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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01845077
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 72
• Location: 1
• Arms: 6
• Duration (Months): 3
• Patients Per Site Per Month: 23.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	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	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. AUC0-72 of Linagliptin [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]

   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.

2. Cmax of Linagliptin [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]

   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.

3. AUC0-tz of Metformin [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]

   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.

4. Cmax of Metformin [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]

   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.

Secondary Outcome Measures

1. AUC0-infinity of Linagliptin [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]

   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.

2. AUC0-infinity of Metformin [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]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. Healthy males or females

2. Age 18 -50 years (incl)

3. Body Mass Index (BMI) 18.5 to 29.9 kg/m2 (incl.)

4. Subjects must be able to understand and comply with study requirements

Exclusion criteria:

Any deviation from healthy condition

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1288.8.1 Boehringer Ingelheim Investigational Site	Austin	Texas	United States

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: NCT01845077
• Other Study ID Numbers: 1288.8
• First Posted: May 3, 2013
• Last Update Posted: Aug 19, 2014
• Last Verified: Jul 1, 2014

• Additional relevant MeSH terms: Metformin; Linagliptin

Study Results

Participant Flow

Arm/Group Title	FDC1000 Fasted, Then L+M1000 Fasted	L+M1000 Fasted, Then FDC1000 Fasted	FDC1000 Fed, Then L+M1000 Fed	L+M1000 Fed, Then FDC1000 Fed	FDC1500 Fasted, Then L+M1500 Fasted	L+M1500 Fasted, Then FDC1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered on Day 1 of the first treatment period orally in the morning under fasted conditions, then 1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered on Day 1 of the second treatment period orally in the morning under fasted conditions. Both periods lasted 4 days, separated by a washout period of at least 35 days.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered on Day 1 of the first treatment period orally in the morning under fasted conditions, then 1 FDC tablet 5 mg linagliptin/1000 mg metformin XR administered on Day 1 of the second treatment period orally in the morning under fasted conditions. Both periods lasted 4 days, separated by a washout period of at least 35 days.	1 FDC tablet 5 mg linagliptin/1000 mg metformin XR administered on Day 1 of the first treatment period orally in the morning under fed conditions, then 1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered on Day 1 of the second treatment period orally in the morning under fed conditions. Both periods lasted 4 days, separated by a washout period of at least 35 days.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered on Day 1 of the first treatment period orally in the morning under fed conditions, then 1 FDC tablet 5 mg linagliptin/1000 mg metformin XR administered on Day 1 of the second treatment period orally in the morning under fed conditions. Both periods lasted 4 days, separated by a washout period of at least 35 days.	2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered on Day 1 of the first treatment period orally in the morning under fasted conditions, then 1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered on Day 1 of the second treatment period orally in the morning under fasted conditions. Both periods lasted 4 days, separated by a washout period of at least 35 days.	1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered on Day 1 of the first treatment period orally in the morning under fasted conditions, then 2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered on Day 1 of the second treatment period orally in the morning under fasted conditions. Both periods lasted 4 days, separated by a washout period of at least 35 days.
Period Title: Treatment Period 1
STARTED	12	12	12	12	12	12
COMPLETED	12	12	12	12	12	12
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1
STARTED	12	12	12	12	12	12
COMPLETED	11	11	11	10	11	11
NOT COMPLETED	1	1	1	2	1	1
Period Title: Treatment Period 1
STARTED	11	11	11	10	11	11
COMPLETED	11	11	11	10	11	11
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Total 1000 Fasted	Total 1000 Fed	Total 1500 Fasted	Total
Arm/Group Description	Patients were administered 1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) orally in the morning under fasted conditions in one treatment period and 1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR orally in the morning under fasted conditions in the other treatment period. Both periods lasted 4 days, separated by a washout period of at least 35 days.	Patients were administered 1 FDC tablet 5 mg linagliptin/1000 mg metformin XR orally in the morning under fed conditions in one treatment period and 1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR orally in the morning under fed conditions in the other treatment period. Both periods lasted 4 days, separated by a washout period of at least 35 days.	Patients were administered 2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR orally in the morning under fasted conditions in one treatment period and 1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR orally in the morning under fasted conditions in the other treatment period. Both periods lasted 4 days, separated by a washout period of at least 35 days.	Total of all reporting groups
Overall Participants	24	24	24	72
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.8 (9.3)	30.6 (9.0)	28.4 (7.1)	31.3 (8.8)
Sex: Female, Male (Count of Participants)
Female	8 33.3%	8 33.3%	14 58.3%	30 41.7%
Male	16 66.7%	16 66.7%	10 41.7%	42 58.3%

