Bioequivalence of Empagliflozin and Metformin Given as a Fixed Dose Combination Compared to Single Tablets

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01844531
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 4
• Duration (Months): 7
• Patients Per Site Per Month: 3.4

Study Details

Study Description

Brief Summary

The primary objective of this trial is to establish bioequivalence of two fixed dose combination (FDC) tablets (containing medium dose empagliflozin/500 mg metformin [Test 1] and low dose empagliflozin/500 mg metformin [Test 2]) and of the single tablets (medium dose empagliflozin tablets + Glucophage® 500 mg tablet [Reference 1] and low dose empagliflozin tablet + Glucophage® 500 mg tablet [Reference 2]) when administered together after a high fat, high caloric meal.

The assessment of safety and tolerability will be an additional objective of this trial.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: empagliflozin; Drug: metformin (Glucophage®); Drug: metformin (Glucophage®); Drug: empagliflozin; Drug: empagliflozin and metformin; Drug: empagliflozin and metformin	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bioequivalence of Empagliflozin/Metformin (500 mg) Fixed Dose Combination Tablets Compared to Single Tablets Administered Together in Healthy Male and Female Volunteers Under Fed Conditions (an Open-label, Randomised, Single-dose, Four-way Crossover Study)
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Nov 1, 2013
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FDC empagliflozin dose 1 and metformin fix dose combination tablet after intake of a high fat, high caloric meal	Drug: empagliflozin and metformin; FDC tablet empagliflozin and metformin
Active Comparator: empagliflozin dose 1 + metformin tablets single tablets after intake of a high fat, high caloric meal	Drug: empagliflozin; single tablet empagliflozin; Drug: metformin (Glucophage®); single tablet metformin
Experimental: FDC empagliflozin dose 2 and metformin fix dose combination tablet after intake of a high fat, high caloric meal	Drug: empagliflozin and metformin; FDC tablet empagliflozin and metformin
Active Comparator: empagliflozin dose 2 + metformin tablets single tablets after intake of a high fat, high caloric meal	Drug: metformin (Glucophage®); single tablet metformin; Drug: empagliflozin; single tablet empagliflozin

Outcome Measures

Primary Outcome Measures

1. AUC0-∞ for Empagliflozin [1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake]

   AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin

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

   AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin

3. Cmax for Empagliflozin [1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake]

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

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

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

Secondary Outcome Measures

1. AUC0-tz for Empagliflozin [1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake]

   AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) for Empagliflozin

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

   AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) for 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 male and female subjects

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

3. Age 18 to 50 years

4. Body mass index (BMI) 18.5 to 29.9 kg/m2

Exclusion criteria:

1. Any relevant deviation from healthy conditions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1276.6.1 Boehringer Ingelheim Investigational Site	Biberach		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

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: NCT01844531
• Other Study ID Numbers: 1276.6; 2012-000082-20
• First Posted: May 1, 2013
• Last Update Posted: Jul 27, 2015
• Last Verified: Jun 1, 2015

• Additional relevant MeSH terms: Metformin; Empagliflozin

Study Results

Participant Flow

Arm/Group Title	FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500	Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5	FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500	Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5
Arm/Group Description	Participants first received Treatment T1 (12.5 mg empagliflozin/500 mg metformin Fixed Dose Combination (FDC)). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Participants first received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). Oral administration.	Participants first received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets)Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Participants first received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). Oral administration.
Period Title: Overall Study
STARTED	6	6	6	6
COMPLETED	6	5	6	6
NOT COMPLETED	0	1	0	0

Baseline Characteristics

Arm/Group Title	FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500	Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5	FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500	Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5	Total
Arm/Group Description	Participants first received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Participants first received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). Oral administration.	Participants first received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets)Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Participants first received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). Oral administration.	Total of all reporting groups
Overall Participants	6	6	6	6	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.2 (8.6)	30.8 (7.6)	35.8 (10.5)	37.5 (9.0)	35.6 (8.9)
Sex: Female, Male (Count of Participants)
Female	5 83.3%	2 33.3%	4 66.7%	4 66.7%	15 62.5%
Male	1 16.7%	4 66.7%	2 33.3%	2 33.3%	9 37.5%

