Trial Outcomes & Findings for Drug Drug Interaction of Empagliflozin (BI 10773) and Warfarin in Healthy Volunteers (NCT NCT01111331)

NCT ID: NCT01111331

Last Updated: 2014-07-23

Results Overview

Area under the plasma concentration-time curve for the dosing interval τ at steady state In addition to the specified time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 18 participants
• Primary outcome timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.
• Results posted on: 2014-07-23

Participant Flow

Participant milestones

Measure	Empa / Empa Plus Warfarin / Warfarin Patients received three treatments in the following order * Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5 * Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1 * Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1 There was a washout period of at least 14 days between the second and third treatment periods.	Warfarin / Empa / Empa Plus Warfarin Patients received three treatments in the following order * Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1 * Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5 * Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1 There was a washout period of at least 14 days between the first and second treatment periods.
Overall Study STARTED	9	9
Overall Study COMPLETED	9	9
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Drug Drug Interaction of Empagliflozin (BI 10773) and Warfarin in Healthy Volunteers

Baseline characteristics by cohort

Measure	Study Overall n=18 Participants Total number of patients randomised and treated in the study. This was a randomised, cross-over, open-label trial consisting of three treatments. 18 patients were randomised to one of two possible treatment sequences. The three treatments were * Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5 * Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1 * Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
Age, Continuous	34.8 years STANDARD_DEVIATION 7.0 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	18 Participants n=5 Participants

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Area under the plasma concentration-time curve for the dosing interval τ at steady state

In addition to the specified time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss)	4580.38 nmol*h/L Geometric Coefficient of Variation 7.0	4621.37 nmol*h/L Geometric Coefficient of Variation 7.0	—

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Maximum measured plasma concentration of empagliflozin (empa) for the dosing interval τ at steady state.

In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Maximum Measured Concentration at Steady State(Cmax,ss)	759.96 nmol/L Geometric Coefficient of Variation 19.9	764.82 nmol/L Geometric Coefficient of Variation 19.9	—

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)	63585.71 ng*h/mL Geometric Coefficient of Variation 5.7	62626.35 ng*h/mL Geometric Coefficient of Variation 5.7	—

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Maximum measured concentration of the analyte in plasma.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Maximum Measured Concentration (Cmax)	1404.07 ng/mL Geometric Coefficient of Variation 12.4	1374.40 ng/mL Geometric Coefficient of Variation 12.4	—

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)	37493.28 ng*h/mL Geometric Coefficient of Variation 4.5	35949.84 ng*h/mL Geometric Coefficient of Variation 4.5	—

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Maximum measured concentration of the analyte in plasma

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Maximum Measured Concentration (Cmax)	1441.66 ng/mL Geometric Coefficient of Variation 12.7	1425.56 ng/mL Geometric Coefficient of Variation 12.7	—

SECONDARY outcome

Timeframe: 24 hours after dose 4 or 6 respectively (day 5 and day 7)

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Plasma concentration of empagliflozin (empa) measured 24 hours after administration of the fourth dose (Cpre,5) and after the sixth dose (Cpre,7).

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) Cpre,5	40.8 nmol/L Geometric Coefficient of Variation 33.4	NA nmol/L Geometric Coefficient of Variation NA Warfarin not administered	—
Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) Cpre,7	NA nmol/L Geometric Coefficient of Variation NA Empa alone not administered	41.6 nmol/L Geometric Coefficient of Variation 36.7	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal rate constant of empagliflozin (empa) in plasma at steady state.

In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Terminal Rate Constant at Steady State (λz,ss)	0.10 1/h Geometric Coefficient of Variation 10.6	0.10 1/h Geometric Coefficient of Variation 11.7	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal half-life of empagliflozin (empa) in plasma at steady state.

In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Terminal Half-life at Steady State (t1/2,ss)	6.67 h Geometric Coefficient of Variation 10.6	7.07 h Geometric Coefficient of Variation 11.7	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Time from last dosing to maximum plasma concentration at steady state over a uniform dosing interval τ.