Outcome Measures

1. Primary Outcome

Title	AUC0-72 of Linagliptin
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set including all subjects of the TS 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	FDC1000 Fasted	L+M1000 Fasted	FDC1000 Fed	L+M1000 Fed	FDC1500 Fasted	L+M1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions
Measure Participants	23	23	21	21	21	22
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	317.0 (8.0)	319.2 (8.0)	309.6 (5.5)	304.9 (5.5)	325.8 (5.1)	322.9 (5.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fasted, L+M1000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	99.3
	Confidence Interval	(2-Sided) 90%; 95.3 to 103.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fed, L+M1000 Fed
	Comments	One patient was excluded from this analysis due to the lack of the 72h sample for the L+M1000 fed treatment.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	101.5
	Confidence Interval	(2-Sided) 90%; 98.4 to 104.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC1500 Fasted, L+M1500 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	100.9
	Confidence Interval	(2-Sided) 90%; 98.2 to 103.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Cmax of Linagliptin
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set including all subjects of the TS 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	FDC1000 Fasted	L+M1000 Fasted	FDC1000 Fed	L+M1000 Fed	FDC1500 Fasted	L+M1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.
Measure Participants	23	23	22	22	21	22
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	10.1 (17.1)	10.6 (17.1)	7.7 (13.0)	7.9 (13.0)	11.6 (16.5)	10.7 (16.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fasted, L+M1000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	94.9
	Confidence Interval	(2-Sided) 90%; 86.8 to 103.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fed, L+M1000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	96.8
	Confidence Interval	(2-Sided) 90%; 90.2 to 103.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC1500 Fasted, L+M1500 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	108.6
	Confidence Interval	() 90%; 99.5 to 118.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	AUC0-infinity of Linagliptin
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set including all subjects of the TS 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	FDC1000 Fasted	L+M1000 Fasted	FDC1000 Fed	L+M1000 Fed	FDC1500 Fasted	L+M1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions
Measure Participants	23	23	22	22	21	22
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	546.1 (12.8)	526.5 (12.8)	537.1 (9.6)	510.0 (9.6)	562.9 (13.5)	581.1 (13.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fasted, L+M1000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	103.7
	Confidence Interval	(2-Sided) 90%; 97.1 to 110.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fed, L+M1000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	105.3
	Confidence Interval	(2-Sided) 90%; 99.9 to 111.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC1500 Fasted, L+M1500 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	96.9
	Confidence Interval	(2-Sided) 90%; 90.2 to 104.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	AUC0-infinity of Metformin
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set including all subjects of the TS 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	FDC1000 Fasted	L+M1000 Fasted	FDC1000 Fed	L+M1000 Fed	FDC1500 Fasted	L+M1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions
Measure Participants	23	23	22	23	21	22
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	9037.6 (21.5)	9326.5 (21.5)	14031.3 (7.0)	14069.7 (7.0)	11037.7 (19.1)	11512.2 (19.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fasted, L+M1000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	96.9
	Confidence Interval	(2-Sided) 90%; 86.8 to 108.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fed, L+M1000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	99.7
	Confidence Interval	(2-Sided) 90%; 96.1 to 103.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC1500 Fasted, L+M1500 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	95.9
	Confidence Interval	(2-Sided) 90%; 86.7 to 106.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	AUC0-tz of Metformin
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set including all subjects of the TS 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	FDC1000 Fasted	L+M1000 Fasted	FDC1000 Fed	L+M1000 Fed	FDC1500 Fasted	L+M1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions
Measure Participants	23	23	22	23	21	22
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	8629.0 (21.8)	8913.7 (21.8)	13772.0 (7.4)	13851.1 (7.4)	10472.9 (18.5)	10543.5 (18.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fasted, L+M1000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	96.8
	Confidence Interval	(2-Sided) 90%; 86.6 to 108.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fed, L+M1000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	99.4
	Confidence Interval	(2-Sided) 90%; 95.6 to 103.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC1500 Fasted, L+M1500 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	99.3
	Confidence Interval	(2-Sided) 90%; 90.1 to 109.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Cmax of Metformin
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set including all subjects of the TS 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	FDC1000 Fasted	L+M1000 Fasted	FDC1000 Fed	L+M1000 Fed	FDC1500 Fasted	L+M1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.	2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.	1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.
Measure Participants	23	23	22	23	21	22
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1047.4 (25.5)	1085.6 (25.5)	1119.0 (8.1)	1084.5 (8.1)	1347.0 (29.3)	1250.6 (29.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fasted, L+M1000 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	96.5
	Confidence Interval	(2-Sided) 90%; 84.8 to 109.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC1000 Fed, L+M1000 Fed
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	103.2
	Confidence Interval	(2-Sided) 90%; 98.9 to 107.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC1500 Fasted, L+M1500 Fasted
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Standard acceptance criterion for bioequivalence: 90% confidence interval is completely within the bounds of 80-125%. No formal hypothesis test was conducted as study is exploratory.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	107.7
	Confidence Interval	(2-Sided) 90%; 92.5 to 125.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	8 weeks
Arm/Group Title	FDC1000 Fasted		L+M1000 Fasted		FDC1000 Fed		L+M1000 Fed		FDC1500 Fasted		L+M1500 Fasted
Arm/Group Description	1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.		1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.		1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.		1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fed conditions.		2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions.		1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR administered orally in the morning of Day 1 of the corresponding treatment period under fasted conditions
All Cause Mortality
	FDC1000 Fasted		L+M1000 Fasted		FDC1000 Fed		L+M1000 Fed		FDC1500 Fasted		L+M1500 Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	FDC1000 Fasted		L+M1000 Fasted		FDC1000 Fed		L+M1000 Fed		FDC1500 Fasted		L+M1500 Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/23 (0%)		0/22 (0%)		1/23 (4.3%)		0/23 (0%)		0/23 (0%)
Injury, poisoning and procedural complications
Road traffic accident	0/23 (0%)		0/23 (0%)		0/22 (0%)		1/23 (4.3%)		0/23 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	FDC1000 Fasted		L+M1000 Fasted		FDC1000 Fed		L+M1000 Fed		FDC1500 Fasted		L+M1500 Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)		1/23 (4.3%)		1/22 (4.5%)		0/23 (0%)		3/23 (13%)		2/23 (8.7%)
Gastrointestinal disorders
Nausea	0/23 (0%)		0/23 (0%)		0/22 (0%)		0/23 (0%)		2/23 (8.7%)		1/23 (4.3%)
Vomiting	0/23 (0%)		0/23 (0%)		0/22 (0%)		0/23 (0%)		2/23 (8.7%)		1/23 (4.3%)
Nervous system disorders
Headache	1/23 (4.3%)		1/23 (4.3%)		1/22 (4.5%)		0/23 (0%)		0/23 (0%)		2/23 (8.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.