This Study in Healthy People Tests Whether Taking a Low Strength of Empagliflozin, Linagliptin, and Metformin Together in 1 Pill is the Same as Taking Them in Separate Pills

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03629054
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 2.3
• Patients Per Site Per Month: 13

Study Details

Study Description

Brief Summary

The primary objective of this trial is to establish the bioequivalence of two empagliflozin/linagliptin/metformin extended release (XR) fixed dose combination (FDC) tablets (Test, T) compared with the same doses of the individual components given in separate tablets (Reference, R) when administered together after a high-fat, high-calorie meal.

The assessment of safety and tolerability will be the secondary objective of this trial.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Empagliflozin, Metformin HCl, Linagliptin (fixed dose combination); 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 Low Strength 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 27, 2018
• Actual Primary Completion Date: Nov 5, 2018
• Actual Study Completion Date: Nov 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Test treatment (T) Low strength empagliflozin/linagliptin/metformin XR fixed dose combination tablet	Drug: Empagliflozin, Metformin HCl, Linagliptin (fixed dose combination); single dose; Other Names: TRIJARDY® XR
Experimental: Reference treatment (R) Single tablets of empagliflozin + linagliptin + metformin XR	Drug: Empagliflozin; single dose; Drug: Linagliptin; single dose; Drug: Metformin HCl; single dose

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) [Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) 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 h:m after drug administration.]

   AUC0-tz, Area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE.

2. Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) [Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) 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 h:m after drug administration.]

   AUC0-tz, Area under the concentration-time curve of the metformin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE.

3. Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (h) (AUC0-72) [PK samples were collected 1:30 h:m 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 h:m after drug administration.]

   AUC0-72, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 to 72 h is presented. SE is a geometric SE.

4. Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) [PK samples were collected 1:30 h:m 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 h:m after drug administration.]

   Cmax, maximum measured concentration of the empagliflozin in plasma is presented. SE is a geometric SE.

5. Maximum Measured Concentration of the Linagliptin in Plasma (Cmax) [PK samples were collected 1:30 h:m 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 h:m after drug administration.]

   Cmax, maximum measured concentration of the linagliptin in plasma is presented. SE is a geometric SE.

6. Maximum Measured Concentration of the Metformin in Plasma (Cmax) [PK samples were collected 1:30 h:m 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 h:m after drug administration.]

   Cmax, maximum measured concentration of the metformin in plasma is presented. SE is a geometric SE.

Secondary Outcome Measures

1. Area Under the Concentration-time Curve of the Empagliflozin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) [PK samples were collected 1:30 h:m 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 h:m after drug administration.]

   AUC0-∞, area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.

2. Area Under the Concentration-time Curve of the Linagliptinin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) [PK samples were collected 1:30 h:m 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 h:m after drug administration.]

   AUC0-∞, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.

3. Area Under the Concentration-time Curve of the Metformin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) [PK samples were collected 1:30 h:m 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 h:m after drug administration.]

   AUC0-∞, area under the concentration-time curve of the metformin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.

4. Percentage of Patients With Drug-related Adverse Events (AEs) [All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP), up to 7 days.]

   Percentage of patients with investigator defined drug-related AEs are presented.

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.)

• 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 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

• 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

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Dec 6, 2018
• Study Protocol - Jul 24, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03629054
• Other Study ID Numbers: 1361-0011; 2018-001266-42
• First Posted: Aug 14, 2018
• Last Update Posted: Feb 21, 2020
• Last Verified: Feb 1, 2020

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

Study Results

Participant Flow

Recruitment Details	It was planned to include healthy participants in this randomised, open-label, two-way crossover trial with 2 treatments (test treatment (T) and reference treatment (R)) and 2 treatment sequences (TR or RT) in order to compare the treatment T to the treatment R under fed conditions. They were recruited from the volunteers' pool of the study site.
Pre-assignment Detail	All participants were screened for eligibility to participate in the trial and to ensure that all participants met all inclusion/exclusion criteria. Participants were not to be included in the trial if any of the specific exclusion criteria were met.

Arm/Group Title	Test Treatment (T)/ Reference Treatment (R)	Reference Treatment (R)/ Test Treatment (T)
Arm/Group Description	Participants were administered 2 fixed dose combination (FDC) coated tablets of 5 milligram (mg) empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin extended release (XR) orally as a single dose in the fed state in period 1, followed by the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state in period 2. The T and R treatments were separated by a washout period of at least 35 days.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state in period 1 and followed by 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state in period 2. The T and R treatments were separated by a washout period of at least 35 days.
Period Title: Period 1 (4 Days)
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Period 1 (4 Days)
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Period 1 (4 Days)
STARTED	15	15
Treated	15	14
COMPLETED	15	14
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Test Treatment (T)/ Reference Treatment (R)	Reference Treatment (R)/ Test Treatment (T)	Total
Arm/Group Description	Participants were administered 2 fixed dose combination (FDC) coated tablet of 5 milligram(mg) empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin extended release (XR) orally in the fed state in period 1, followed by free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR in the fed state in period 2. The T and R treatments were separated by a washout period of at least 35 days.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state in period 1 and followed by 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state in period 2. The T and R treatments were separated by a washout period of at least 35 days.	Total of all reporting groups
Overall Participants	15	15	30
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	46.9 (7.6)	41.5 (9.7)	44.2 (9.0)
Sex: Female, Male (Count of Participants)
Female	6 40%	5 33.3%	11 36.7%
Male	9 60%	10 66.7%	19 63.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	15 100%	15 100%	30 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
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%	1 6.7%	1 3.3%
White	15 100%	14 93.3%	29 96.7%
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 Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	AUC0-tz, Area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE.
Time Frame	Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter set (PKS): PKS included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded due to protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nanomole*hour/litre (nmol*h/L)]	2134.53 (1.03)	2125.57 (1.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (gMean) (T/R).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	100.42
	Confidence Interval	(2-Sided) 90%; 98.17 to 102.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.8
	Estimation Comments	gMean ratio = T/R. Standard error of the mean is actually intra-individual geometric coefficient of variation (gCV).