In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Time to Maximum Plasma Concentration at Steady State (Tmax,ss)	1.50 h Full Range 35.0 • Interval 1.0 to 3.0	1.00 h Full Range 55.5 • Interval 0.67 to 6.0	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Mean residence time of empagliflozin (empa) in the body at steady state after oral administration.

In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Mean Residence Time at Steady State After Oral Administration (MRTpo,ss)	8.64 h Geometric Coefficient of Variation 12.6	9.08 h Geometric Coefficient of Variation 17.5	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Apparent clearance in plasma after extravascular administration at steady state.

In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Apparent Clearance at Steady State (CL/F,ss)	187 mL/min Geometric Coefficient of Variation 14.8	183 mL/min Geometric Coefficient of Variation 16.9	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Apparent volume of distribution during the terminal phase at steady state following extravascular administration.

In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss)	108 L Geometric Coefficient of Variation 8.63	112 L Geometric Coefficient of Variation 12.7	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)	58556.93 ng*h/mL Geometric Coefficient of Variation 5.3	57911.05 ng*h/mL Geometric Coefficient of Variation 5.3	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Time from dosing until maximum plasma concentration is reached

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax)	0.84 h Full Range 79.5 • Interval 0.33 to 4.0	1.00 h Full Range 98.7 • Interval 0.33 to 7.98	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal rate constant in plasma

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Terminal Rate Constant (λz)	0.0147 1/h Geometric Coefficient of Variation 12.1	0.0151 1/h Geometric Coefficient of Variation 15.4	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal half-life of the analyte in plasma

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Terminal Half-life (t1/2)	47.1 h Geometric Coefficient of Variation 12.1	45.8 h Geometric Coefficient of Variation 15.4	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Mean residence time of the analyte in the body after oral administration

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo)	62.9 h Geometric Coefficient of Variation 16.0	61.2 h Geometric Coefficient of Variation 19.1	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Apparent clearance in plasma after extravascular administration

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)	6.55 mL/min Geometric Coefficient of Variation 20.8	6.65 mL/min Geometric Coefficient of Variation 24.2	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Apparent volume of distribution during the terminal phase λz following extravascular administration

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)	26.7 L Geometric Coefficient of Variation 15.5	26.4 L Geometric Coefficient of Variation 13.6	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)	36386.49 ng*h/mL Geometric Coefficient of Variation 4.4	34962.95 ng*h/mL Geometric Coefficient of Variation 4.4	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Time from dosing until maximum plasma concentration is reached

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax)	0.68 h Full Range 74.6 • Interval 0.33 to 4.0	0.84 h Full Range 85.6 • Interval 0.33 to 7.98	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal rate constant in plasma

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Terminal Rate Constant (λz)	0.0187 1/h Geometric Coefficient of Variation 13.7	0.0189 1/h Geometric Coefficient of Variation 12.4	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal half-life of the analyte in plasma

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Terminal Half-life (t1/2)	37.0 h Geometric Coefficient of Variation 13.7	36.7 h Geometric Coefficient of Variation 12.4	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Mean residence time of the analyte in the body after oral administration

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo)	40.8 h Geometric Coefficient of Variation 13.8	38.9 h Geometric Coefficient of Variation 15.0	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Apparent clearance in plasma after extravascular administration

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)	11.1 mL/min Geometric Coefficient of Variation 17.8	11.6 mL/min Geometric Coefficient of Variation 16.1	—

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Apparent volume of distribution during the terminal phase λz following extravascular administration

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)	35.6 L Geometric Coefficient of Variation 21.1	36.8 L Geometric Coefficient of Variation 12.7	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Peak international normalised ratio for warfarin, measured as the maximum INR over time.

Outcome measures

Measure	Empa n=16 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=16 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Peak International Normalised Ratio (INRmax)	1.76 Ratio 95% Confidence Interval NA • Interval 1.52 to 2.05	1.53 Ratio 95% Confidence Interval 23.68 • Interval 1.32 to 1.78	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Area under the concentration time curve of the INR measurements over the time interval from 0 to the time of the last quantifiable data point.

