Bioequivalence of a Fixed Dose Combination Tablet of Empagliflozin/Linagliptin Compared With the Free Combination of Empagliflozin Tablet and Linagliptin Tablet in Healthy Male and Female Subjects

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02758171
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 56
• Location: 1
• Arms: 2
• Actual Duration (Months): 2.6
• Patients Per Site Per Month: 21.9

Study Details

Study Description

Brief Summary

The primary objective of this trial is to investigate the bioequivalence of one fixed dose combination tablet of empagliflozin/linagliptin (Test, T) compared with the free combination of one empagliflozin tablet and one linagliptin tablet (Reference, R) administered as single dose under fasted conditions.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 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 Compared With the Free Combination of Empagliflozin Tablet and Linagliptin Tablet in Healthy Male and Female Subjects (an Open-label, Randomised, Single-dose, Crossover Study)
• Actual Study Start Date: May 17, 2016
• Actual Primary Completion Date: Jul 29, 2016
• Actual Study Completion Date: Aug 3, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Empagliflozin+Linagliptin FDC One tablet fix dose combination (FDC)	Drug: Empagliflozin; Drug: Linagliptin
Active Comparator: Empagliflozin+Linagliptin single tablets	Drug: Empagliflozin; Drug: Linagliptin

Outcome Measures

Primary Outcome Measures

1. AUC0-tz (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) [1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.]

   This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point. Time frame description: The time -1:00 hour (h) was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-tz (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point).

2. AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours) [1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.]

   This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-72 (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours).

3. Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma) [1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.]

   This outcome measure presents maximum measured concentration of Empagliflozin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Empagliflozin analyte in plasma).

4. Cmax (Maximum Measured Concentration of Linagliptin Analyte in Plasma) [1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.]

   This outcome measure presents maximum measured concentration of Linagliptin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Linagliptin analyte in plasma).

Secondary Outcome Measures

1. AUC0-infinity (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) [1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.]

   This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-infinity (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity).

2. AUC0-infinity (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity) [1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.]

   This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity).

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 investigators assessment, 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.)

• Body Mass Index (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 GCP (Good Clinical Practice) and local legislation

• Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and until 30 days after trial completion:

• Use of adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral or vaginal contraceptives, intrauterine device

• Sexually abstinent

• A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)

• Surgically sterilised (including hysterectomy)

• Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of FSH (Follicle Stimulating Hormone) above 40 U/L and estradiol below 30 ng/L is confirmatory)

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 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

• Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)

• 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

• 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: NCT02758171
• Other Study ID Numbers: 1275.21; 2015-004234-98
• First Posted: May 2, 2016
• Last Update Posted: Nov 22, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Empagliflozin; Linagliptin

Study Results

Participant Flow

Arm/Group Title	FDC/Empagliflozin+Linagliptin	Empagliflozin+Linagliptin/FDC
Arm/Group Description	The subjects were administered one FDC (Fixed-Dose Combination) film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T) in period 1, followed by one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) administered orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 2. A wash-out period of at least 35 days was set following the drug administration in each period.	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 1, followed by one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin administered orally with 240 mL of water after an overnight fast of at least 10 h, as a single dose in the fasted state on Day 1 of Test treatment (T) in period 2. A wash-out period of at least 35 days was set following the drug administration in each period.
Period Title: Treatment Period 1
STARTED	28	28
COMPLETED	28	28
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	28	28
COMPLETED	26	28
NOT COMPLETED	2	0
Period Title: Treatment Period 1
STARTED	26	28
COMPLETED	26	28
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	FDC/Empagliflozin+Linagliptin	Empagliflozin+Linagliptin/FDC	Total
Arm/Group Description	The subjects were administered one FDC (Fixed-Dose Combination) film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T) in period 1, followed by one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) administered orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 2. A wash-out period of at least 35 days was set following the drug administration in each period.	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 1, followed by one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin administered orally with 240 mL of water after an overnight fast of at least 10 h, as a single dose in the fasted state on Day 1 of Test treatment (T) in period 2. A wash-out period of at least 35 days was set following the drug administration in each period.	Total of all reporting groups
Overall Participants	28	28	56
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.1 (9.7)	38.9 (10.2)	39.0 (9.9)
Sex: Female, Male (Count of Participants)
Female	19 67.9%	18 64.3%	37 66.1%
Male	9 32.1%	10 35.7%	19 33.9%

Outcome Measures

1. Primary Outcome

Title	AUC0-tz (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point)
Description	This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point. Time frame description: The time -1:00 hour (h) was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-tz (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point).
Time Frame	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.

