Demonstration of Bioequivalence of Empagliflozin and Metformin Given in One Tablet Compared to the Intake of Single Tablets

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01672788
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 4
• Duration (Months): 3
• Patients Per Site Per Month: 11.9

Study Details

Study Description

Brief Summary

The primary objective of this trial is to establish bioequivalence of two FDC tablets and the single tablets when administered together after a high fat high caloric meal.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Empagliflozin; Drug: Empagliflozin + Metformin; Drug: Metformin; Drug: Metformin; Drug: Empagliflozin + Metformin; Drug: Empagliflozin	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bioequivalence of Empagliflozin/Metformin (850 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: Aug 1, 2012
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Test 1 fixed dose combination tablet	Drug: Empagliflozin + Metformin; fixed dose combination tablet (low)
Active Comparator: Reference 1 empagliflozin tablets and metformin tablet	Drug: Empagliflozin; empagliflozin tablets and metformin tablet; Drug: Metformin; empagliflozin tablets and metformin tablet
Experimental: Test 2 fixed dose combination tablet	Drug: Empagliflozin + Metformin; fixed dose combination tablet (low)
Active Comparator: Reference 2 empagliflozin tablet and metformin tablet	Drug: Metformin; empagliflozin tablet and metformin tablet; Drug: Empagliflozin; empagliflozin tablet and metformin tablet

Outcome Measures

Primary Outcome Measures

1. Empa: Area Under the Curve 0 to Infinity (AUC0-∞) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

2. Metformin: Area Under the Curve 0 to Infinity (AUC0-∞) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

3. Empa: Maximum Measured Concentration (Cmax) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration]

   Maximum measured concentration of the analyte in plasma, per period. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

4. Metformin: Maximum Measured Concentration (Cmax) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration]

   Maximum measured concentration of the analyte in plasma, per period. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Secondary Outcome Measures

1. Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 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. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

2. Metformin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) [1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 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. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

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

Exclusion criteria:

1. Any relevant deviation from healthy conditions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1276.7.1 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: NCT01672788
• Other Study ID Numbers: 1276.7; 2012-002277-65
• First Posted: Aug 27, 2012
• Last Update Posted: Aug 31, 2015
• Last Verified: Aug 1, 2015

• Additional relevant MeSH terms: Metformin; Empagliflozin

Study Results

Participant Flow

Pre-assignment Detail	This was an open-label, randomized, 4-way crossover trial. 36 patients were randomised to one of 4 treatment sequences and treated. Each treatment period consisted of a single dose of medication followed by 72 hours of pharmacokinetic sampling, with a washout of at least 7 days between treatment periods.

Arm/Group Title	T1 / R1 / T2 / R2	R1 / T1 / R2 / T2	T2 / R2 / T1 / R1	R2 / T2 / R1 / T1
Arm/Group Description	Patients received the 4 treatments in the following order: Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1) Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1) Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2) Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)	Patients received the 4 treatments in the following order: Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1) Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1) Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2) Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)	Patients received the 4 treatments in the following order: Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2) Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2) Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1) Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)	Patients received the 4 treatments in the following order: Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2) Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2) Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1) Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
Period Title: Treatment Period 1 (3 Days)
STARTED	9	9	9	9
COMPLETED	9	9	9	9
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (3 Days)
STARTED	9	9	9	9
COMPLETED	9	9	9	9
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (3 Days)
STARTED	9	9	9	9
COMPLETED	9	9	9	9
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (3 Days)
STARTED	9	9	9	9
COMPLETED	9	9	9	8
NOT COMPLETED	0	0	0	1
Period Title: Treatment Period 1 (3 Days)
STARTED	9	9	9	8
COMPLETED	9	9	9	8
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (3 Days)
STARTED	9	9	9	8
COMPLETED	9	9	9	8
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (3 Days)
STARTED	9	9	9	8
COMPLETED	9	9	9	8
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Total number of patients randomised and treated in the study. This was an open-label, randomized, 4-way crossover trial. 36 patients were randomised to one of 4 treatment sequences and treated. Each treatment period consisted of a single dose of medication followed by 72hours of pharmacokinetic sampling, with a washout of at least 7 days between treatment periods.
Overall Participants	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.6 (9.2)
Sex: Female, Male (Count of Participants)
Female	14 38.9%
Male	22 61.1%

