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

Study Overview
=================
Brief Summary
-----------------
The purpose of the trial is to demonstrate the relative bioavailability of 2 newly developed fixed dose combination (FDC) tablets containing linagliptin & metformin and the single tablets of linagliptin and metformin when administered singularly.

Official Title
-----------------
Relative Bioavailability of Two Newly Developed Extended Release FDC Tablet Strengths (5mg/1000mg and 2.5 mg/750 mg) of Linagliptin/Metformin Extended Release Compared With the Free Combination of Linagliptin and Metformin Extended Release in Healthy Subjects (an Open-label, Randomised, Single Dose, Two-way Crossover Study)

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: 2x500 mg Metformin (Glumetza)
* Drug: 5 mg Linagliptin/1000 mg Metformin FDC
* Drug: 5 mg Linagliptin (Tradjenta)
* Drug: 5 mg Linagliptin (Tradjenta)
* Drug: 3x500 mg Metformin (Glumetza)
* Drug: 5 mg Linagliptin (Tradjenta)
* Drug: 2 x 500 mg Metformin (Glumetza)
* Drug: 5 mg Linagliptin/1000mg Metformin FDC
* Drug: 2 x 2.5 mg Linagliptin/750 mg Metformin FDC


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Healthy males or females Age 18 -50 years (incl) Body Mass Index (BMI) 18.5 to 29.9 kg/m2 (incl.) Subjects must be able to understand and comply with study requirements Exclusion criteria: Any deviation from healthy condition

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 5 mg Linagliptin/1000 mg Metformin, fed<br>3 single tablets under fed conditions | Drug: 2x500 mg Metformin (Glumetza)<br>* 2 tablets<br>Drug: 5 mg Linagliptin (Tradjenta)<br>* 1 tablet<br>|
| Experimental: 5 mg Linagliptin/1500 mg Metformin FDC<br>2 FDC tablets under fasted conditions | Drug: 2 x 2.5 mg Linagliptin/750 mg Metformin FDC<br>* 2 FDC tablets<br>|
| Active Comparator: 5 mg Linagliptin/1500 mg Metformin<br>4 single tablets under fasted conditions | Drug: 3x500 mg Metformin (Glumetza)<br>* 3 tablets<br>Drug: 5 mg Linagliptin (Tradjenta)<br>* 1 tablet<br>|
| Experimental: 5 mg Linagliptin/1000 mg Metformin FDC<br>1 fixed dose combination(FDC) tablet under fasted conditions | Drug: 5 mg Linagliptin/1000mg Metformin FDC<br>* FDC Tablet<br>|
| Active Comparator: 5 mg Linagliptin/1000 mg Metformin<br>3 single tablets under fasted conditions | Drug: 5 mg Linagliptin (Tradjenta)<br>* 1 tablet<br>Drug: 2 x 500 mg Metformin (Glumetza)<br>* 2 tablets<br>|
| Experimental: 5mg Linagliptin/1000mg Metformin, FDCfed<br>1 FDC tablet under fed conditions | Drug: 5 mg Linagliptin/1000 mg Metformin FDC<br>* FDC tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-72 of Linagliptin | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval 0 to 72 Hours (AUC0-72). The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | 
| Cmax of Linagliptin | Maximum Measured Concentration (Cmax) of Linagliptin in plasma. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | 
| AUC0-tz of Metformin | Area under the concentration-time curve of Metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | 
| Cmax of Metformin | Maximum Measured Concentration (Cmax) of Metformin in plasma. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-infinity of Linagliptin | Area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity based on predicted last concentration values. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | 
| AUC0-infinity of Metformin | Area under the concentration-time curve of Metformin in plasma over the time interval from 0 extrapolated to infinity based on predicted last concentration values. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period |