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Trial record 21 of 187 for:    BI10773

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

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ClinicalTrials.gov Identifier: NCT01111331
Recruitment Status : Completed
First Posted : April 27, 2010
Results First Posted : July 23, 2014
Last Update Posted : July 23, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Healthy
Interventions Drug: BI 10773 25 mg
Drug: Warfarin 25 mg
Drug: Warfarin
Enrollment 18
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Empa / Empa Plus Warfarin / Warfarin Warfarin / Empa / Empa Plus Warfarin
Hide Arm/Group Description

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.

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.

Period Title: Overall Study
Started 9 9
Completed 9 9
Not Completed 0 0
Arm/Group Title Study Overall
Hide Arm/Group Description

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
Overall Number of Baseline Participants 18
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants
34.8  (7.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants
Female
0
   0.0%
Male
18
 100.0%
1.Primary Outcome
Title Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss)
Hide Description

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.

Time Frame 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
4580.38
(7.0%)
4621.37
(7.0%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Empa, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by empa
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for subject and treatment
Method of Estimation Estimation Parameter Geometric Mean ratio
Estimated Value 100.89
Confidence Interval (2-Sided) 90%
96.86 to 105.10
Parameter Dispersion
Type: Standard Deviation
Value: 7.0
Estimation Comments Standard deviation is actually the intra-individual geometric coefficient of variation (gCV)
2.Primary Outcome
Title Empagliflozin: Maximum Measured Concentration at Steady State(Cmax,ss)
Hide Description

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.

Time Frame 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
759.96
(19.9%)
764.82
(19.9%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Empa, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by empa
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value 0.0021
Comments p-value for geometric mean ratio being outside interval 80% to 125%
Method ANOVA
Comments Based on ANOVA with terms for subject and treatment
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 100.64
Confidence Interval (2-Sided) 90%
89.79 to 112.80
Parameter Dispersion
Type: Standard Deviation
Value: 19.9
Estimation Comments Standard deviation is actually the intra-individual gCV
3.Primary Outcome
Title Warfarin R-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)
Hide Description Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
63585.71
(5.7%)
62626.35
(5.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 98.49
Confidence Interval (2-Sided) 90%
95.29 to 101.80
Parameter Dispersion
Type: Standard Deviation
Value: 5.7
Estimation Comments Standard deviation is actually the geometric coefficient of variation (gCV)
4.Primary Outcome
Title Warfarin R-enantiomers: Maximum Measured Concentration (Cmax)
Hide Description Maximum measured concentration of the analyte in plasma.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
1404.07
(12.4%)
1374.40
(12.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 97.89
Confidence Interval (2-Sided) 90%
91.12 to 105.15
Parameter Dispersion
Type: Standard Deviation
Value: 12.4
Estimation Comments Standard deviation is actually the geometric coefficient of variation (gCV)
5.Primary Outcome
Title Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)
Hide Description Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
37493.28
(4.5%)
35949.84
(4.5%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 95.88
Confidence Interval (2-Sided) 90%
93.40 to 98.43
Parameter Dispersion
Type: Standard Deviation
Value: 4.5
Estimation Comments Standard deviation is actually the intra-individual gCV
6.Primary Outcome
Title Warfarin S-enantiomers: Maximum Measured Concentration (Cmax)
Hide Description Maximum measured concentration of the analyte in plasma
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
1441.66
(12.7%)
1425.56
(12.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value 0.0001
Comments p-value for geometric mean ratio being outside interval 80% to 125%
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 98.88
Confidence Interval (2-Sided) 90%
91.84 to 106.47
Parameter Dispersion
Type: Standard Deviation
Value: 12.7
Estimation Comments Standard deviation is actually the intra-individual gCV
7.Secondary Outcome
Title Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N)
Hide Description Plasma concentration of empagliflozin (empa) measured 24 hours after administration of the fourth dose (Cpre,5) and after the sixth dose (Cpre,7).
Time Frame 24 hours after dose 4 or 6 respectively (day 5 and day 7)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Cpre,5
40.8
(33.4%)
NA [1] 
(NA%)
Cpre,7
NA [2] 
(NA%)
41.6
(36.7%)
[1]
Warfarin not administered
[2]
Empa alone not administered
8.Secondary Outcome
Title Empagliflozin: Terminal Rate Constant at Steady State (λz,ss)
Hide Description

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.

Time Frame 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/h
0.10
(10.6%)
0.10
(11.7%)
9.Secondary Outcome
Title Empagliflozin: Terminal Half-life at Steady State (t1/2,ss)
Hide Description

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.

Time Frame 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h
6.67
(10.6%)
7.07
(11.7%)
10.Secondary Outcome
Title Empagliflozin: Time to Maximum Plasma Concentration at Steady State (Tmax,ss)
Hide Description

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.

Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Median (Full Range)
Unit of Measure: h
1.50
(1.00 to 3.00)
1.00
(0.67 to 6.00)
11.Secondary Outcome
Title Empagliflozin: Mean Residence Time at Steady State After Oral Administration (MRTpo,ss)
Hide Description

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.

Time Frame 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h
8.64
(12.6%)
9.08
(17.5%)
12.Secondary Outcome
Title Empagliflozin: Apparent Clearance at Steady State (CL/F,ss)
Hide Description

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.

Time Frame 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mL/min
187
(14.8%)
183
(16.9%)
13.Secondary Outcome
Title Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss)
Hide Description

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.

Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Empa Empa Plus Warfarin
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L
108
(8.63%)
112
(12.7%)
14.Secondary Outcome
Title Warfarin R-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)
Hide Description Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
58556.93
(5.3%)
57911.05
(5.3%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 98.90
Confidence Interval (2-Sided) 90%
95.89 to 102.00
Parameter Dispersion
Type: Standard Deviation
Value: 5.3
Estimation Comments Standard deviation is actually the geometric coefficient of variation (gCV)
15.Secondary Outcome
Title Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax)
Hide Description Time from dosing until maximum plasma concentration is reached
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Median (Full Range)
Unit of Measure: h
0.84
(0.33 to 4.00)
1.00
(0.33 to 7.98)
16.Secondary Outcome
Title Warfarin R-enantiomers: Terminal Rate Constant (λz)
Hide Description Terminal rate constant in plasma
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/h
0.0147
(12.1%)
0.0151
(15.4%)
17.Secondary Outcome
Title Warfarin R-enantiomers: Terminal Half-life (t1/2)
Hide Description Terminal half-life of the analyte in plasma
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h
47.1
(12.1%)
45.8
(15.4%)
18.Secondary Outcome
Title Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo)
Hide Description Mean residence time of the analyte in the body after oral administration
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h
62.9
(16.0%)
61.2
(19.1%)
19.Secondary Outcome
Title Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)
Hide Description Apparent clearance in plasma after extravascular administration
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mL/min
6.55
(20.8%)
6.65
(24.2%)
20.Secondary Outcome
Title Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)
Hide Description Apparent volume of distribution during the terminal phase λz following extravascular administration
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L
26.7
(15.5%)
26.4
(13.6%)
21.Secondary Outcome
Title Warfarin S-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)
Hide Description Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
36386.49
(4.4%)
34962.95
(4.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Ratio calculated as empa plus warfarin divided by warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 96.09
Confidence Interval (2-Sided) 90%
93.64 to 98.60
Parameter Dispersion
Type: Standard Deviation
Value: 4.4
Estimation Comments Standard deviation is actually the intra-individual gCV
22.Secondary Outcome
Title Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax)
Hide Description Time from dosing until maximum plasma concentration is reached
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Median (Full Range)
Unit of Measure: h
0.68
(0.33 to 4.00)
0.84
(0.33 to 7.98)
23.Secondary Outcome
Title Warfarin S-enantiomers: Terminal Rate Constant (λz)
Hide Description Terminal rate constant in plasma
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/h
0.0187
(13.7%)
0.0189
(12.4%)
24.Secondary Outcome
Title Warfarin S-enantiomers: Terminal Half-life (t1/2)
Hide Description Terminal half-life of the analyte in plasma
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h
37.0
(13.7%)
36.7
(12.4%)
25.Secondary Outcome
Title Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo)
Hide Description Mean residence time of the analyte in the body after oral administration
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h
40.8
(13.8%)
38.9
(15.0%)
26.Secondary Outcome
Title Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)
Hide Description Apparent clearance in plasma after extravascular administration
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mL/min
11.1
(17.8%)
11.6
(16.1%)
27.Secondary Outcome
Title Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)
Hide Description Apparent volume of distribution during the terminal phase λz following extravascular administration
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L
35.6
(21.1%)
36.8
(12.7%)
28.Secondary Outcome
Title Warfarin: Peak International Normalised Ratio (INRmax)
Hide Description Peak international normalised ratio for warfarin, measured as the maximum INR over time.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 16 16
Geometric Mean (95% Confidence Interval)
Unit of Measure: Ratio
1.76
(1.52 to 2.05)
1.53
(1.32 to 1.78)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline INR value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.73 to 1.04
Estimation Comments [Not Specified]
29.Secondary Outcome
Title Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point (INR AUEC0-tz)
Hide Description 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.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 10 15
Geometric Mean (95% Confidence Interval)
Unit of Measure: ratio*h
202.54
(185.69 to 220.91)
178.08
(166.63 to 190.32)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline INR value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.79 to 0.98
