Bioequivalence of a FDC Tablet of Linagliptin/Metformin (5mg/1000mg) Extended Release in Healthy Subjects

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02084082
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 68
• Location: 1
• Arms: 4
• Duration (Months): 3
• Patients Per Site Per Month: 22.7

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, both under fed and fasted conditions.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 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 (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 ER FDC followed by single tablets of linagliptin and metformin ER, fasted condition	Drug: Linagliptin/Metformin ER FDC; 1x Linagliptin/Metformin FDC tablet; Drug: Linagliptin; 1x Linagliptin tablet; Drug: Metformin ER; 2x Metformin ER tablets
Experimental: Single tablets first, fasted single tablets of linagliptin and metformin ER followed by Linagliptin/Metformin ER FDC, fasted condition	Drug: Linagliptin/Metformin ER FDC; 1x Linagliptin/Metformin FDC tablet; Drug: Linagliptin; 1x Linagliptin tablet; Drug: Metformin ER; 2x Metformin ER tablets
Experimental: FDC first, fed Linagliptin/Metformin ER FDC followed by single tablets of linagliptin and metformin ER, fed condition	Drug: Linagliptin/Metformin ER FDC; 1x Linagliptin/Metformin FDC tablet; Drug: Linagliptin; 1x Linagliptin tablet; Drug: Metformin ER; 2x Metformin ER tablets
Experimental: Single tablets first, fed single tablets of linagliptin and metformin ER followed by Linagliptin/Metformin ER FDC, fed condition	Drug: Linagliptin/Metformin ER FDC; 1x Linagliptin/Metformin FDC tablet; Drug: Linagliptin; 1x Linagliptin tablet; Drug: Metformin ER; 2x Metformin ER tablets

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 concentration-time curve of the 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-t (Area under the concentration-time curve of the analyte 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 the 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 the analyte 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 analyte 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	1288.9.1 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: NCT02084082
• Other Study ID Numbers: 1288.9; 2013-005142-11
• First Posted: Mar 11, 2014
• Last Update Posted: Aug 4, 2016
• Last Verified: Aug 1, 2015

• Additional relevant MeSH terms: Metformin; Linagliptin

Study Results

Participant Flow

Recruitment Details	The study is conducted in two parts: Part 1 of the study was conducted in fasting conditions. Part 2 of the study was conducted in fed conditions.

Arm/Group Title	FDC 1000 Fast/ L+M 1000 Fast	L+M1000 Fast/ FDC1000 Fast	FDC1000 Fed/L+M1000 Fed	L+M1000 Fed/ FDC1000 Fed
Arm/Group Description	Linagliptin/Metformin Extended Release (XR) Fixed dose combination (given as 1 FDC tablet) followed by single tablets of linagliptin and metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR), oral with 240 mL of water after an overnight fast of at least 10 h. Where, L+M = Linagliptin 5mg+Metformin 1000mg	Single tablets of linagliptin and metformin Extended Release (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) followed by Linagliptin/Metformin XR Fixed Dose Combination (given as 1 FDC tablet), oral with 240 mL of water after an overnight fast of at least 10 h. Where, L+M = Linagliptin 5mg+Metformin 1000mg	Linagliptin/Metformin XR FDC (given as 1 FDC tablet) followed by single tablets of linagliptin and metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR), oral with 240 mL of water after a high-fat, high-calorie meal. Where, L+M = Linagliptin 5mg+Metformin 1000mg	Single tablets of linagliptin and metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) followed by Linagliptin/Metformin XR FDC (given as 1 FDC tablet), oral with 240 mL of water after a high-fat, high-calorie meal. Where, L+M = Linagliptin 5mg+Metformin 1000mg
Period Title: Treatment Period 1 (4 Days)
STARTED	26	26	8	8
COMPLETED	26	26	8	8
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (4 Days)
STARTED	26	26	8	8
COMPLETED	26	26	7	6
NOT COMPLETED	0	0	1	2
Period Title: Treatment Period 1 (4 Days)
STARTED	26	26	7	6
COMPLETED	26	26	7	6
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	FDC 1000 Fast or L+M 1000 Fast	FDC 1000 Fed or L+M 1000 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 1000 fast (T fasted): 5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h. L+M 1000 fast (R fasted): 5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h. Where, L+M = Linagliptin 5mg+Metformin 1000mg	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 1000 fed (T fed): 5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal. L+M 1000 fed (R fed): 5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal. Where, L+M = Linagliptin 5mg+Metformin 1000mg	Total of all reporting groups
Overall Participants	52	16	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.7 (10.4)	36.1 (11.9)	35.0 (10.7)
Sex: Female, Male (Count of Participants)
Female	29 55.8%	10 62.5%	39 57.4%
Male	23 44.2%	6 37.5%	29 42.6%

