Bioequivalence of a FDC Tablet of Linagliptin/Metformin (2.5mg/1000mg) Extended Release in Healthy Subjects.

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02084056
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 74
• Location: 1
• Arms: 4
• Duration (Months): 3
• Patients Per Site Per Month: 24.8

Study Details

Study Description

Brief Summary

The purpose of this trial is to demonstrate bioequivalence of a newly developed fixed dose combination (FDC) tablet containing linagliptin and metformin extended release compared to the free combination of linagliptin and metformin extended release.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Linagliptin; Drug: Metformin; Drug: Linagliptin/Metformin FDC	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bioequivalence of a Fixed Dose Combination Tablet of Linagliptin/Metformin Extended Release (2.5 mg/1000 mg) Compared With the Free Combination of Linagliptin and Metformin Extended Release Tablets in Healthy Subjects (an Open-label, Randomised, Single Dose, Two-way Crossover Trial)
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FDC first, fasted Linagliptin/Metformin FDC followed by single tablets of linagliptin and metformin, fasted	Drug: Linagliptin; Linagliptin; Drug: Metformin; Metformin; Drug: Linagliptin/Metformin FDC; Linagliptin/Metformin FDC
Experimental: Single tablets first, fasted single tablets of linagliptin and metformin followed by Linagliptin/Metformin FDC, fasted	Drug: Linagliptin; Linagliptin; Drug: Metformin; Metformin; Drug: Linagliptin/Metformin FDC; Linagliptin/Metformin FDC
Experimental: FDC first, fed Linagliptin/Metformin FDC followed by single tablets of linagliptin and metformin, fed	Drug: Linagliptin; Linagliptin; Drug: Metformin; Metformin; Drug: Linagliptin/Metformin FDC; Linagliptin/Metformin FDC
Experimental: Single tablets first, fed single tablets of linagliptin and metformin followed by Linagliptin/Metformin FDC, fed	Drug: Linagliptin; Linagliptin; Drug: Metformin; Metformin; Drug: Linagliptin/Metformin FDC; Linagliptin/Metformin FDC

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration]

   AUC 0-72 (area under the concentration-time curve of Linagliptin in plasma from 0 to 72 hours) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.

2. Maximum Measured Concentration of Linagliptin in Plasma (Cmax) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration]

   Cmax (maximum measured concentration of Linagliptin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.

3. Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration]

   AUC 0-tz (Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.

4. Cmax of Metformin in Plasma [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration]

   Cmax (maximum measured concentration of Metformin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.

Secondary Outcome Measures

1. Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration]

   AUC0-inf (area under the concentration-time curve of linagliptin in plasma over the time interval from 0 extrapolated to infinity) for Linagliptin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.

2. AUC0-inf of Metformin in Plasma [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration]

   AUC0-inf(area under the concentration-time curve of the metformin in plasma over the time interval from 0 extrapolated to infinity) for Metformin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

• Healthy male or female subjects

Exclusion criteria:

• Any relevant deviation from healthy condition

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1288.11.1 Boehringer Ingelheim Investigational Site	Biberach		Germany

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02084056
• Other Study ID Numbers: 1288.11; 2013-005144-28
• First Posted: Mar 11, 2014
• Last Update Posted: Aug 4, 2016
• Last Verified: Jun 1, 2016

• Additional relevant MeSH terms: Metformin; Linagliptin

Study Results

Participant Flow

Recruitment Details	This study was conducted in two parts. Part 1: Fasting study Part 2: Fed Study