Outcome Measures

1. Primary Outcome

Title	Empa: Area Under the Curve 0 to Infinity (AUC0-∞)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications

Arm/Group Title	Empa 12.5mg Fixed-dose	Empa 12.5mg Free Dose	Empa 5mg Fixed-dose	Empa 5mg Free Dose
Arm/Group Description	Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin	Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)	Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin	Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
Measure Participants	34	34	35	33
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	2560 (25.5)	2530 (29.5)	986 (26.9)	968 (23.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa 12.5mg Fixed-dose, Empa 12.5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	101.31
	Confidence Interval	(2-Sided) 90%; 96.89 to 105.93
	Parameter Dispersion	Type: Standard Deviation; Value: 10.7
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empa 5mg Fixed-dose, Empa 5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	100.30
	Confidence Interval	(2-Sided) 90%; 97.40 to 103.29
	Parameter Dispersion	Type: Standard Deviation; Value: 7.0
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

2. Primary Outcome

Title	Metformin: Area Under the Curve 0 to Infinity (AUC0-∞)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications

Arm/Group Title	Empa 12.5mg Fixed-dose	Empa 12.5mg Free Dose	Empa 5mg Fixed-dose	Empa 5mg Free Dose
Arm/Group Description	Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin	Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)	Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin	Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
Measure Participants	34	34	35	33
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	8640 (18.0)	8450 (24.4)	8520 (23.8)	8560 (25.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa 12.5mg Fixed-dose, Empa 12.5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	101.61
	Confidence Interval	(2-Sided) 90%; 97.94 to 105.41
	Parameter Dispersion	Type: Standard Deviation; Value: 8.8
	Estimation Comments	Standard deviation is actually the gCV

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empa 5mg Fixed-dose, Empa 5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	98.56
	Confidence Interval	(2-Sided) 90%; 94.24 to 103.08
	Parameter Dispersion	Type: Standard Deviation; Value: 10.8
	Estimation Comments	Standard deviation is actually the gCV

3. Secondary Outcome

Title	Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications

Arm/Group Title	Empa 12.5mg Fixed-dose	Empa 12.5mg Free Dose	Empa 5mg Fixed-dose	Empa 5mg Free Dose
Arm/Group Description	Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin	Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)	Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin	Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
Measure Participants	34	34	35	33
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	2520 (25.1)	2490 (29.3)	963 (27.1)	946 (24.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa 12.5mg Fixed-dose, Empa 12.5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	101.20
	Confidence Interval	(2-Sided) 90%; 96.89 to 105.71
	Parameter Dispersion	Type: Standard Deviation; Value: 10.4
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empa 5mg Fixed-dose, Empa 5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	100.31
	Confidence Interval	(2-Sided) 90%; 97.41 to 103.30
	Parameter Dispersion	Type: Standard Deviation; Value: 7.0
	Estimation Comments	Standard deviation is actually the gCV

4. Primary Outcome

Title	Empa: Maximum Measured Concentration (Cmax)
Description	Maximum measured concentration of the analyte in plasma, per period. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications

Arm/Group Title	Empa 12.5mg Fixed-dose	Empa 12.5mg Free Dose	Empa 5mg Fixed-dose	Empa 5mg Free Dose
Arm/Group Description	Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin	Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)	Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin	Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
Measure Participants	34	34	35	33
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	266 (20.3)	258 (21.3)	103 (22.1)	101 (24.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa 12.5mg Fixed-dose, Empa 12.5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	102.70
	Confidence Interval	(2-Sided) 90%; 98.75 to 106.81
	Parameter Dispersion	Type: Standard Deviation; Value: 9.4
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empa 5mg Fixed-dose, Empa 5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	100.97
	Confidence Interval	(2-Sided) 90%; 95.94 to 106.27
	Parameter Dispersion	Type: Standard Deviation; Value: 12.3
	Estimation Comments	Standard deviation is actually the gCV

