This Study Tests Whether Taking the Medicines Empagliflozin, Linagliptin, and Metformin Together in 1 Pill is the Same as Taking Them in Separate Pills. The Study is Done in Healthy Men and Women and Measures the Amount of Each Medicine in the Blood

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03259490
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 2.4
• Patients Per Site Per Month: 12.3

Study Details

Study Description

Brief Summary

To establish the bioequivalence of one fixed dose combination (FDC) tablet of empagliflozin/linagliptin/metformin extended release (XR) versus the free combination of empagliflozin tablet, linagliptin tablet, and metformin XR tablets administered as a single dose under fed conditions

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Empagliflozin/linagliptin/metformin HCl; Drug: Empagliflozin; Drug: Linagliptin; Drug: Metformin HCl	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bioequivalence of a Fixed Dose Combination Tablet of Empagliflozin/Linagliptin/Metformin Extended Release Compared to the Free Combination of Empagliflozin, Linagliptin, and Metformin Extended Release Tablets Following Oral Administration in Healthy Male and Female Subjects (an Open-label, Randomised, Single-dose, Two-period, Two-sequence Crossover Study)
• Actual Study Start Date: Aug 31, 2017
• Actual Primary Completion Date: Nov 13, 2017
• Actual Study Completion Date: Nov 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Test Treatment High dose empagliflozin/linagliptin/metformin XR fixed dose combination tablet	Drug: Empagliflozin/linagliptin/metformin HCl; Once daily; Other Names: TRIJARDY® XR
Experimental: Reference Treatment Single tablets of empagliflozin + linagliptin + metformin XR	Drug: Empagliflozin; Once daily; Drug: Linagliptin; Once daily; Drug: Metformin HCl; Once daily

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 (AUC0-tz) for Empagliflozin [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) for empagliflozin. Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example: The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis) A predose concentration was >5% Cmax value of that subject Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve. Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.

2. AUC0-tz for Metformin. [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   AUC0-tz for metformin.

3. Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin

4. Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   Maximum measured concentration of the empagliflozin in plasma (Cmax)

5. Cmax for Metformin in Plasma [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   Cmax for metformin in plasma.

6. Cmax for Linagliptin in Plasma [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   Cmax for linagliptin in plasma.

Secondary Outcome Measures

1. Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞) [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

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

2. AUC(0-∞) for Metformin [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   AUC(0-∞) for Metformin

3. AUC(0-∞) for Linagliptin [Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose]

   AUC(0-∞) for Linagliptin

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male or female subjects according to the assessment of the investigator, based on a complete medical history including a physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests

• Age of 18 to 55 years (incl.)

• BMI of 18.5 to 29.9 kg/m2 (incl.)

• Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation

• Female subjects of childbearing potential willing to use adequate contraception.

• Further inclusion criteria apply

Exclusion Criteria:

• Any finding in the medical examination (including Blood Pressure (BP), Pulse Rate (PR), or Electrocardiogram (ECG)) is deviating from normal and judged as clinically relevant by the investigator

• Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 beats per minute (BPM)

• Any laboratory value outside the reference range that the investigator considers to be of clinical relevance

• Any evidence of a concomitant disease judged as clinically relevant by the investigator

• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorders

• Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders

• Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Humanpharmakologisches Zentrum Biberach	Biberach		Germany	88397

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 28, 2017
• Statistical Analysis Plan - Dec 8, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03259490
• Other Study ID Numbers: 1361-0003; 2017-000425-12
• First Posted: Aug 23, 2017
• Last Update Posted: Mar 5, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Metformin; Empagliflozin; Linagliptin

Study Results

Participant Flow

Recruitment Details	It was planned to include healthy male and female subjects in this randomised, open label study. They were recruited from the volunteers' pool of the study site.
Pre-assignment Detail	This trial was a two-way crossover study. All subjects received the 2 treatments in randomised order.

Arm/Group Title	Test/ Reference (TR)	Reference/ Test (RT)
Arm/Group Description	Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.	Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.
Period Title: Period 1
STARTED	15	15
COMPLETED	15	14
NOT COMPLETED	0	1
Period Title: Period 1
STARTED	15	14
COMPLETED	14	14
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Test/ Reference (TR)	Reference/ Test (RT)	Total
Arm/Group Description	Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.	Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.1 (12.2)	43.5 (8.0)	40.3 (10.7)
Sex: Female, Male (Count of Participants)
Female	5 33.3%	8 53.3%	13 43.3%
Male	10 66.7%	7 46.7%	17 56.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	15 100%	15 100%	30 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

