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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01975220
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 72
• Location: 1
• Arms: 3
• Duration (Months): 2
• Patients Per Site Per Month: 35.9

Study Details

Study Description

Brief Summary

The purpose of this trial is to demonstrate the relative bioavailability of 2 newly developed fixed dose combination (FDC) tablets containing empagliflozin & metformin and the single tablets of empagliflozin and metformin when administered singularly.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Empagliflozin/Metformin XR, FDC; Drug: Empagliflozin/Metformin XR FDC; Drug: 25 mg Empagliflozin/1000 mg Metformin XR, FDC; Drug: 1 tablet Empagliflozin/2 tablets Metformin XR; Drug: 1 tablet Empagliflozin/3 tablets Metformin XR; Drug: 1 tablet Empagliflozin/2 tablets Metformin XR	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 FDC Tablet Strengths (25mg/1000mg and 12.5mg/750mg) of Empagliflozin/Metformin Extended Release Compared With the Free Combination of Empagliflozin and Metformin Extended Release in Healthy Subjects (an Open-label, Randomised, Single Dose, Two-way Crossover Study)
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High dose, fasted 1 fixed dose combination (FDC) tablet vs. 3 single tablets under fasted conditions	Drug: 25 mg Empagliflozin/1000 mg Metformin XR, FDC; Experimental, high dose Empagliflozin/Metformin XR,FDC Tablet; Drug: 1 tablet Empagliflozin/2 tablets Metformin XR; Active Comparator: 1x empagliflozin/2x metformin XR tablets
Experimental: High dose, fed 1 fixed dose combination (FDC) tablet vs. 3 single tablets under fed conditions	Drug: Empagliflozin/Metformin XR, FDC; Experimental: high dose empagliflozin/metformin XR, FDC tablet; Drug: 1 tablet Empagliflozin/2 tablets Metformin XR; Active Comparator: 1x empagliflozin/2x metformin XR tablets
Experimental: Low dose, fasted 2 fixed low dose combination (FDC) tablets vs. 4 single tablets under fed conditions	Drug: Empagliflozin/Metformin XR FDC; Experimental: low dose empagliflozin/metformin XR, FDC tablet; Drug: 1 tablet Empagliflozin/3 tablets Metformin XR; Active Comparator: 1x empagliflozin/3x metformin XR tablets

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration]

   Area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz); Empagliflozin

2. AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration]

   AUC 0-tz (area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point); Metformin

3. Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration]

   Cmax (maximum measured concentration of the analyte in plasma); Empagliflozin

4. Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration]

   Cmax (maximum measured concentration of the analyte in plasma); Metformin

Secondary Outcome Measures

1. AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration]

   AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Empagliflozin

2. AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration]

   AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Metformin

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	1276.13.1 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: NCT01975220
• Other Study ID Numbers: 1276.13
• First Posted: Nov 3, 2013
• Last Update Posted: Mar 8, 2017
• Last Verified: Aug 1, 2016