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 concentration-time curve of the 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

PKS 1000 fast and PKS 1000 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 1000 Fasted	FDC 1000 Fasted	L+M 1000 Fed	FDC 1000 Fed
Arm/Group Description	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
Measure Participants	52	52	15	14
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	286.639 (11.8)	287.696 (11.8)	234.052 (9.2)	221.644 (9.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fasted, FDC 1000 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	100.37
	Confidence Interval	(2-Sided) 90%; 96.562 to 104.326
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.023
	Estimation Comments	Ratio of (FDC 1000_fasted/ L+M 1000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fed, FDC 1000 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	0.0004
	Comments
	Method	ANOVA
	Comments	ANOVA on the logarithmic scale including effects for 'sequence', 'subjects within sequences', 'period', and 'treatment'.
Method of Estimation	Estimation Parameter	Geometric mean ratio (net)
	Estimated Value	94.70
	Confidence Interval	(2-Sided) 90%; 88.712 to 101.089
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.037
	Estimation Comments	Ratio of (FDC 1000 Fed/ L+M 1000 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

PKS 1000 fast and PKS 1000 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 1000 Fasted	FDC 1000 Fasted	L+M 1000 Fed	FDC 1000 Fed
Arm/Group Description	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
Measure Participants	52	52	15	14
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	8.826 (27.1)	9.540 (27.1)	5.791 (6.1)	5.689 (6.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fasted, FDC 1000 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	0.0038
	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 Mean ratio
	Estimated Value	108.09
	Confidence Interval	(2-Sided) 90%; 99.022 to 117.989
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.054
	Estimation Comments	Ratio of (FDC 1000_fasted/ L+M 1000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fed, FDC 1000 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	<0.0001
	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	98.24
	Confidence Interval	(2-Sided) 90%; 94.067 to 102.597
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.024
	Estimation Comments	Ratio of (FDC 1000_fed / L+M 1000 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-t (Area under the concentration-time curve of the analyte 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

PKS 1000 fast and PKS 1000 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 1000 Fasted	FDC 1000 Fasted	L+M 1000 Fed	FDC 1000 Fed
Arm/Group Description	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
Measure Participants	52	52	15	14
Geometric Mean (Geometric Coefficient of Variation) [ng∙h/mL]	7146.61 (22.2)	7146.00 (22.2)	11326.12 (7.1)	10980.17 (7.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fasted, FDC 1000 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 Mean ratio
	Estimated Value	99.99
	Confidence Interval	(2-Sided) 90%; 93.03 to 107.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.04
	Estimation Comments	Ratio of (FDC 1000_fasted/ L+M 1000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fed, FDC 1000 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	<0.0001
	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	96.95
	Confidence Interval	(2-Sided) 90%; 92.24 to 101.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.03
	Estimation Comments	Ratio of (FDC 1000_fed / L+M 1000 fed)

4. Primary Outcome

Title	Cmax of Metformin in Plasma
Description	Cmax (maximum measured concentration of the 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

PKS 1000 fast and PKS 1000 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 1000 Fasted	FDC 1000 Fasted	L+M 1000 Fed	FDC 1000 Fed
Arm/Group Description	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
Measure Participants	52	52	15	14
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	925.709 (23.4)	923.543 (23.4)	947.445 (5.9)	937.685 (5.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fasted, FDC 1000 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	99.77
	Confidence Interval	(2-Sided) 90%; 92.464 to 107.645
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.046
	Estimation Comments	Ratio of (FDC 1000_fasted/ L+M 1000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fed, FDC 1000 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	<0.0001
	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	98.97
	Confidence Interval	(2-Sided) 90%; 94.950 to 103.160
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.023
	Estimation Comments	Ratio of (FDC 1000_fed / L+M 1000 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 the analyte 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

