Conditions
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Healthy

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Metformin
* Drug: Empagliflozin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test - Empagliflozin/Metformin<br>fixed dose combination of 2 tablets of 12.5 mg Empagliflozin and 500 mg Metformin, oral with 200 mL of water uder fed conditions | Drug: Empagliflozin<br>* Test Therapy - fixed dose combination of 2 tablets of 12.5 mg Empagliflozin and 500 mg Metformin<br>Drug: Metformin<br>* Test Therapy - fixed dose combination of 2 tablets of 12.5 mg Empagliflozin and 500 mg Metformin<br>|
| Experimental: Reference - Empagliflozin + Metformin<br>free combination of 1 tablet of 25 mg Empagliflozin and 1 tablet of 1000 mg of Metformin, oral with 200 mL of water under fed conditions | Drug: Empagliflozin<br>* Reference Therapy - free combination of 1 tablets of 25 mg Empagliflozin and 1000 mg Metformin<br>Drug: Metformin<br>* Reference Therapy - free combination of 1 tablets of 25 mg Empagliflozin and 1000 mg Metformin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 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. | 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) | 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. | 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) | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 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. | 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. |