Arm/Group Title	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
Arm/Group Description	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).
Measure Participants	55	54
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	2550 (18.0)	2510 (19.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC (10 mg Empagliflozin and 5 mg Linagliptin), Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Comments	The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence acceptable range of 80.00% to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	101.71
	Confidence Interval	(2-Sided) 90%; 99.818 to 103.644
	Parameter Dispersion	Type: Standard Deviation; Value: 5.8
	Estimation Comments	The ratio [%] calculated as T [FDC (10 mg Empagliflozin and 5 mg Linagliptin)]/R [Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets]. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].

2. Primary Outcome

Title	AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours)
Description	This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-72 (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours).
Time Frame	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.

Arm/Group Title	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
Arm/Group Description	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).
Measure Participants	55	54
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	281 (22.5)	283 (23.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC (10 mg Empagliflozin and 5 mg Linagliptin), Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Comments	The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence acceptable range of 80.00% to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	99.39
	Confidence Interval	(2-Sided) 90%; 95.290 to 103.672
	Parameter Dispersion	Type: Standard Deviation; Value: 13.1
	Estimation Comments	The ratio [%] calculated as T [FDC (10 mg Empagliflozin and 5 mg Linagliptin)]/R [Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets]. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].

3. Primary Outcome

Title	Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma)
Description	This outcome measure presents maximum measured concentration of Empagliflozin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Empagliflozin analyte in plasma).
Time Frame	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.

Arm/Group Title	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
Arm/Group Description	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).
Measure Participants	55	54
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	370 (23.9)	365 (23.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC (10 mg Empagliflozin and 5 mg Linagliptin), Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Comments	The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence acceptable range of 80.00% to 125.00%.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	102.33
	Confidence Interval	(2-Sided) 90%; 97.945 to 106.910
	Parameter Dispersion	Type: Standard Deviation; Value: 13.6
	Estimation Comments	The ratio [%] calculated as T [FDC (10 mg Empagliflozin and 5 mg Linagliptin)]/R [Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets]. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].

4. Primary Outcome

Title	Cmax (Maximum Measured Concentration of Linagliptin Analyte in Plasma)
Description	This outcome measure presents maximum measured concentration of Linagliptin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Linagliptin analyte in plasma).
Time Frame	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.

Arm/Group Title	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
Arm/Group Description	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).
Measure Participants	55	54
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	9.33 (36.2)	8.73 (37.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC (10 mg Empagliflozin and 5 mg Linagliptin), Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Comments	The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence acceptable range of 80.00% to 125.00%.
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	107.51
	Confidence Interval	(2-Sided) 90%; 98.561 to 117.282
	Parameter Dispersion	Type: Standard Deviation; Value: 27.4
	Estimation Comments	The ratio [%] calculated as T [FDC (10 mg Empagliflozin and 5 mg Linagliptin)]/R [Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets]. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].

5. Secondary Outcome

Title	AUC0-infinity (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
Description	This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-infinity (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity).
Time Frame	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.

Arm/Group Title	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
Arm/Group Description	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).
Measure Participants	55	54
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	2580 (18.0)	2550 (19.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC (10 mg Empagliflozin and 5 mg Linagliptin), Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Comments	The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	101.44
	Confidence Interval	(2-Sided) 90%; 99.574 to 103.336
	Parameter Dispersion	Type: Standard Deviation; Value: 5.7
	Estimation Comments	The ratio [%] calculated as T [FDC (10 mg Empagliflozin and 5 mg Linagliptin)]/R [Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets]. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].

6. Secondary Outcome

Title	AUC0-infinity (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
Description	This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity).
Time Frame	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PharmacoKinetic parameter analysis Set (PKS): This subject set included all subjects from the TS who provided at least 1 primary or secondary PK parameter that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.

Arm/Group Title	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
Arm/Group Description	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).
Measure Participants	55	54
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	451 (25.9)	462 (29.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC (10 mg Empagliflozin and 5 mg Linagliptin), Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Comments	The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	98.15
	Confidence Interval	(2-Sided) 90%; 93.456 to 103.082
	Parameter Dispersion	Type: Standard Deviation; Value: 15.2
	Estimation Comments	The ratio [%] calculated as T [FDC (10 mg Empagliflozin and 5 mg Linagliptin)]/R [Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets]. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].

Adverse Events

Time Frame	From first drug administration until 1 day after last drug administration, up to 77 days.
Arm/Group Title	FDC (10 mg Empagliflozin and 5 mg Linagliptin)		Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
Arm/Group Description	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).		The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).
All Cause Mortality
	FDC (10 mg Empagliflozin and 5 mg Linagliptin)		Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	FDC (10 mg Empagliflozin and 5 mg Linagliptin)		Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/56 (0%)		0/54 (0%)
Other (Not Including Serious) Adverse Events
	FDC (10 mg Empagliflozin and 5 mg Linagliptin)		Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/56 (14.3%)		7/54 (13%)
Nervous system disorders
Headache	8/56 (14.3%)		7/54 (13%)

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.