• Additional relevant MeSH terms: Metformin; Empagliflozin

Study Results

Participant Flow

Arm/Group Title	High Dose, Fasted: 1 FDC Tablet First, Then 3 Single Tablets	High Dose, Fasted: 3 Single Tablets First, Then 1 FDC Tablet	High Dose, Fed: 1 FDC Tablet First, Then 3 Single Tablets	High Dose, Fed: 3 Single Tablets First, Then 1 FDC Tablet	Low Dose, Fasted: 2 FDC Tablets First, Then 4 Single Tablets	Low Dose, Fasted: 4 Single Tablets First, Then 2 FDC Tablets
Arm/Group Description	1 fixed dose combination (FDC) tablet first, then 3 single tablets under fasted conditions: 25 mg Empagliflozin/1000 mg Metformin extended release (XR), FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet; 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets	3 single tablets first, then 1 fixed dose combination (FDC) tablet under fasted conditions: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets; 25 mg Empagliflozin/1000 mg Metformin XR, FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet	1 fixed dose combination (FDC) tablet first, then 3 single tablets under fed conditions: 25 mg Empagliflozin/1000 mg Metformin XR, FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet; 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets	3 single tablets first, then 1 fixed dose combination (FDC) tablet under fed conditions: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets; 25 mg Empagliflozin/1000 mg Metformin XR, FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet	2 fixed low dose combination (FDC) tablets first, then 4 single tablets under fasted conditions: 12.5 mg Empagliflozin / 750 mg Metformin XR FDC tablets: Experimental: low dose Empagliflozin/Metformin XR, 2 FDC tablets; 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 3x Metformin XR tablets	4 single tablets first, then 2 fixed low dose combination (FDC) tablets under fasted conditions: 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 3x Metformin XR tablets; 12.5 mg Empagliflozin/750 mg Metformin XR FDC tablets: Experimental: low dose Empagliflozin/Metformin XR, 2 FDC tablets
Period Title: Test Period 1
STARTED	12	12	12	12	12	12
COMPLETED	12	11	12	12	12	12
NOT COMPLETED	0	1	0	0	0	0
Period Title: Test Period 1
STARTED	12	11	12	12	12	12
COMPLETED	12	11	12	12	12	12
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	High Dose, Fasted	High Dose, Fed	Low Dose, Fasted	Total
Arm/Group Description	1 fixed dose combination (FDC) tablet vs. 3 single tablets under fasted conditions: 25 mg Empagliflozin/1000 mg Metformin XR (extended release), FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet; 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets	1 fixed dose combination (FDC) tablet vs. 3 single tablets under fed conditions: 25 mg Empagliflozin/1000 mg Metformin XR, FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet; 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets	2 fixed low dose combination (FDC) tablets vs. 4 single tablets under fasted conditions: 12.5 mg Empagliflozin / 750 mg Metformin XR FDC tablets: Experimental: low dose Empagliflozin/Metformin XR, 2 FDC tablets; 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 3x Metformin XR tablets	Total of all reporting groups
Overall Participants	23	24	24	71
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.4 (8.7)	34.2 (9.2)	30.8 (8.4)	32.5 (8.8)
Gender (Count of Participants)
Female	10 43.5%	10 41.7%	10 41.7%	30 42.3%
Male	13 56.5%	14 58.3%	14 58.3%	41 57.7%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC 0-tz); Empagliflozin
Description	Area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz); Empagliflozin
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): This set includes all subjects of the Treated set (TS) who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of Pharmacokinetic (PK) endpoints.

Arm/Group Title	High Dose, Fasted: 1 FDC Tablet	High Dose, Fasted: 3 Single Tablets	High Dose, Fed: 1 FDC Tablet	High Dose, Fed: 3 Single Tablets	Low Dose, Fasted: 2 FDC Tablets	Low Dose, Fasted: 4 Single Tablets
Arm/Group Description	1 FDC tablet, high dose, fasted: 25 mg Empagliflozin/1000 mg Metformin XR (extended release)	3 single tablets, high dose, fasted: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	1 FDC tablet, high dose, fed: 25 mg Empagliflozin/1000 mg Metformin XR	3 single tablets, high dose, fed: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	2 FDC tablets, low dose, fasted: 12.5 mg Empagliflozin / 750 mg Metformin XR	4 single tablets, low dose, fasted: 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR
Measure Participants	23	23	23	24	24	24
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	6430 (22.3)	6430 (21.7)	5690 (21.0)	5850 (19.6)	7160 (19.5)	7110 (20.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fasted: 1 FDC Tablet, High Dose, Fasted: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	99.98
	Confidence Interval	(2-Sided) 90%; 97.275 to 102.751
	Parameter Dispersion	Type: Standard Deviation; Value: 5.4
	Estimation Comments	Adjusted geometric mean (GM) ratio(%) was calculated as GM of 'High dose, fasted:1 FDC tablet' divided by GM of 'High dose, fasted:3 single tablets'.The 'standard deviation' is actually intra-individual geometric coefficient of variation (gCV (%)).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fed: 1 FDC Tablet, High Dose, Fed: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	97.09
	Confidence Interval	(2-Sided) 90%; 93.857 to 100.436
	Parameter Dispersion	Type: Standard Deviation; Value: 6.7
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fed: 1 FDC tablet' divided by the geometric mean of 'High dose, fed: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Fasted: 2 FDC Tablets, Low Dose, Fasted: 4 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	100.70
	Confidence Interval	(2-Sided) 90%; 98.28 to 103.18
	Parameter Dispersion	Type: Standard Deviation; Value: 4.9
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'Low dose, fasted: 2 FDC tablets' divided by the geometric mean of 'Low dose, fasted: 4 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