Outcome measures

Measure	Empa n=10 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=15 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point (INR AUEC0-tz)	202.54 ratio*h 95% Confidence Interval NA • Interval 185.69 to 220.91	178.08 ratio*h 95% Confidence Interval 10.75 • Interval 166.63 to 190.32	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Peak international normalised ratio for warfarin adjusted for baseline value (before any trial drug administration) of peak international normalised ratio

Outcome measures

Measure	Empa n=15 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=14 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Peak International Normalised Ratio Adjusted to Baseline (INRmax,Base)	0.69 Ratio 95% Confidence Interval NA • Interval 0.48 to 1.01	0.69 Ratio 95% Confidence Interval 46.12 • Interval 0.46 to 1.03	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Peak prothrombin time

Outcome measures

Measure	Empa n=16 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=16 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Peak Prothrombin Time (PTmax)	20.17 s 95% Confidence Interval NA • Interval 18.03 to 22.56	18.07 s 95% Confidence Interval 17.34 • Interval 16.15 to 20.21	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Area under the INR-time curve from time of dosing to time of last measurable data point adjusted for baseline value (before any trial drug administration) of area under the INR-time curve

Outcome measures

Measure	Empa n=11 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=13 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base)	32.42 ratio*h 95% Confidence Interval NA • Interval 18.87 to 55.69	36.30 ratio*h 95% Confidence Interval 55.85 • Interval 21.44 to 61.48	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Area under the PT-time curve from time of dosing to time of last measurable data point

Outcome measures

Measure	Empa n=10 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=15 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point (PT AUEC0-tz)	2508.34 s*hr 95% Confidence Interval NA • Interval 2357.25 to 2669.12	2281.54 s*hr 95% Confidence Interval 7.61 • Interval 2174.71 to 2393.62	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Peak prothrombin time adjusted for baseline value (before any trial drug administration) of peak prothrombin

Outcome measures

Measure	Empa n=15 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=14 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base)	6.69 s 95% Confidence Interval NA • Interval 4.74 to 9.45	6.51 s 95% Confidence Interval 41.50 • Interval 4.49 to 9.42	—

SECONDARY outcome

Timeframe: 0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.

Area under the PT-time curve from time of dosing to time of last measurable data point adjusted for baseline value (before any trial drug administration) of area under the PT-time curve

Outcome measures

Measure	Empa n=10 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=13 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (PT AUEC0-tz,Base)	419.24 s*hr 95% Confidence Interval NA • Interval 258.46 to 680.05	354.97 s*hr 95% Confidence Interval 54.49 • Interval 230.86 to 545.79	—

SECONDARY outcome

Timeframe: Drug administration until beginning of next sequence/end of trial, 35 days

Population: Treated set (TS) included all subjects who had taken at least one dose of trial medication.

Clinically relevant abnormalities for physical examination, vital signs, ECG, blood chemistry and assessment of tolerability by investigator. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.

Outcome measures

Measure	Empa n=18 Participants Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1	Empa Plus Warfarin n=18 Participants Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator	0 participants	0 participants	0 participants

Adverse Events

Empa

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Warfarin

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Empa Plus Warfarin

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Empa n=18 participants at risk Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5	Warfarin n=18 participants at risk Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1	Empa Plus Warfarin n=18 participants at risk Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
Gastrointestinal disorders Vomiting	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	5.6% 1/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days
General disorders Induration	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	5.6% 1/18 • Drug administration until beginning of next sequence/end of trial, 35 days
Injury, poisoning and procedural complications Arthropod sting	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	5.6% 1/18 • Drug administration until beginning of next sequence/end of trial, 35 days
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	5.6% 1/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days
Nervous system disorders Headache	16.7% 3/18 • Drug administration until beginning of next sequence/end of trial, 35 days	11.1% 2/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.6% 1/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days
Skin and subcutaneous tissue disorders Petechiae	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 days	5.6% 1/18 • Drug administration until beginning of next sequence/end of trial, 35 days	0.00% 0/18 • Drug administration until beginning of next sequence/end of trial, 35 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
• Publication restrictions are in place