Relative Bioavailability of 2 Fixed Dose Combinations of Empagliflozin/Linagliptin/Metformin Extended Release Compared With Single Tablets

Study Overview
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Brief Summary
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The purpose of this trial is to demonstrate the relative bioavailability of 2 newly developed fixed dose combinations (FDC) tablets containing empagliflozin, linagliptin & metformin extended release (XR) and the single tablets of empagliflozin, linagliptin and metformin XR administered simultaneously.

Official Title
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Relative Bioavailability of Two FDC Tablet Strengths of Empagliflozin/Linagliptin/Metformin Extended Release Compared to the Free Combination of Empagliflozin, Linagliptin and Metformin Extended Release Following Oral Administration in Healthy Male and Female Subjects (an Open-label, Randomised, Single-dose, Two-period, Two-sequence Crossover Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: High dose FDC Empagliflozin/Linagliptin/Metformin XR, fed
* Drug: 1 tab Empagliflozin +1 tab Linagliptin +2 tabs Metformin XR
* Drug: High dose FDC Empagliflozin/Linagliptin/Metformin XR, fasted
* Drug: 1 tab Empagliflozin +1 tab Linagliptin +2 tabs Metformin XR
* Drug: Low dose FDC Empagliflozin/Linagliptin/Metformin XR, fed
* Drug: 1 tab Empagliflozin +1 tab Linagliptin +2 tabs Metformin XR


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy male or female subjects according to the investigator's assessment, based on a complete medical history including a physical examination, vital signs (blood pressure, pulse rate), 12-lead electrocardiogram, and clinical laboratory tests Age of 18 to 55 years (incl.) BMI of 18.5 to 29.9 kg/m2 (incl.) Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and 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) Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of follicle-stimulating hormone above 40 U/L and estradiol below 30 ng/L is confirmatory) Exclusion criteria: Any finding in the medical examination (including blood pressure, pulse rate or electrocardiogram) is deviating from normal and judged as clinically relevant by the investigator Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm Any laboratory value outside the reference range that the investigator considers to be of clinical relevance Any evidence of a concomitant disease judged as clinically relevant by the investigator Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: High dose, fed<br>1 fixed dose combination (FDC) tablet vs. 4 single tablets under fed conditions | Drug: High dose FDC Empagliflozin/Linagliptin/Metformin XR, fed<br>* High dose Empagliflozin/Linagliptin/Metformin extended release (XR) fixed dose combination (FDC) tablet<br>Drug: 1 tab Empagliflozin +1 tab Linagliptin +2 tabs Metformin XR<br>* 1x Empagliflozin + 1x Linagliptin + 2x Metformin extended release (XR) tablets<br>|
| Experimental: High dose, fasted<br>1 fixed dose combination (FDC) tablet vs. 4 single tablets under fasted conditions | Drug: High dose FDC Empagliflozin/Linagliptin/Metformin XR, fasted<br>* High dose Empagliflozin/Linagliptin/Metformin extended release (XR) fixed dose combination (FDC) tablet<br>Drug: 1 tab Empagliflozin +1 tab Linagliptin +2 tabs Metformin XR<br>* 1x Empagliflozin + 1x Linagliptin + 2x Metformin extended release (XR) tablets<br>|
| Experimental: Low dose, fed<br>1 fixed dose combination (FDC) tablet vs. 4 single tablets under fed conditions | Drug: Low dose FDC Empagliflozin/Linagliptin/Metformin XR, fed<br>* Low dose Empagliflozin/Linagliptin/Metformin extended release (XR) fixed dose combination (FDC) tablet<br>Drug: 1 tab Empagliflozin +1 tab Linagliptin +2 tabs Metformin XR<br>* 1x Empagliflozin + 1x Linagliptin + 2x Metformin extended release (XR) tablets<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 Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | Area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) is presented. Plasma concentrations and/or parameters of a subject were considered as non-evaluable, if for example The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subject's experiencing emesis) A pre-dose concentration was >5% of the Cmax value measured in that subject Missing samples or concentration data at important phases of PK disposition curve | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | 
| Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | Area under the concentration-time curve of Metformin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | 
| Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | Maximum measured concentration of Empagliflozin in plasma (Cmax) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | 
| Maximum Measured Concentration of Metformin in Plasma (Cmax) | Maximum measured concentration of Metformin in plasma (Cmax) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | 
| Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | Maximum measured concentration of Linagliptin in plasma (Cmax) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | 
| Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | Area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours (AUC0-72) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 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 (AUC0-∞) | Area under the concentration-time curve of the Empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | 
| Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Area under the concentration-time curve of the Metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | 
| Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Area under the concentration-time curve of the Linagliptin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration |