Trial Outcomes & Findings for Rel. BA of Empagliflozin (BI 10773)/Linagliptin FDC Tbl, Comparison With Mono-components, With a Second FDC Tablet and Influence of Food (NCT NCT01189201)

NCT ID: NCT01189201

Last Updated: 2015-03-19

Results Overview

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the last quantifiable drug plasma concentration. In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 42 participants
• Primary outcome timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration
• Results posted on: 2015-03-19

Participant Flow

Participant milestones

Measure	Study Overall A randomised, open label, three period, crossover trial. Each subject was to receive 3 of 4 possible treatments. The treatments were * Empagliflozin plus linagliptin fixed dose combination (FDC) A1 (fasted) * Empagliflozin plus linagliptin, individual tablets (fasted) * Empagliflozin plus linagliptin FDC A1 (fed) * Empagliflozin plus linagliptin FDC A3 (fasted) Drug administrations were separated by a washout period of at least 35 days. A total of 42 subjects were entered into the study, all subjects were allocated to the FDC A1 (fasted) and individual tablet treatments as this was the primary objective of the study. Along with this 18 of the subjects were allocated to receive the FDC A1 (fed) treatment and other 24 subjects to the FDC A3 treatment.
Overall Study STARTED	42
Overall Study Received Empa/Linagliptin FDC A1(Fasted)	42
Overall Study Rec. Empa/Linagliptin Ind.Tablet(Fasted)	41
Overall Study Received Empa/Linagliptin FDC A1 (Fed)	18
Overall Study Received Empa/Linagliptin FDC A3(Fasted)	24
Overall Study COMPLETED	41
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure

Study Overall A randomised, open label, three period, crossover trial. Each subject was to receive 3 of 4 possible treatments. The treatments were * Empagliflozin plus linagliptin fixed dose combination (FDC) A1 (fasted) * Empagliflozin plus linagliptin, individual tablets (fasted) * Empagliflozin plus linagliptin FDC A1 (fed) * Empagliflozin plus linagliptin FDC A3 (fasted) Drug administrations were separated by a washout period of at least 35 days. A total of 42 subjects were entered into the study, all subjects were allocated to the FDC A1 (fasted) and individual tablet treatments as this was the primary objective of the study. Along with this 18 of the subjects were allocated to receive the FDC A1 (fed) treatment and other 24 subjects to the FDC A3 treatment.

Overall Study Adverse Event

1

Baseline Characteristics

Rel. BA of Empagliflozin (BI 10773)/Linagliptin FDC Tbl, Comparison With Mono-components, With a Second FDC Tablet and Influence of Food

Baseline characteristics by cohort

Measure	Study Overall n=42 Participants A randomised, open label, three period, crossover trial. Each subject was to receive 3 of 4 possible treatments. The treatments were * Empagliflozin plus linagliptin fixed dose combination (FDC) A1 (fasted) * Empagliflozin plus linagliptin, individual tablets (fasted) * Empagliflozin plus linagliptin FDC A1 (fed) * Empagliflozin plus linagliptin FDC A3 (fasted) Drug administrations were separated by a washout period of at least 35 days. A total of 42 subjects were entered into the study, all subjects were allocated to the FDC A1 (fasted) and individual tablet treatments as this was the primary objective of the study. Along with this 18 of the subjects were allocated to receive the FDC A1 (fed) treatment and other 24 subjects to the FDC A3 treatment.
Age, Continuous	40.3 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the last quantifiable drug plasma concentration.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin: Area Under the Curve 0 to the Last Quantifiable Drug Plasma Concentration (AUC0-tz)	5990 nmol*h/L Geometric Coefficient of Variation 21.0	5720 nmol*h/L Geometric Coefficient of Variation 20.8	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of linagliptin in plasma over the time interval from 0 to 72 hours.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin: Area Under the Curve 0 to 72 Hours (AUC0-72)	264 nmol*h/L Geometric Coefficient of Variation 22.1	250 nmol*h/L Geometric Coefficient of Variation 22.1	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Maximum measured concentration of empagliflozin (empa) in plasma.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin: Maximum Measured Concentration (Cmax)	862 nmol/L Geometric Coefficient of Variation 26.8	803 nmol/L Geometric Coefficient of Variation 24.9	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Maximum measured concentration of linagliptin in plasma.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin: Maximum Measured Concentration (Cmax)	8.19 nmol/L Geometric Coefficient of Variation 36.4	7.49 nmol/L Geometric Coefficient of Variation 31.0	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Maximum measured concentration of empagliflozin (empa) in plasma, comparing fed with fasted.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin Fed vs Fasted: Maximum Measured Concentration (Cmax)	949 nmol/L Geometric Coefficient of Variation 23.7	583 nmol/L Geometric Coefficient of Variation 21.7	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the last quantifiable drug plasma concentration.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin Fed vs Fasted: Area Under the Curve 0 to the Last Quantifiable Drug Plasma Concentration (AUC0-tz)	6330 nmol*h/L Geometric Coefficient of Variation 16.4	5400 nmol*h/L Geometric Coefficient of Variation 16.3	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Maximum measured concentration of linagliptin in plasma.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin Fed vs Fasted: Maximum Measured Concentration (Cmax)	8.97 nmol/L Geometric Coefficient of Variation 40.0	6.14 nmol/L Geometric Coefficient of Variation 17.0	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of linagliptin in plasma over the time interval from 0 to 72 hours.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin Fed vs Fasted: Area Under the Curve 0 to 72 Hours (AUC0-72)	275 nmol*h/L Geometric Coefficient of Variation 21.7	250 nmol*h/L Geometric Coefficient of Variation 19.2	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Maximum measured concentration of empagliflozin (empa) in plasma.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin Formulation Comparison: Maximum Measured Concentration (Cmax)	802 nmol/L Geometric Coefficient of Variation 27.0	787 nmol/L Geometric Coefficient of Variation 25.2	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the last quantifiable drug plasma concentration.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin Formulation Comparison: Area Under the Curve 0 to the Last Quantifiable Drug Plasma Concentration (AUC0-tz)	5740 nmol*h/L Geometric Coefficient of Variation 23.3	5490 nmol*h/L Geometric Coefficient of Variation 21.1	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Maximum measured concentration of linagliptin in plasma.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin Formulation Comparison: Maximum Measured Concentration (Cmax)	7.65 nmol/L Geometric Coefficient of Variation 32.7	7.93 nmol/L Geometric Coefficient of Variation 33.5	—	—

PRIMARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of linagliptin in plasma over the time interval from 0 to 72 hours.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin Formulation Comparison: Area Under the Curve 0 to 72 Hours (AUC0-72)	256 nmol*h/L Geometric Coefficient of Variation 22.4	247 nmol*h/L Geometric Coefficient of Variation 26.3	—	—

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Time from last dosing to the maximum measured concentration of empagliflozin (empa) in plasma.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin: Time From Last Dosing to Maximum Measured Concentration (Tmax)	1.50 hours Interval 0.67 to 4.0	1.25 hours Interval 0.67 to 3.98	2.00 hours Interval 0.67 to 4.0	1.50 hours Interval 0.67 to 3.0

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Time from last dosing to the maximum measured concentration of linagliptin in plasma

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin: Time From Last Dosing to Maximum Measured Concentration (Tmax)	1.50 hours Interval 0.33 to 6.03	1.75 hours Interval 0.67 to 10.0	2.25 hours Interval 1.0 to 4.0	1.50 hours Interval 0.33 to 4.0

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 extrapolated to infinity.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin: Area Under the Curve 0 to Infinity (AUC0-∞)	6060 nmol*h/L Geometric Coefficient of Variation 20.7	5800 nmol*h/L Geometric Coefficient of Variation 20.9	—	—

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of linagliptin in plasma over the time interval from 0 extrapolated to infinity.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=40 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin: Area Under the Curve 0 to Infinity (AUC0-∞)	435 nmol*h/L Geometric Coefficient of Variation 26.5	410 nmol*h/L Geometric Coefficient of Variation 29.8	—	—

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 extrapolated to infinity.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin Fed vs Fasted: Area Under the Curve 0 to Infinity (AUC0-∞)	6410 nmol*h/L Geometric Coefficient of Variation 16.0	5500 nmol*h/L Geometric Coefficient of Variation 16.8	—	—

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of linagliptin in plasma over the time interval from 0 extrapolated to infinity.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin Fed vs Fasted: Area Under the Curve 0 to Infinity (AUC0-∞)	453 nmol*h/L Geometric Coefficient of Variation 24.2	421 nmol*h/L Geometric Coefficient of Variation 19.0	—	—

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 extrapolated to infinity.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Empagliflozin Formulation Comparison: Area Under the Curve 0 to Infinity (AUC0-∞)	5810 nmol*h/L Geometric Coefficient of Variation 23.1	5560 nmol*h/L Geometric Coefficient of Variation 20.8	—	—

SECONDARY outcome

Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration

Population: Pharmacokinetic (PK) set: Included all subjects who were documented to have taken at least one dose of investigational treatment, who provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.

