Relative Bioavailability of Two Different Batches of a Linagliptin / Metformin Combination Tablet in Healthy Volunteers

Study Overview
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Brief Summary
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The objective of the current study is to investigate the relative bioavailability of two different batches of a 2.5 mg linagliptin / 1000 mg metformin fixed dose combination tablet (FDC).

Official Title
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Relative Bioavailability of Two Different Batches of a 2.5 mg Linagliptin / 1000 mg Metformin Fixed Dose Combination Tablet (FDC) in Healthy Male and Female Volunteers (an Open-label, Randomised, Single Dose, Two-way Crossover, Phase I Trial)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Linagliptin/Metformin (standard batch)
* Drug: Linagliptin/Metformin (side batch)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy males and females according to the following criteria: Based upon a complete medical history, including physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), clinical laboratory tests Age 21 to 50 years (incl.) Body Mass Index (BMI) 18.5 to 29.9 kg/m2 (incl.) Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation Exclusion criteria: Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance Any evidence of a clinically relevant concomitant disease Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of the gastrointestinal tract (except appendectomy) Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of relevant orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections History of relevant allergy or hypersensitivity (including allergy to drug or its excipients) Intake of drugs within one month or less than 10 half-lives of the respective drug prior to first study drug administration Participation in another trial with an investigational drug within 2 months prior to administration or during the trial Smoker (more than 10 cigarettes or 3 cigars 3 pipes daily) Alcohol abuse (average consumption of more than 20 g/day in females and 30 g/day in males) Drug abuse Blood donation (more than 100 mL within four weeks prior to day 1 of visit 2) Any laboratory value outside the reference range that is of clinical relevance Inability to comply with dietary regimen of trial site For female subjects of childbearing potential only: Positive pregnancy test, pregnancy or planning to become pregnant 1 month before study or within 2 months after study completion No adequate contraception 1 month before study and until 2 month after study completion, e.g. not any of the following: implants, injectables, combined hormonal contraceptives, hormonal IUD (intrauterine device), sexual abstinence for at least 1 month prior to first study drug administration, vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who do not have a vasectomised partner, are not sexually abstinent or surgically sterile will be asked to use an additional barrier method (e.g. condom). Lactation

Ages Eligible for Study
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Minimum Age: 21 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: Linagliptin/Metformin (standard batch)<br>Fixed dose combination tablet | Drug: Linagliptin/Metformin (standard batch)<br>* Fixed dose combination tablet<br>|
| Experimental: Linagliptin/Metformin (side batch)<br>Fixed dose combination tablet | Drug: Linagliptin/Metformin (side batch)<br>* Fixed dose combination tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Linagliptin: Maximum Measured Concentration (Cmax) | Geometric mean of Cmax of Linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval 0 to 72 Hours (AUC0-72) | Geometric mean of AUC0-72 of Linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: Cmax | Geometric Mean of Cmax of Metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: AUC0-tz | Geometric Mean of AUC0-tz of Metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Linagliptin: AUC0-infinity | Geometric mean of AUC0-infinity of Linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Linagliptin: Percentage of AUCtz-∞ Obtained by Extrapolation | Geometric Mean of percentage of AUCtz-∞ of linagliptin, where percentage is the unit of measurement. | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Linagliptin: Time to Maximum Measured Concentration of the Analyte in Plasma (Tmax) | Median of the t_max of linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Linagliptin: λz (Terminal Elimination Rate Constant in Plasma) | Geometric mean of the λ_z of linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| t1/2 (Terminal Half-life of the Analyte in Plasma) | Geometric mean of the t1/2 of linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Linagliptin: MRTpo (Mean Residence Time of the Analyte in the Body After Peroral Administration) | Geometric mean of the MRTpo of linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Linagliptin: Apparent Clearance of the Analyte in Plasma After Extravascular Administration (CL/F) | Geometric mean of the CL/F of linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Linagliptin: Apparent Volume of Distribution During the Terminal Phase Following an Extravascular Dose (Vz/F) | Geometric mean of the Vz/F of linagliptin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: AUC0-infinity | Geometric Mean of AUC0-infinity of Metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: Percentage of AUCtz-∞ Obtained by Extrapolation | Geometric Mean of the percentage of AUCtz-infinity of Metformin, where percentage is the unit of measurement. | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: Tmax | Median of tmax of metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: λz (Terminal Elimination Rate Constant in Plasma) | Geometric mean of λz of metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: t1/2 (Terminal Half-life of the Analyte in Plasma) | Geometric mean of t1/2 of metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: MRTpo (Mean Residence Time of the Analyte in the Body After Peroral Administration) | Geometric mean of MRTpo of metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: CL/F | Geometric mean of CL/F of metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Metformin: Vz/F | Geometric mean of Vz/F of metformin | Day 1 to 35 for period 1, and Day 36 to 70 for period 2 | 
| Electrocardiogram (ECG), Vital Signs, Physical Finding or Laboratory Finding Abnormalities | 12-lead-Electrocardiogram (ECG), vital sign (blood pressure and pulse rate), physical finding and laboratory abnormalities | Day 1 to 4 for period 1, and day 36 to 39 for period 2 | 
| Participants With Treatment Emergent Adverse Events | Number of patients with treatment emergent AEs | Day 1 to 4 for period 1, and day 36 to 39 for period 2 | 
| Participants Who Discontinued the Trial Because of an Adverse Event | Number of participants who discontinued the trial because of an adverse event | Day 1 to 4 for period 1, and day 36 to 39 for period 2 | 
| Assessment of Tolerability by the Investigator | Qualitative variable assessing the tolerability by the investigator | Day 1 to 4 for period 1, and day 36 to 39 for period 2 |