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

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: FDC 12.5mg empagliflozin/850mg metformin
Drug: Empagliflozin
Drug: Glifage®

Registration Number: NCT05083949

Lead Sponsor: Boehringer Ingelheim

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Not provided

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
(B): FDC 12.5mg empagliflozin/850mg metformin,then (A): empagliflozin 10mg(R1) + Glifage® 850mg(R2)	FDC 12.5mg empagliflozin/850mg metformin	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.
(B): FDC 12.5mg empagliflozin/850mg metformin,then (A): empagliflozin 10mg(R1) + Glifage® 850mg(R2)	Glifage®	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.
(A): empagliflozin 10mg (R1)+Glifage® 850mg (R2),then (B): FDC 12.5mg empagliflozin/850mg metformin	FDC 12.5mg empagliflozin/850mg metformin	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.
(A): empagliflozin 10mg (R1)+Glifage® 850mg (R2),then (B): FDC 12.5mg empagliflozin/850mg metformin	Glifage®	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.
(A): empagliflozin 10mg (R1)+Glifage® 850mg (R2),then (B): FDC 12.5mg empagliflozin/850mg metformin	Empagliflozin	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.
(B): FDC 12.5mg empagliflozin/850mg metformin,then (A): empagliflozin 10mg(R1) + Glifage® 850mg(R2)	Empagliflozin	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.

Primary Outcome Measures

Name	Time	Method
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)	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 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.
Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)	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) 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.
Dose-normalized Maximum Measured Concentration of Empagliflozin (Cmax)	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 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.
Maximum Measured Concentration of Metformin (Cmax)	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 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.

Secondary Outcome Measures

Name	Time	Method
Time From Last Dosing to the Maximum Measured Concentration of Metformin in Plasma (Tmax)	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) is presented.
Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)	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-∞ ) 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.
Time From Last Dosing to the Maximum Measured Concentration of Empagliflozin in Plasma (Tmax)	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) is presented.
Percentage (%) of the AUC of Empagliflozin That Has Been Derived After Extrapolation	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.	The percentage (%) of the AUC of empagliflozin that has been derived after extrapolation is reported.
Percentage (%) of the AUC of Metformin That Has Been Derived After Extrapolation	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.	The percentage (%) of the AUC of metformin that has been derived after extrapolation is reported.
Elimination Rate Constant (Kel) for Metformin	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.	The elimination rate constant (Kel) for metformin is reported.
Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞ )	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 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.
Terminal Half-life of Empagliflozin in Plasma (t1/2)	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.	The terminal half-life of empagliflozin in plasma (t1/2) is presented.
Terminal Half-life of Metformin in Plasma (t1/2)	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.	The terminal half-life of metformin in plasma (t1/2) is presented.
Elimination Rate Constant (Kel) for Empagliflozin	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.	The elimination rate constant (Kel) for empagliflozin is reported.