5. Primary Outcome

Title	Metformin: Maximum Measured Concentration (Cmax)
Description	Maximum measured concentration of the analyte in plasma, per period. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications

Arm/Group Title	Empa 12.5mg Fixed-dose	Empa 12.5mg Free Dose	Empa 5mg Fixed-dose	Empa 5mg Free Dose
Arm/Group Description	Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin	Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)	Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin	Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
Measure Participants	34	34	35	33
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1080 (16.4)	1080 (19.6)	1090 (16.5)	1100 (17.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa 12.5mg Fixed-dose, Empa 12.5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose .
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	99.64
	Confidence Interval	(2-Sided) 90%; 95.39 to 104.09
	Parameter Dispersion	Type: Standard Deviation; Value: 10.5
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empa 5mg Fixed-dose, Empa 5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	97.89
	Confidence Interval	(2-Sided) 90%; 93.82 to 102.15
	Parameter Dispersion	Type: Standard Deviation; Value: 10.2
	Estimation Comments	Standard deviation is actually the gCV

6. Secondary Outcome

Title	Metformin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications

Arm/Group Title	Empa 12.5mg Fixed-dose	Empa 12.5mg Free Dose	Empa 5mg Fixed-dose	Empa 5mg Free Dose
Arm/Group Description	Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin	Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)	Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin	Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
Measure Participants	34	34	35	33
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	8370 (18.1)	8190 (24.1)	8280 (23.2)	8320 (25.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa 12.5mg Fixed-dose, Empa 12.5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose .
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	101.51
	Confidence Interval	(2-Sided) 90%; 97.95 to 105.21
	Parameter Dispersion	Type: Standard Deviation; Value: 8.6
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empa 5mg Fixed-dose, Empa 5mg Free Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose .
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	98.57
	Confidence Interval	(2-Sided) 90%; 94.50 to 102.81
	Parameter Dispersion	Type: Standard Deviation; Value: 10.1
	Estimation Comments	Standard deviation is actually the gCV

Adverse Events

Time Frame	Treatment period and following washout period, up to 35 days
Arm/Group Title	Empa 12.5mg Fixed-dose		Empa 12.5mg Free Dose		Empa 5mg Fixed-dose		Empa 5mg Free Dose
Arm/Group Description	Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin		Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)		Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin		Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
All Cause Mortality
	Empa 12.5mg Fixed-dose		Empa 12.5mg Free Dose		Empa 5mg Fixed-dose		Empa 5mg Free Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Empa 12.5mg Fixed-dose		Empa 12.5mg Free Dose		Empa 5mg Fixed-dose		Empa 5mg Free Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/36 (0%)		0/34 (0%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Empa 12.5mg Fixed-dose		Empa 12.5mg Free Dose		Empa 5mg Fixed-dose		Empa 5mg Free Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/35 (40%)		13/36 (36.1%)		14/34 (41.2%)		9/35 (25.7%)
Gastrointestinal disorders
Diarrhoea	8/35 (22.9%)		8/36 (22.2%)		5/34 (14.7%)		7/35 (20%)
Nausea	3/35 (8.6%)		1/36 (2.8%)		0/34 (0%)		1/35 (2.9%)
Vomiting	2/35 (5.7%)		1/36 (2.8%)		0/34 (0%)		1/35 (2.9%)
Nasopharyngitis	3/35 (8.6%)		2/36 (5.6%)		4/34 (11.8%)		0/35 (0%)
Nervous system disorders
Headache	5/35 (14.3%)		3/36 (8.3%)		5/34 (14.7%)		2/35 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.