2. Primary Outcome

Title	AUC 0-tz (Area Under the Concentration -Time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point); Metformin
Description	AUC 0-tz (area under the concentration -time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point); Metformin
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	High Dose, Fasted: 1 FDC Tablet	High Dose, Fasted: 3 Single Tablets	High Dose, Fed: 1 FDC Tablet	High Dose, Fed: 3 Single Tablets	Low Dose, Fasted: 2 FDC Tablets	Low Dose, Fasted: 4 Single Tablets
Arm/Group Description	1 FDC tablet, high dose, fasted: 25 mg Empagliflozin/1000 mg Metformin XR (extended release)	3 single tablets, high dose, fasted: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	1 FDC tablet, high dose, fed: 25 mg Empagliflozin/1000 mg Metformin XR	3 single tablets, high dose, fed: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	2 FDC tablets, low dose, fasted: 12.5 mg Empagliflozin / 750 mg Metformin XR	4 single tablets, low dose, fasted: 1 x 25 mg tablets Empagliflozin / 3 x 500 mg tablets Metformin XR
Measure Participants	23	23	24	24	24	24
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	6350 (32.8)	6700 (28.9)	13000 (23.6)	13100 (21.1)	10200 (38.5)	10300 (38.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fasted: 1 FDC Tablet, High Dose, Fasted: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	0.0256
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	94.65
	Confidence Interval	(2-Sided) 90%; 82.29 to 108.88
	Parameter Dispersion	Type: Standard Deviation; Value: 28.1
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fasted: 1 FDC tablet' divided by the geometric mean of 'High dose, fasted: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fed: 1 FDC Tablet, High Dose, Fed: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	99.69
	Confidence Interval	(2-Sided) 90%; 96.25 to 103.26
	Parameter Dispersion	Type: Standard Deviation; Value: 7.1
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fed: 1 FDC tablet' divided by the geometric mean of 'High dose, fed: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Fasted: 2 FDC Tablets, Low Dose, Fasted: 4 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	0.0020
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	99.76
	Confidence Interval	(2-Sided) 90%; 88.65 to 112.27
	Parameter Dispersion	Type: Standard Deviation; Value: 24.2
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'Low dose, fasted: 2 FDC tablets' divided by the geometric mean of 'Low dose, fasted: 4 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

3. Secondary Outcome

Title	AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Empagliflozin
Description	AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Empagliflozin
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	High Dose, Fasted: 1 FDC Tablet	High Dose, Fasted: 3 Single Tablets	High Dose, Fed: 1 FDC Tablet	High Dose, Fed: 3 Single Tablets	Low Dose, Fasted: 2 FDC Tablets	Low Dose, Fasted: 4 Single Tablets
Arm/Group Description	1 FDC tablet, high dose, fasted: 25 mg Empagliflozin/1000 mg Metformin XR (extended release)	3 single tablets, high dose, fasted: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	1 FDC tablet, high dose, fed: 25 mg Empagliflozin/1000 mg Metformin XR	3 single tablets, high dose, fed: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	2 FDC tablets, low dose, fasted: 12.5 mg Empagliflozin / 750 mg Metformin XR	4 single tablets, low dose, fasted: 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR
Measure Participants	23	23	23	24	24	24
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	6510 (22.9)	6490 (21.6)	5800 (21.8)	5970 (20.5)	7240 (19.7)	7180 (20.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fasted: 1 FDC Tablet, High Dose, Fasted: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	100.10
	Confidence Interval	(2-Sided) 90%; 97.555 to 102.719
	Parameter Dispersion	Type: Standard Deviation; Value: 5.1
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fasted: 1 FDC tablet' divided by the geometric mean of 'High dose, fasted: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fed: 1 FDC Tablet, High Dose, Fed: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	97.01
	Confidence Interval	(2-Sided) 90%; 93.622 to 100.531
	Parameter Dispersion	Type: Standard Deviation; Value: 7.0
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fed: 1 FDC tablet' divided by the geometric mean of 'High dose, fed: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Fasted: 2 FDC Tablets, Low Dose, Fasted: 4 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	100.78
	Confidence Interval	(2-Sided) 90%; 98.36 to 103.27
	Parameter Dispersion	Type: Standard Deviation; Value: 4.9
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'Low dose, fasted: 2 FDC tablets' divided by the geometric mean of 'Low dose, fasted: 4 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