2. Primary Outcome

Title	Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	AUC0-tz, Area under the concentration-time curve of the metformin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE.
Time Frame	Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nanogram*h/mL (ng*h/mL)]	21687.12 (1.04)	22748.21 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	95.34
	Confidence Interval	(2-Sided) 90%; 91.58 to 99.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.5
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

3. Primary Outcome

Title	Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (h) (AUC0-72)
Description	AUC0-72, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 to 72 h is presented. SE is a geometric SE.
Time Frame	PK samples were collected 1:30 h:m 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nmol*h/L]	270.19 (1.03)	269.77 (1.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	100.16
	Confidence Interval	(2-Sided) 90%; 96.17 to 104.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.6
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

4. Primary Outcome

Title	Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)
Description	Cmax, maximum measured concentration of the empagliflozin in plasma is presented. SE is a geometric SE.
Time Frame	PK samples were collected 1:30 h:m 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nanomole/Litre (nmol/ L)]	209.67 (1.05)	226.50 (1.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	92.57
	Confidence Interval	(2-Sided) 90%; 85.21 to 100.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.9
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

5. Primary Outcome

Title	Maximum Measured Concentration of the Linagliptin in Plasma (Cmax)
Description	Cmax, maximum measured concentration of the linagliptin in plasma is presented. SE is a geometric SE.
Time Frame	PK samples were collected 1:30 h:m 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nanomole/Litre (nmol/ L)]	7.02 (1.05)	7.21 (1.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	97.33
	Confidence Interval	(2-Sided) 90%; 89.99 to 105.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.9
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

6. Primary Outcome

Title	Maximum Measured Concentration of the Metformin in Plasma (Cmax)
Description	Cmax, maximum measured concentration of the metformin in plasma is presented. SE is a geometric SE.
Time Frame	PK samples were collected 1:30 h:m 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nanogram/ millilitre (ng/ mL)]	1853.03 (1.04)	1767.69 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	104.83
	Confidence Interval	(2-Sided) 90%; 98.56 to 111.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.2
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

7. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Empagliflozin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Description	AUC0-∞, area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.
Time Frame	PK samples were collected 1:30 h:m 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nmol*h/L]	2182.26 (1.03)	2166.54 (1.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	100.73
	Confidence Interval	(2-Sided) 90%; 98.33 to 103.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.1
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

8. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Linagliptinin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Description	AUC0-∞, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.
Time Frame	PK samples were collected 1:30 h:m 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [nmol*h/L]	471.40 (1.05)	455.13 (1.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	103.57
	Confidence Interval	(2-Sided) 90%; 96.90 to 110.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.3
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

9. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Metformin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Description	AUC0-∞, area under the concentration-time curve of the metformin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.
Time Frame	PK samples were collected 1:30 h:m 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 h:m after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Geometric Mean (Standard Error) [ng*h/mL]	22288.72 (1.04)	23280.48 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Treatment (T), Reference Treatment (R)
	Comments	An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.
	Type of Statistical Test	Equivalence
	Comments	The assessment of bioequivalence was based upon two-sided 90% CIs for the ratios of the geometric means (T/R).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	95.74
	Confidence Interval	(2-Sided) 90%; 92.29 to 99.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.8
	Estimation Comments	gMean ratio = T/R. Standard Error of the mean is actually intra-individual gCV.

10. Secondary Outcome

Title	Percentage of Patients With Drug-related Adverse Events (AEs)
Description	Percentage of patients with investigator defined drug-related AEs are presented.
Time Frame	All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP), up to 7 days.

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Test Treatment (T)	Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.	Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
Measure Participants	29	30
Number [Participants]	7 46.7%	6 40%

Adverse Events

Time Frame	All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP), up to 7 days. All cause mortality and serious AEs are considering the entire duration of the trial, 49 days.
Arm/Group Title	Test Treatment (T)		Reference Treatment (R)
Arm/Group Description	Participants were administered 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state.		Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state.
All Cause Mortality
	Test Treatment (T)		Reference Treatment (R)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/30 (0%)
Serious Adverse Events
	Test Treatment (T)		Reference Treatment (R)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Test Treatment (T)		Reference Treatment (R)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/29 (27.6%)		6/30 (20%)
Gastrointestinal disorders
Nausea	4/29 (13.8%)		3/30 (10%)
Infections and infestations
Nasopharyngitis	2/29 (6.9%)		1/30 (3.3%)
Metabolism and nutrition disorders
Decreased appetite	1/29 (3.4%)		2/30 (6.7%)
Nervous system disorders
Headache	4/29 (13.8%)		2/30 (6.7%)

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.