A Study in Healthy Humans to Assess the Relative Bioavailability of One Fixed-dose Combination Tablet Empagliflozin/Metformin Versus Jardiance® Tablet and Glifage® Tablet Administered Together

Study Overview
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Brief Summary
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This trial is to establish bioequivalence of the fixed dose combination (FDC) tablets (containing 12.5 mg empagliflozin/850 mg metformin) (Test, T) compared with the single tablets (10 mg empagliflozin and Glifage® 850 mg tablets) (Reference, R).

Official Title
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Relative Bioavailability of Empagliflozin/Metformin Fixed-dose Combination - Empagliflozin 12.5 mg + Metformin 850mg (Boehringer Ingelheim) Coated Tablet Versus Jardiance® 10mg (Reference 1: Boehringer Ingelheim) Coated Tablet and Glifage® 850mg (Reference 2: Merck S / A. ) Coated Tablet, Administered Together in Healthy Male and Female Subjects Under Fed Conditions: an Open-label, Randomised, Single-dose, Two-way Crossover Study

Conditions
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Healthy

Intervention / Treatment
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* Drug: FDC 12.5mg empagliflozin/850mg metformin
* Drug: Empagliflozin
* Drug: Glifage®


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy male or female subjects according to the assessment of the investigator, as 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 at least 18 (inclusive) to 50 years (inclusive) Body mass index (BMI) of 18.5 to 29.9 weight divided by height squared (kg/m2) (inclusive) Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation Male subjects, or female subjects who meet any of the following criteria from at least 30 days before the first administration of trial medication 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) Exclusion Criteria: Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator Repeated measurement of systolic blood pressure outside the range of 90 to 140 millimetre of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 beats per minute (bpm) Any laboratory value outside the reference range that the investigator considers to be of clinical relevance Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) History of relevant orthostatic hypotension, fainting spells, or blackouts Chronic or relevant acute infections Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause time from the start of the Q wave to the end of the T wave (QT) / corrected QT (QTc) interval prolongation) Smoker (more than 5 cigarettes or 1 cigar or 1 pipe per day) Detection or indeterminate / inconclusive result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Coronavirus ribonucleic acid (RNA) in the quantitative real-time polymerase chain reaction (RT-qPCR) exam performed on the day before the admission of each period; The research participant presents symptoms of coronavirus disease 2019 (COVID-19) infection (even if the result is undetected in the RT-PCR exam for COVID-19) Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: (A): empagliflozin 10mg (R1)+Glifage® 850mg (R2),then (B): FDC 12.5mg empagliflozin/850mg metformin<br>On Day 1 of Period 1 subjects received treatment A: Single dose tablet of 10 milligram(mg) empagliflozin film-coated and a 850mg of metformin hydrochloride (HCl) (Glifage®) tablet, orally with 200 milliliter(mL) of water. On Day 1 of Period 2 subjects received treatment B: Fixed dose combination (FDC) tablet of 12.5mg empagliflozin/850 mg metformin HCl, orally with 200mL of water. A high-fat, high-calorie meal was served 30 minutes(min) before drug administration. The treatments were separated by a wash-out phase of at least 7 days. | Drug: FDC 12.5mg empagliflozin/850mg metformin<br>* empagliflozin/metformin<br>Drug: Empagliflozin<br>* empagliflozin 10mg (R1)<br>Drug: Glifage®<br>* Glifage® 850mg (R2)<br>* Other names: metformin;|
| Experimental: (B): FDC 12.5mg empagliflozin/850mg metformin,then (A): empagliflozin 10mg(R1) + Glifage® 850mg(R2)<br>On Day 1 of Period 1 subjects received treatment B: Fixed dose combination (FDC) tablet containing 12.5 milligram (mg) empagliflozin/850 mg metformin HCl, orally with 200 milliliter (mL) of water. On Day 1 of Period 2 subjects received treatment A: Single dose tablet of 10mg empagliflozin and 850 mg of metformin hydrochloride (HCl) (Glifage®) tablet, orally with 200mL of water. A high-fat, high-calorie meal was served 30 minutes (min) before drug administration. The treatments were separated by a wash-out phase of at least 7 days. | Drug: FDC 12.5mg empagliflozin/850mg metformin<br>* empagliflozin/metformin<br>Drug: Empagliflozin<br>* empagliflozin 10mg (R1)<br>Drug: Glifage®<br>* Glifage® 850mg (R2)<br>* Other names: metformin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (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-tz) normalized to the actual administered dose is presented. The AUC0-tz was divided by the actual dose strength to get the normalized area under the concentration-time curve. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. 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. Unit of measure:(hour*nanogram/milliliter)/milligram. | Within 5 minutes (min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Dose-normalized Maximum Measured Concentration of Empagliflozin (Cmax) | Dose-normalized Maximum measured concentration of empagliflozin in plasma is presented. The maximum measured concentration was divided by the actual dose strength to get the dose-normalised Cmax. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. 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. The unit of measure reported is: (nanogram/milliliter)/milligram. | Within 5 minutes (min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. 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. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Maximum Measured Concentration of Metformin (Cmax) | Maximum measured concentration of metformin in plasma is presented. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. 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. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞ ) | Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity from the last quantifiable data point (AUC0-inf) normalized to the actual administered dose is presented. The AUC0-oo was divided by the actual dose strength to get the normalized area under the concentration-time curve. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. 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. Unit of measure: (hour*nanogram/milliliter)/milligram. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) is presented. The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. 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. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Time From Last Dosing to the Maximum Measured Concentration of Empagliflozin in Plasma (Tmax) | Time from last dosing to the maximum measured concentration of empagliflozin in plasma (tmax) is presented. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Time From Last Dosing to the Maximum Measured Concentration of Metformin in Plasma (Tmax) | Time from last dosing to the maximum measured concentration of metformin in plasma (tmax) is presented. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Percentage (%) of the AUC of Empagliflozin That Has Been Derived After Extrapolation | The percentage (%) of the AUC of empagliflozin that has been derived after extrapolation is reported. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Percentage (%) of the AUC of Metformin That Has Been Derived After Extrapolation | The percentage (%) of the AUC of metformin that has been derived after extrapolation is reported. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Terminal Half-life of Empagliflozin in Plasma (t1/2) | The terminal half-life of empagliflozin in plasma (t1/2) is presented. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Terminal Half-life of Metformin in Plasma (t1/2) | The terminal half-life of metformin in plasma (t1/2) is presented. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Elimination Rate Constant (Kel) for Empagliflozin | The elimination rate constant (Kel) for empagliflozin is reported. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | 
| Elimination Rate Constant (Kel) for Metformin | The elimination rate constant (Kel) for metformin is reported. | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. |