Outcome Measures

1. Primary Outcome

Title	AUC0-∞ for Empagliflozin
Description	AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin
Time Frame	1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Outcome Measure Data

Analysis Population Description

Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Arm/Group Title	12.5 mg Empagliflozin and 500 mg Metformin as FDC	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets	5 mg Empagliflozin and 500 mg Metformin as FDC	5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Arm/Group Description	12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Measure Participants	21	23	23	20
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	2780 (16.1)	2870 (17.3)	1110 (15.7)	1070 (19.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments	Model included effects:sequence;subjects within sequences;period and treatment with subjects within sequences as random effect.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	97.92
	Confidence Interval	(2-Sided) 90%; 93.529 to 102.520
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.4
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Model included effects:sequence;subjects within sequences;period and treatment with all effects as fixed.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	98.00
	Confidence Interval	(2-Sided) 90%; 93.57 to 102.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.3
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500 , PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments	Model included effects:sequence;subjects within sequences;period and treatment with subjects within sequences as random effect.
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	102.79
	Confidence Interval	(2-Sided) 90%; 99.077 to 106.633
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.7
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 (T2) : Empa5 + Met500 (R2), PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	102.50
	Confidence Interval	(2-Sided) 90%; 98.78 to 106.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.7
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

2. Primary Outcome

Title	AUC0-∞ for Metformin
Description	AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin
Time Frame	1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Outcome Measure Data

Analysis Population Description

Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Arm/Group Title	12.5 mg Empagliflozin and 500 mg Metformin as FDC	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets	5 mg Empagliflozin and 500 mg Metformin as FDC	5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Arm/Group Description	12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Measure Participants	21	23	23	20
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	5590 (19.0)	5820 (21.8)	5960 (18.0)	6190 (19.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	96.25
	Confidence Interval	(2-Sided) 90%; 88.542 to 104.628
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.4
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 (T1) : Empa12.5 + Met500 (R1), PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	97.21
	Confidence Interval	(2-Sided) 90%; 89.41 to 105.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.1
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	96.79
	Confidence Interval	(2-Sided) 90%; 91.772 to 102.093
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.8
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	96.91
	Confidence Interval	(2-Sided) 90%; 91.79 to 102.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.8
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

3. Secondary Outcome

Title	AUC0-tz for Empagliflozin
Description	AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) for Empagliflozin
Time Frame	1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Outcome Measure Data

Analysis Population Description

Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Arm/Group Title	12.5 mg Empagliflozin and 500 mg Metformin as FDC	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets	5 mg Empagliflozin and 500 mg Metformin as FDC	5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Arm/Group Description	12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Measure Participants	21	23	23	20
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	2740 (16.3)	2830 (17.3)	1080 (15.7)	1040 (19.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	98.00
	Confidence Interval	(2-Sided) 90%; 93.530 to 102.686
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.5
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	98.07
	Confidence Interval	(2-Sided) 90%; 93.55 to 102.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.5
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	102.77
	Confidence Interval	(2-Sided) 90%; 99.146 to 106.522
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.5
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	102.49
	Confidence Interval	(2-Sided) 90%; 98.85 to 106.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.5
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

4. Primary Outcome

Title	Cmax for Empagliflozin
Description	Cmax (maximum measured concentration of the analyte in plasma) for Empagliflozin
Time Frame	1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Outcome Measure Data