Area under the concentration-time curve of linagliptin in plasma over the time interval from 0 extrapolated to infinity.

In this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Linagliptin Formulation Comparison: Area Under the Curve 0 to Infinity (AUC0-∞)	423 nmol*h/L Geometric Coefficient of Variation 28.3	393 nmol*h/L Geometric Coefficient of Variation 33.8	—	—

SECONDARY outcome

Timeframe: Drug administration until next treatment period/end-of-study examination, up to 36 days

Population: Treated set (TS) included all subjects who were documented to have taken at least one dose of investigational treatment.

Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by the Investigator. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Time frame for adverse event was until the end-of-study examination.

Outcome measures

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 Participants A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin FDC A1 (Fed) n=41 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A1 (Fed) n=18 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) n=24 Participants A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by the Investigator	0 participants	0 participants	0 participants	0 participants

Adverse Events

Empa Plus Linagliptin FDC A1 (Fasted)

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Empa Plus Linagliptin Individual Tablets (Fasted)

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Empa Plus Linagliptin FDC A1 (Fed)

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Empa Plus Linagliptin FDC A3 (Fasted)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Empa Plus Linagliptin FDC A1 (Fasted) n=42 participants at risk A single dose of empa 25 mg and linagliptin 5 mg fixed dose combination (FDC) tablet formulation A1 (FDC A1)	Empa Plus Linagliptin Individual Tablets (Fasted) n=41 participants at risk Individual tablets of empa 25 mg and linagliptin 5 mg administered together	Empa Plus Linagliptin FDC A1 (Fed) n=18 participants at risk A single dose of empa 25 mg and linagliptin 5 mg FDC A1 tablet given after a high-fat, high-caloric meal.	Empa Plus Linagliptin FDC A3 (Fasted) n=24 participants at risk A single dose of empa 25 mg and linagliptin 5 mg FDC tablet formulation A3 (FDC A3).
Gastrointestinal disorders Abdominal pain	0.00% 0/42 • Treatment period and following washout period, up to 36 days	0.00% 0/41 • Treatment period and following washout period, up to 36 days	5.6% 1/18 • Treatment period and following washout period, up to 36 days	4.2% 1/24 • Treatment period and following washout period, up to 36 days
Gastrointestinal disorders Nausea	4.8% 2/42 • Treatment period and following washout period, up to 36 days	0.00% 0/41 • Treatment period and following washout period, up to 36 days	5.6% 1/18 • Treatment period and following washout period, up to 36 days	4.2% 1/24 • Treatment period and following washout period, up to 36 days
Gastrointestinal disorders Vomiting	4.8% 2/42 • Treatment period and following washout period, up to 36 days	4.9% 2/41 • Treatment period and following washout period, up to 36 days	5.6% 1/18 • Treatment period and following washout period, up to 36 days	4.2% 1/24 • Treatment period and following washout period, up to 36 days
Infections and infestations Nasopharyngitis	2.4% 1/42 • Treatment period and following washout period, up to 36 days	2.4% 1/41 • Treatment period and following washout period, up to 36 days	16.7% 3/18 • Treatment period and following washout period, up to 36 days	0.00% 0/24 • Treatment period and following washout period, up to 36 days
Musculoskeletal and connective tissue disorders Back pain	2.4% 1/42 • Treatment period and following washout period, up to 36 days	0.00% 0/41 • Treatment period and following washout period, up to 36 days	5.6% 1/18 • Treatment period and following washout period, up to 36 days	0.00% 0/24 • Treatment period and following washout period, up to 36 days
Nervous system disorders Headache	9.5% 4/42 • Treatment period and following washout period, up to 36 days	9.8% 4/41 • Treatment period and following washout period, up to 36 days	5.6% 1/18 • Treatment period and following washout period, up to 36 days	8.3% 2/24 • Treatment period and following washout period, up to 36 days
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/42 • Treatment period and following washout period, up to 36 days	0.00% 0/41 • Treatment period and following washout period, up to 36 days	5.6% 1/18 • Treatment period and following washout period, up to 36 days	0.00% 0/24 • Treatment period and following washout period, up to 36 days

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
• Publication restrictions are in place

Restriction type: OTHER