4. Primary Outcome

Title	Cmax (Maximum Measured Concentration of the Analyte in Plasma); Empagliflozin
Description	Cmax (maximum measured concentration of the analyte in plasma); Empagliflozin
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	High Dose, Fasted: 1 FDC Tablet	High Dose, Fasted: 3 Single Tablets	High Dose, Fed: 1 FDC Tablet	High Dose, Fed: 3 Single Tablets	Low Dose, Fasted: 2 FDC Tablets	Low Dose, Fasted: 4 Single Tablets
Arm/Group Description	1 FDC tablet, high dose, fasted: 25 mg Empagliflozin/1000 mg Metformin XR (extended release)	3 single tablets, high dose, fasted: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	1 FDC tablet, high dose, fed: 25 mg Empagliflozin/1000 mg Metformin XR	3 single tablets, high dose, fed: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	2 FDC tablets, low dose, fasted: 12.5 mg Empagliflozin / 750 mg Metformin XR	4 single tablets, low dose, fasted: 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR
Measure Participants	23	23	23	24	24	24
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	886 (27.3)	810 (28.1)	559 (29.0)	601 (25.0)	1010 (27.0)	963 (29.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fasted: 1 FDC Tablet, High Dose, Fasted: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	0.0072
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	109.07
	Confidence Interval	(2-Sided) 90%; 99.892 to 119.100
	Parameter Dispersion	Type: Standard Deviation; Value: 17.4
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fasted: 1 FDC tablet' divided by the geometric mean of 'High dose, fasted: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fed: 1 FDC Tablet, High Dose, Fed: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	92.42
	Confidence Interval	(2-Sided) 90%; 86.781 to 98.428
	Parameter Dispersion	Type: Standard Deviation; Value: 12.5
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fed: 1 FDC tablet' divided by the geometric mean of 'High dose, fed: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Fasted: 2 FDC Tablets, Low Dose, Fasted: 4 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	105.37
	Confidence Interval	(2-Sided) 90%; 96.600 to 114.942
	Parameter Dispersion	Type: Standard Deviation; Value: 17.7
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'Low dose, fasted: 2 FDC tablets' divided by the geometric mean of 'Low dose, fasted: 4 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

5. Primary Outcome

Title	Cmax (Maximum Measured Concentration of the Analyte in Plasma); Metformin
Description	Cmax (maximum measured concentration of the analyte in plasma); Metformin
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	High Dose, Fasted: 1 FDC Tablet	High Dose, Fasted: 3 Single Tablets	High Dose, Fed: 1 FDC Tablet	High Dose, Fed: 3 Single Tablets	Low Dose, Fasted: 2 FDC Tablets	Low Dose, Fasted: 4 Single Tablets
Arm/Group Description	1 FDC tablet, high dose, fasted: 25 mg Empagliflozin/1000 mg Metformin XR (extended release)	3 single tablets, high dose, fasted: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	1 FDC tablet, high dose, fed: 25 mg Empagliflozin/1000 mg Metformin XR	3 single tablets, high dose, fed: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	2 FDC tablets, low dose, fasted: 12.5 mg Empagliflozin / 750 mg Metformin XR	4 single tablets, low dose, fasted: 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR
Measure Participants	23	23	24	24	24	24
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	822 (37.4)	851 (28.8)	1180 (27.4)	1070 (22.8)	1300 (34.4)	1330 (41.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fasted: 1 FDC Tablet, High Dose, Fasted: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	0.0198
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	96.65
	Confidence Interval	(2-Sided) 90%; 83.337 to 112.079
	Parameter Dispersion	Type: Standard Deviation; Value: 29.8
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fasted: 1 FDC tablet' divided by the geometric mean of 'High dose, fasted: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fed: 1 FDC Tablet, High Dose, Fed: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	110.17
	Confidence Interval	(2-Sided) 90%; 103.809 to 116.926
	Parameter Dispersion	Type: Standard Deviation; Value: 12.0
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fed: 1 FDC tablet' divided by the geometric mean of 'High dose, fed: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Fasted: 2 FDC Tablets, Low Dose, Fasted: 4 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	0.0037
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	97.68
	Confidence Interval	(2-Sided) 90%; 86.942 to 109.734
	Parameter Dispersion	Type: Standard Deviation; Value: 23.8
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'Low dose, fasted: 2 FDC tablets' divided by the geometric mean of 'Low dose, fasted: 4 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

6. Secondary Outcome

Title	AUC 0-infinity (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity); Metformin
Description	AUC 0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity); Metformin
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 20min, 1h 40min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