Estimation Comments [Not Specified]
30.Secondary Outcome
Title Warfarin: Peak International Normalised Ratio Adjusted to Baseline (INRmax,Base)
Hide Description Peak international normalised ratio for warfarin adjusted for baseline value (before any trial drug administration) of peak international normalised ratio
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 15 14
Geometric Mean (95% Confidence Interval)
Unit of Measure: Ratio
0.69
(0.48 to 1.01)
0.69
(0.46 to 1.03)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline INR value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.67 to 1.48
Estimation Comments [Not Specified]
31.Secondary Outcome
Title Warfarin: Peak Prothrombin Time (PTmax)
Hide Description Peak prothrombin time
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 16 16
Geometric Mean (95% Confidence Interval)
Unit of Measure: s
20.17
(18.03 to 22.56)
18.07
(16.15 to 20.21)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline PT value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.79 to 1.02
Estimation Comments [Not Specified]
32.Secondary Outcome
Title Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base)
Hide Description 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
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 11 13
Geometric Mean (95% Confidence Interval)
Unit of Measure: ratio*h
32.42
(18.87 to 55.69)
36.30
(21.44 to 61.48)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline PT value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.12
Confidence Interval (2-Sided) 95%
0.64 to 1.95
Estimation Comments [Not Specified]
33.Secondary Outcome
Title Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point (PT AUEC0-tz)
Hide Description Area under the PT-time curve from time of dosing to time of last measurable data point
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 10 15
Geometric Mean (95% Confidence Interval)
Unit of Measure: s*hr
2508.34
(2357.25 to 2669.12)
2281.54
(2174.71 to 2393.62)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline PT value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.91
Confidence Interval (2-Sided) 95%
0.84 to 0.98
Estimation Comments [Not Specified]
34.Secondary Outcome
Title Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base)
Hide Description Peak prothrombin time adjusted for baseline value (before any trial drug administration) of peak prothrombin
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 15 14
Geometric Mean (95% Confidence Interval)
Unit of Measure: s
6.69
(4.74 to 9.45)
6.51
(4.49 to 9.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline PT value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.68 to 1.40
Estimation Comments [Not Specified]
35.Secondary Outcome
Title Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (PT AUEC0-tz,Base)
Hide Description 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
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 10 13
Geometric Mean (95% Confidence Interval)
Unit of Measure: s*hr
419.24
(258.46 to 680.05)
354.97
(230.86 to 545.79)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin, Empa Plus Warfarin
Comments Difference calculated as empa plus warfarin minus warfarin
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period, treatment and the baseline PT value
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.47 to 1.51
Estimation Comments [Not Specified]
36.Secondary Outcome
Title Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator
Hide Description 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.
Time Frame Drug administration until beginning of next sequence/end of trial, 35 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS) included all subjects who had taken at least one dose of trial medication.
Arm/Group Title Empa Warfarin Empa Plus Warfarin
Hide Arm/Group Description:
Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5
Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1
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
Overall Number of Participants Analyzed 18 18 18
Measure Type: Number
Unit of Measure: participants
0 0 0
Time Frame Drug administration until beginning of next sequence/end of trial, 35 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Empa Warfarin Empa Plus Warfarin
Hide Arm/Group Description Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5 Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1 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
All-Cause Mortality
Empa Warfarin Empa Plus Warfarin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Empa Warfarin Empa Plus Warfarin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/18 (0.00%)   0/18 (0.00%)   0/18 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Empa Warfarin Empa Plus Warfarin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/18 (22.22%)   5/18 (27.78%)   2/18 (11.11%) 
Gastrointestinal disorders       
Vomiting  1  0/18 (0.00%)  1/18 (5.56%)  0/18 (0.00%) 
General disorders       
Induration  1  0/18 (0.00%)  0/18 (0.00%)  1/18 (5.56%) 
Injury, poisoning and procedural complications       
Arthropod sting  1  0/18 (0.00%)  0/18 (0.00%)  1/18 (5.56%) 
Musculoskeletal and connective tissue disorders       
Muscle spasms  1  0/18 (0.00%)  1/18 (5.56%)  0/18 (0.00%) 
Nervous system disorders       
Headache  1  3/18 (16.67%)  2/18 (11.11%)  0/18 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Oropharyngeal pain  1  1/18 (5.56%)  0/18 (0.00%)  0/18 (0.00%) 
Skin and subcutaneous tissue disorders       
Petechiae  1  0/18 (0.00%)  1/18 (5.56%)  0/18 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 13.1
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01111331     History of Changes
Other Study ID Numbers: 1245.18
2009-018088-29 ( EudraCT Number: EudraCT )
First Submitted: April 26, 2010
First Posted: April 27, 2010
Results First Submitted: May 16, 2014
Results First Posted: July 23, 2014
Last Update Posted: July 23, 2014