Arm/Group Title	FDC 2000 Fasted / L+M 2000 Fasted	L+M 2000 Fasted / FDC 2000 Fasted	FDC 2000 Fed / L+M 2000 Fed	L+M 2000 Fed / FDC 2000 Fed
Arm/Group Description	Linagliptin+ Metformin Fixed dose combination (FDC)-(T fasted): 2X2.5 mg linagliptin/1000 mg metformin Extended Release (XR) (given as FDC tablet) followed by 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h. Where, L+M = Linagliptin 5mg+Metformin XR 2000mg	Linagliptin+ Metformin-(R fasted): 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR) followed by Linagliptin+ Metformin (FDC)-(T fasted): 2X2.5 mg linagliptin/1000 mg metformin XR orally with 240 mL of water after an overnight fast of at least 10 h. Where, L+M = Linagliptin 5mg+Metformin XR 2000mg	Linagliptin+ Metformin (FDC)-(T fed): 2X2.5 mg linagliptin/1000 mg metformin XR (given as FDC tablet) followed by 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after after a high-fat, high-calorie meal. Where, L+M = Linagliptin 5mg+Metformin XR 2000mg	Linagliptin+ Metformin-(R fed): 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR) followed by Linagliptin+ Metformin (FDC)-(T fed): 2X2.5 mg linagliptin/1000 mg metformin XR orally with 240 mL of water after a high-fat, high-calorie meal. Where, L+M = Linagliptin 5mg+Metformin XR 2000mg
Period Title: Treatment Period 1 (4 Days)
STARTED	28	30	8	8
COMPLETED	27	30	8	8
NOT COMPLETED	1	0	0	0
Period Title: Treatment Period 1 (4 Days)
STARTED	27	30	8	8
COMPLETED	26	30	8	8
NOT COMPLETED	1	0	0	0
Period Title: Treatment Period 1 (4 Days)
STARTED	26	30	8	8
COMPLETED	26	30	8	8
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	FDC 2000 Fasted or L+M 2000 Fasted	FDC 2000 Fed or L+M 2000 Fed	Total
Arm/Group Description	The subjects in Part 1 were randomly allocated to 1 of the 2 treatment sequences T fasted_R fasted or R fasted_T fasted. FDC 2000 fasted (T fasted): 2X2.5 mg linagliptin/1000 mg metformin XR (given as FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h. L+M 2000 fasted (R fasted): 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h. Where, L+M = Linagliptin 5mg+Metformin XR 2000mg	The subjects in Part 2 were randomly allocated to 1 of the 2 treatment sequences T fed_R fed or R fed_T fed. FDC 2000 fed (T fed): 2X2.5 mg linagliptin/1000 mg metformin XR (given as FDC tablet) orally with 240 mL of water after a high-fat, high-calorie meal. L+M 2000 fed (R fed): 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal. Where, L+M = Linagliptin 5mg+Metformin XR 2000mg	Total of all reporting groups
Overall Participants	58	16	74
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.1 (9.8)	32.6 (8.2)	33.0 (9.4)
Sex: Female, Male (Count of Participants)
Female	38 65.5%	7 43.8%	45 60.8%
Male	20 34.5%	9 56.3%	29 39.2%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72)
Description	AUC 0-72 (area under the concentration-time curve of Linagliptin in plasma from 0 to 72 hours) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.

Arm/Group Title	L+M 2000 Fasted	FDC 2000 Fasted	L+M 2000 Fed	FDC 2000 Fed
Arm/Group Description	5 mg linagliptin/2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/2000 mg metformin XR given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
Measure Participants	55	57	16	15
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	278.460 (9.1)	288.709 (9.1)	264.509 (12.7)	268.814 (12.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fasted, FDC 2000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	103.68
	Confidence Interval	(2-Sided) 90%; 100.703 to 106.747
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.018
	Estimation Comments	Ratio of (FDC 2000 fasted/ L+M 2000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fed, FDC 2000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'.
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	101.63
	Confidence Interval	(2-Sided) 90%; 93.721 to 110.202
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.047
	Estimation Comments	Ratio of (FDC 2000 fed/ L+M 2000 fed)

2. Primary Outcome

Title	Maximum Measured Concentration of Linagliptin in Plasma (Cmax)
Description	Cmax (maximum measured concentration of Linagliptin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.