PKS: This set includes all subjects of the TS who provided at least one observation for at least one primary endpoint and had no important protocol violations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	High Dose, Fasted: 1 FDC Tablet	High Dose, Fasted: 3 Single Tablets	High Dose, Fed: 1 FDC Tablet	High Dose, Fed: 3 Single Tablets	Low Dose, Fasted: 2 FDC Tablets	Low Dose, Fasted: 4 Single Tablets
Arm/Group Description	1 FDC tablet, high dose, fasted: 25 mg Empagliflozin/1000 mg Metformin XR (extended release)	3 single tablets, high dose, fasted: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	1 FDC tablet, high dose, fed: 25 mg Empagliflozin/1000 mg Metformin XR	3 single tablets, high dose, fed: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR	2 FDC tablets, low dose, fasted: 12.5 mg Empagliflozin / 750 mg Metformin XR	4 single tablets, low dose, fasted: 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR
Measure Participants	23	23	24	24	24	24
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	6490 (35.2)	6790 (29.6)	13200 (24.0)	13200 (21.6)	10500 (41.9)	10400 (39.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fasted: 1 FDC Tablet, High Dose, Fasted: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	0.0254
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	95.40
	Confidence Interval	(2-Sided) 90%; 82.42 to 110.44
	Parameter Dispersion	Type: Standard Deviation; Value: 29.4
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fasted: 1 FDC tablet' divided by the geometric mean of 'High dose, fasted: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Fed: 1 FDC Tablet, High Dose, Fed: 3 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	99.63
	Confidence Interval	(2-Sided) 90%; 96.21 to 103.17
	Parameter Dispersion	Type: Standard Deviation; Value: 7.1
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'High dose, fed: 1 FDC tablet' divided by the geometric mean of 'High dose, fed: 3 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Fasted: 2 FDC Tablets, Low Dose, Fasted: 4 Single Tablets
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing.
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (%)
	Estimated Value	101.06
	Confidence Interval	(2-Sided) 90%; 89.70 to 113.86
	Parameter Dispersion	Type: Standard Deviation; Value: 24.4
	Estimation Comments	The adjusted geometric mean ratio (%) was calculated as the geometric mean of 'Low dose, fasted: 2 FDC tablets' divided by the geometric mean of 'Low dose, fasted: 4 single tablets'. The 'standard deviation' is actually the intra-individual gCV (%).

Adverse Events

Time Frame	From first trial medication intake until next intake or the end-of-trial visit, 10 days
Arm/Group Title	High Dose, Fasted: 1 FDC Tablet		High Dose, Fasted: 3 Single Tablets		High Dose, Fed: 1 FDC Tablet		High Dose, Fed: 3 Single Tablets		Low Dose, Fasted: 2 FDC Tablets		Low Dose, Fasted: 4 Single Tablets
Arm/Group Description	1 fixed dose combination (FDC) tablet under fasted conditions: 25 mg Empagliflozin/1000 mg Metformin XR (extended release), FDC: Experimental, high dose Empagliflozin/Metformin XR, FDC tablet		3 single tablets under fasted conditions: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets		1 fixed dose combination (FDC) tablet under fed conditions: 25 mg Empagliflozin/1000 mg Metformin XR, FDC: Experimental, high dose Empagliflozin/Metformin XR,FDC tablet		3 single tablets under fed conditions: 1 x 25 mg tablet Empagliflozin / 2 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 2x Metformin XR tablets		2 fixed dose combination (FDC) tablets under fasted conditions: 12.5 mg Empagliflozin / 750 mg Metformin XR FDC tablets: Experimental: low dose Empagliflozin/Metformin XR, 2 FDC tablets		4 single tablets under fed conditions: 1 x 25 mg tablet Empagliflozin / 3 x 500 mg tablets Metformin XR: Active Comparator: 1x Empagliflozin / 3x Metformin XR tablets
All Cause Mortality
	High Dose, Fasted: 1 FDC Tablet		High Dose, Fasted: 3 Single Tablets		High Dose, Fed: 1 FDC Tablet		High Dose, Fed: 3 Single Tablets		Low Dose, Fasted: 2 FDC Tablets		Low Dose, Fasted: 4 Single Tablets
	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
	High Dose, Fasted: 1 FDC Tablet		High Dose, Fasted: 3 Single Tablets		High Dose, Fed: 1 FDC Tablet		High Dose, Fed: 3 Single Tablets		Low Dose, Fasted: 2 FDC Tablets		Low Dose, Fasted: 4 Single Tablets
	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%)		0/24 (0%)		0/24 (0%)		0/24 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	High Dose, Fasted: 1 FDC Tablet		High Dose, Fasted: 3 Single Tablets		High Dose, Fed: 1 FDC Tablet		High Dose, Fed: 3 Single Tablets		Low Dose, Fasted: 2 FDC Tablets		Low Dose, Fasted: 4 Single Tablets
	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	4/23 (17.4%)		1/23 (4.3%)		1/24 (4.2%)		2/24 (8.3%)		4/24 (16.7%)		1/24 (4.2%)
Gastrointestinal disorders
Abdominal pain	0/23 (0%)		0/23 (0%)		0/24 (0%)		0/24 (0%)		3/24 (12.5%)		0/24 (0%)
Nausea	2/23 (8.7%)		1/23 (4.3%)		1/24 (4.2%)		2/24 (8.3%)		0/24 (0%)		1/24 (4.2%)
Nervous system disorders
Headache	3/23 (13%)		0/23 (0%)		0/24 (0%)		1/24 (4.2%)		2/24 (8.3%)		0/24 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Other - Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.