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 (AUC0-tz) for 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 (AUC0-tz) for empagliflozin. Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example: The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis) A predose concentration was >5% Cmax value of that subject Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve. Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [nanomoles*hours/ litres (nmol*h/L)]	5656.07 (1.04)	5488.31 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	103.06
	Confidence Interval	(2-Sided) 95%; 100.36 to 105.83
	Parameter Dispersion	Type: Standard Deviation; Value: 5.8
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

2. Primary Outcome

Title	AUC0-tz for Metformin.
Description	AUC0-tz for metformin.
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [nanogram*hours/ millilitres (ng*h/mL)]	12455.82 (1.05)	12412.57 (1.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	100.35
	Confidence Interval	(2-Sided) 95%; 96.11 to 104.77
	Parameter Dispersion	Type: Standard Deviation; Value: 9.5
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

3. Primary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [nmol*h/L]	238.84 (1.04)	238.11 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	100.31
	Confidence Interval	(2-Sided) 95%; 96.65 to 104.10
	Parameter Dispersion	Type: Standard Deviation; Value: 8.2
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

4. Primary Outcome

Title	Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)
Description	Maximum measured concentration of the empagliflozin in plasma (Cmax)
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [nmol/L]	540.01 (1.04)	540.26 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	99.95
	Confidence Interval	(2-Sided) 95%; 94.52 to 105.70
	Parameter Dispersion	Type: Standard Deviation; Value: 12.4
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

5. Primary Outcome

Title	Cmax for Metformin in Plasma
Description	Cmax for metformin in plasma.
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [ng/mL]	1237.16 (1.04)	1147.88 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	107.78
	Confidence Interval	(2-Sided) 95%; 102.52 to 113.31
	Parameter Dispersion	Type: Standard Deviation; Value: 11.0
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

6. Primary Outcome

Title	Cmax for Linagliptin in Plasma
Description	Cmax for linagliptin in plasma.
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [nmol/L]	5.69 (1.04)	5.86 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	97.17
	Confidence Interval	(2-Sided) 95%; 92.63 to 101.93
	Parameter Dispersion	Type: Standard Deviation; Value: 10.6
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

7. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [nmol*h/L]	5727.20 (1.04)	5554.37 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	103.11
	Confidence Interval	(2-Sided) 95%; 100.38 to 105.92
	Parameter Dispersion	Type: Standard Deviation; Value: 5.9
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

8. Secondary Outcome

Title	AUC(0-∞) for Metformin
Description	AUC(0-∞) for Metformin
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [ng*h/mL]	12745.62 (1.05)	12724.27 (1.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	100.17
	Confidence Interval	(2-Sided) 95%; 95.68 to 104.86
	Parameter Dispersion	Type: Standard Deviation; Value: 10.1
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

9. Secondary Outcome

Title	AUC(0-∞) for Linagliptin
Description	AUC(0-∞) for Linagliptin
Time Frame	Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)	Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast	Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
Measure Participants	29	29
Geometric Mean (Standard Error) [nmol*h/L]	384.27 (1.05)	394.95 (1.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin/Linagliptin/Metformin FDC (Test), Empagliflozin/Linagliptin/Metformin FC (Reference)
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gmean ratio T/R (%)
	Estimated Value	97.30
	Confidence Interval	(2-Sided) 95%; 91.65 to 103.29
	Parameter Dispersion	Type: Standard Deviation; Value: 13.2
	Estimation Comments	The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

Adverse Events

Time Frame	All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
Adverse Event Reporting Description	REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
Arm/Group Title	Empagliflozin/Linagliptin/Metformin FDC (Test)		Empagliflozin/Linagliptin/Metformin FC (Reference)
Arm/Group Description	Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast		Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
All Cause Mortality
	Empagliflozin/Linagliptin/Metformin FDC (Test)		Empagliflozin/Linagliptin/Metformin FC (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/29 (0%)
Serious Adverse Events
	Empagliflozin/Linagliptin/Metformin FDC (Test)		Empagliflozin/Linagliptin/Metformin FC (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/29 (0%)
Other (Not Including Serious) Adverse Events
	Empagliflozin/Linagliptin/Metformin FDC (Test)		Empagliflozin/Linagliptin/Metformin FC (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/29 (37.9%)		6/29 (20.7%)
Gastrointestinal disorders
Nausea	1/29 (3.4%)		2/29 (6.9%)
Infections and infestations
Oral herpes	2/29 (6.9%)		0/29 (0%)
Nervous system disorders
Headache	8/29 (27.6%)		2/29 (6.9%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/29 (3.4%)		2/29 (6.9%)

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.