Arm/Group Title	L+M 2000 Fasted	FDC 2000 Fasted	L+M 2000 Fed	FDC 2000 Fed
Arm/Group Description	5 mg linagliptin/2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/2000 mg metformin XR given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
Measure Participants	55	57	16	15
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	8.274 (19.6)	9.480 (19.6)	6.729 (20.1)	6.613 (20.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fasted, FDC 2000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0113
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	114.58
	Confidence Interval	(2-Sided) 90%; 107.687 to 121.908
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.038
	Estimation Comments	Ratio of (FDC 2000 fasted/ L+M 2000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fed, FDC 2000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0064
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'.
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	98.28
	Confidence Interval	(2-Sided) 90%; 86.543 to 111.609
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.075
	Estimation Comments	Ratio of (FDC 2000 fed/ L+M 2000 fed)

3. Primary Outcome

Title	Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	AUC 0-tz (Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.

Arm/Group Title	L+M 2000 Fasted	FDC 2000 Fasted	L+M 2000 Fed	FDC 2000 Fed
Arm/Group Description	5 mg linagliptin/2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/2000 mg metformin XR given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
Measure Participants	56	56	15	15
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	12028.27 (17.6)	11601.19 (17.6)	20411.01 (11.7)	19952.61 (11.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fasted, FDC 2000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	96.45
	Confidence Interval	(2-Sided) 90%; 91.23 to 101.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.03
	Estimation Comments	Ratio of (FDC 2000 fasted/ L+M 2000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fed, FDC 2000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'.
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	97.75
	Confidence Interval	(2-Sided) 90%; 90.47 to 105.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.04
	Estimation Comments	Ratio of (FDC 2000 fed/ L+M 2000 fed)

4. Primary Outcome

Title	Cmax of Metformin in Plasma
Description	Cmax (maximum measured concentration of Metformin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.

Arm/Group Title	L+M 2000 Fasted	FDC 2000 Fasted	L+M 2000 Fed	FDC 2000 Fed
Arm/Group Description	5 mg linagliptin/2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/2000 mg metformin XR given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
Measure Participants	56	57	15	15
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1516.558 (19.9)	1485.642 (19.9)	1571.040 (13.8)	1662.954 (13.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fasted, FDC 2000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	97.96
	Confidence Interval	(2-Sided) 90%; 92.046 to 104.257
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.038
	Estimation Comments	Ratio of (FDC 2000 fasted/ L+M 2000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fed, FDC 2000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0030
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'.
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	105.85
	Confidence Interval	(2-Sided) 90%; 96.705 to 115.861
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.053
	Estimation Comments	Ratio of (FDC 2000 fed/ L+M 2000 fed)

5. Secondary Outcome

Title	Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf)
Description	AUC0-inf (area under the concentration-time curve of linagliptin in plasma over the time interval from 0 extrapolated to infinity) for Linagliptin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints

Arm/Group Title	L+M 2000 Fasted	FDC 2000 Fasted	L+M 2000 Fed	FDC 2000 Fed
Arm/Group Description	5 mg linagliptin/2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/2000 mg metformin XR given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
Measure Participants	55	57	16	15
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	457.780 (15.8)	473.704 (15.8)	445.884 (16.7)	451.888 (16.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fasted, FDC 2000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	103.48
	Confidence Interval	(2-Sided) 90%; 98.426 to 108.790
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.030
	Estimation Comments	Ratio of (FDC 2000 fasted/ L+M 2000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fed, FDC 2000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'.
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	101.35
	Confidence Interval	(2-Sided) 90%; 91.130 to 112.708
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.062
	Estimation Comments	Ratio of (FDC 2000 fed/ L+M 2000 fed)

6. Secondary Outcome

Title	AUC0-inf of Metformin in Plasma
Description	AUC0-inf(area under the concentration-time curve of the metformin in plasma over the time interval from 0 extrapolated to infinity) for Metformin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS 2000 fast and PKS 2000 fed, included all treated subjects in Part 1 and Part 2, respectively, who provided at least 1 observation for at least 1 primary endpoint, without important protocol violations regarding the statistical evaluation of pharmacokinetic endpoints.