PKS 1000 fast and PKS 1000 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 1000 Fasted	FDC 1000 Fasted	L+M 1000 Fed	FDC 1000 Fed
Arm/Group Description	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
Measure Participants	52	52	15	14
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	461.306 (14.3)	460.009 (14.3)	397.945 (32.4)	387.424 (32.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fasted, FDC 1000 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	99.72
	Confidence Interval	(2-Sided) 90%; 95.163 to 104.493
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.028
	Estimation Comments	Ratio of (FDC 1000_fasted/ L+M 1000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fed, FDC 1000 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	0.0778
	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	97.36
	Confidence Interval	(2-Sided) 90%; 77.082 to 122.963
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.132
	Estimation Comments	Ratio of (FDC 1000_fed / L+M 1000 fed)

6. Secondary Outcome

Title	AUC0-inf of Metformin in Plasma
Description	AUC0-inf(area under the concentration-time curve of the analyte 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 1000 fast and PKS 1000 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 1000 Fasted	FDC 1000 Fasted	L+M 1000 Fed	FDC 1000 Fed
Arm/Group Description	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.	5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
Measure Participants	52	52	15	13
Geometric Mean (Geometric Coefficient of Variation) [ng∙h/mL]	7607.75 (21.7)	7540.21 (21.7)	15047.37 (7.2)	14773.59 (7.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fasted, FDC 1000 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	99.11
	Confidence Interval	(2-Sided) 90%; 92.37 to 106.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.04
	Estimation Comments	Ratio of (FDC 1000_fasted/ L+M 1000 fasted)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	L+M 1000 Fed, FDC 1000 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	<0.0001
	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	98.18
	Confidence Interval	(2-Sided) 90%; 93.34 to 103.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.03
	Estimation Comments	Ratio of (FDC 1000_fed / L+M 1000 fed)

Adverse Events

Time Frame	From the first drug administration for at least 7 days after the last drug administration, up to 49 days.
Arm/Group Title	L+M 1000 Fasted		FDC 1000 Fasted		L+M 1000 Fed		FDC 1000 Fed
Arm/Group Description	5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.		5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.		5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.		5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
All Cause Mortality
	L+M 1000 Fasted		FDC 1000 Fasted		L+M 1000 Fed		FDC 1000 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 1000 Fasted		FDC 1000 Fasted		L+M 1000 Fed		FDC 1000 Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/52 (0%)		2/15 (13.3%)		0/14 (0%)
Injury, poisoning and procedural complications
Acetabulum fracture	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Bone contusion	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Concussion	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Fall	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Muscle contusion	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Pelvic fracture	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Road traffic accident	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	L+M 1000 Fasted		FDC 1000 Fasted		L+M 1000 Fed		FDC 1000 Fed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/52 (7.7%)		9/52 (17.3%)		4/15 (26.7%)		4/14 (28.6%)
Ear and labyrinth disorders
Vertigo	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/52 (0%)		0/52 (0%)		1/15 (6.7%)		0/14 (0%)
Diarrhoea	1/52 (1.9%)		4/52 (7.7%)		0/15 (0%)		1/14 (7.1%)
General disorders
Fatigue	0/52 (0%)		0/52 (0%)		0/15 (0%)		1/14 (7.1%)
Infections and infestations
Rhinitis	0/52 (0%)		2/52 (3.8%)		0/15 (0%)		1/14 (7.1%)
Metabolism and nutrition disorders
Decreased appetite	0/52 (0%)		0/52 (0%)		0/15 (0%)		1/14 (7.1%)
Nervous system disorders
Dizziness	0/52 (0%)		2/52 (3.8%)		1/15 (6.7%)		0/14 (0%)
Headache	3/52 (5.8%)		5/52 (9.6%)		2/15 (13.3%)		0/14 (0%)
Skin and subcutaneous tissue disorders
Rash	0/52 (0%)		0/52 (0%)		0/15 (0%)		1/14 (7.1%)

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.