Analysis Population Description

Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Arm/Group Title	12.5 mg Empagliflozin and 500 mg Metformin as FDC	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets	5 mg Empagliflozin and 500 mg Metformin as FDC	5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Arm/Group Description	12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Measure Participants	21	23	23	20
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	294 (23.7)	282 (27.4)	109 (22.8)	106 (22.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	104.61
	Confidence Interval	(2-Sided) 90%; 99.882 to 109.555
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.4
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	104.53
	Confidence Interval	(2-Sided) 90%; 99.76 to 109.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.4
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	102.96
	Confidence Interval	(2-Sided) 90%; 97.917 to 108.258
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.2
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	102.80
	Confidence Interval	(2-Sided) 90%; 97.72 to 108.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.2
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

5. Primary Outcome

Title	Cmax for Metformin
Description	Cmax (maximum measured concentration of the analyte in plasma) for Metformin
Time Frame	1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Outcome Measure Data

Analysis Population Description

Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Arm/Group Title	12.5 mg Empagliflozin and 500 mg Metformin as FDC	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets	5 mg Empagliflozin and 500 mg Metformin as FDC	5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Arm/Group Description	12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Measure Participants	21	23	23	20
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	686 (14.1)	718 (19.7)	693 (12.8)	743 (19.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	94.76
	Confidence Interval	(2-Sided) 90%; 89.056 to 100.819
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.4
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	94.40
	Confidence Interval	(2-Sided) 90%; 88.64 to 100.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.4
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	93.83
	Confidence Interval	(2-Sided) 90%; 88.006 to 100.034
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.9
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	93.98
	Confidence Interval	(2-Sided) 90%; 87.94 to 100.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.0
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

6. Secondary Outcome

Title	AUC0-tz for Metformin
Description	AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) for Metformin
Time Frame	1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Outcome Measure Data

Analysis Population Description

Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Arm/Group Title	12.5 mg Empagliflozin and 500 mg Metformin as FDC	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets	5 mg Empagliflozin and 500 mg Metformin as FDC	5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Arm/Group Description	12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Measure Participants	21	23	23	20
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	5480 (18.9)	5720 (21.2)	5820 (17.7)	6110 (19.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	95.78
	Confidence Interval	(2-Sided) 90%; 88.000 to 104.256
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.7
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	96.74
	Confidence Interval	(2-Sided) 90%; 88.78 to 105.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.5
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	95.94
	Confidence Interval	(2-Sided) 90%; 91.199 to 100.934
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.3
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Comments	Adjusted by-treatment geometric means and relative bioavailability - analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio FDC/single tablets
	Estimated Value	96.10
	Confidence Interval	(2-Sided) 90%; 91.28 to 101.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.3
	Estimation Comments	*Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].

Adverse Events

Time Frame	From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)
Arm/Group Title	12.5 mg Empagliflozin and 500 mg Metformin as FDC		12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets		5 mg Empagliflozin and 500 mg Metformin as FDC		5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Arm/Group Description	12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration		12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration		5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration		5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
All Cause Mortality
	12.5 mg Empagliflozin and 500 mg Metformin as FDC		12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets		5 mg Empagliflozin and 500 mg Metformin as FDC		5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	12.5 mg Empagliflozin and 500 mg Metformin as FDC		12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets		5 mg Empagliflozin and 500 mg Metformin as FDC		5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/23 (0%)		0/23 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	12.5 mg Empagliflozin and 500 mg Metformin as FDC		12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets		5 mg Empagliflozin and 500 mg Metformin as FDC		5 mg Empagliflozin and 500 mg Metformin as Single Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/21 (14.3%)		6/23 (26.1%)		3/23 (13%)		2/20 (10%)
Gastrointestinal disorders
Diarrhoea	1/21 (4.8%)		2/23 (8.7%)		2/23 (8.7%)		2/20 (10%)
Nausea	0/21 (0%)		2/23 (8.7%)		1/23 (4.3%)		0/20 (0%)
Vomiting	0/21 (0%)		2/23 (8.7%)		0/23 (0%)		0/20 (0%)
Nervous system disorders
Headache	2/21 (9.5%)		3/23 (13%)		2/23 (8.7%)		0/20 (0%)

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.