Arm/Group Title	L+M 2000 Fasted	FDC 2000 Fasted	L+M 2000 Fed	FDC 2000 Fed
Arm/Group Description	5 mg linagliptin/2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/2000 mg metformin XR given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
Measure Participants	56	56	15	15
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	12736.87 (19.7)	12162.37 (19.7)	20721.20 (11.9)	20346.34 (11.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fasted, FDC 2000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	95.49
	Confidence Interval	(2-Sided) 90%; 89.73 to 101.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.04
	Estimation Comments	Ratio of (FDC 2000 fasted/ L+M 2000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 2000 Fed, FDC 2000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means (FDC/free combination) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'.
Method of Estimation	Estimation Parameter	Adjusted Geometric Means ratio
	Estimated Value	98.19
	Confidence Interval	(2-Sided) 90%; 90.73 to 106.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.05
	Estimation Comments	Ratio of (FDC 2000 fed/ L+M 2000 fed)

Adverse Events

Time Frame	From the first drug administration for at least 7 days after the last drug administration, up to 47 days.
Arm/Group Title	L+M 2000 Fasted		FDC 2000 Fasted		L+M 2000 Fed		FDC 2000 Fed
Arm/Group Description	5 mg linagliptin/2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.		5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.		5 mg linagliptin/2000 mg metformin XR given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.		5 mg linagliptin and 2000 mg metformin XR FDC (given as 2 tablet 2.5 mg linagliptin and 1000 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
All Cause Mortality
	L+M 2000 Fasted		FDC 2000 Fasted		L+M 2000 Fed		FDC 2000 Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	L+M 2000 Fasted		FDC 2000 Fasted		L+M 2000 Fed		FDC 2000 Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/56 (0%)		0/58 (0%)		0/16 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	L+M 2000 Fasted		FDC 2000 Fasted		L+M 2000 Fed		FDC 2000 Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/56 (35.7%)		24/58 (41.4%)		8/16 (50%)		5/16 (31.3%)
Gastrointestinal disorders
Abdominal pain	3/56 (5.4%)		6/58 (10.3%)		2/16 (12.5%)		1/16 (6.3%)
Diarrhoea	3/56 (5.4%)		5/58 (8.6%)		4/16 (25%)		1/16 (6.3%)
Nausea	2/56 (3.6%)		5/58 (8.6%)		2/16 (12.5%)		0/16 (0%)
Retching	0/56 (0%)		0/58 (0%)		1/16 (6.3%)		0/16 (0%)
Vomiting	1/56 (1.8%)		1/58 (1.7%)		1/16 (6.3%)		1/16 (6.3%)
General disorders
Discomfort	0/56 (0%)		0/58 (0%)		0/16 (0%)		1/16 (6.3%)
Influenza like illness	0/56 (0%)		0/58 (0%)		1/16 (6.3%)		0/16 (0%)
Infections and infestations
Nasopharyngitis	1/56 (1.8%)		2/58 (3.4%)		1/16 (6.3%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Muscle tightness	0/56 (0%)		0/58 (0%)		1/16 (6.3%)		0/16 (0%)
Nervous system disorders
Dizziness	2/56 (3.6%)		3/58 (5.2%)		0/16 (0%)		0/16 (0%)
Headache	11/56 (19.6%)		9/58 (15.5%)		3/16 (18.8%)		1/16 (6.3%)
Reproductive system and breast disorders
Dysmenorrhoea	1/56 (1.8%)		0/58 (0%)		0/16 (0%)		1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/56 (0%)		1/58 (1.7%)		0/16 (0%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.