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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01111331
First received: April 26, 2010
Last updated: June 25, 2014
Last verified: June 2014
Results First Received: May 16, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Bio-availability Study;   Intervention Model: Crossover Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Healthy
Interventions: Drug: BI 10773 25 mg
Drug: Warfarin 25 mg
Drug: Warfarin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
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.


Participant Flow:   Overall Study
    Empa / Empa Plus Warfarin / Warfarin     Warfarin / Empa / Empa Plus Warfarin  
STARTED     9     9  
COMPLETED     9     9  
NOT COMPLETED     0     0  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Study Overall

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

Baseline Measures
    Study Overall  
Number of Participants  
[units: participants]
  18  
Age  
[units: years]
Mean ± Standard Deviation
  34.8  ± 7.0  
Gender  
[units: participants]
 
Female     0  
Male     18  



  Outcome Measures
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1.  Primary:   Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss)   [ 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. ]

2.  Primary:   Empagliflozin: Maximum Measured Concentration at Steady State(Cmax,ss)   [ 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. ]

3.  Primary:   Warfarin R-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)   [ 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 ]

4.  Primary:   Warfarin R-enantiomers: Maximum Measured Concentration (Cmax)   [ 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 ]

5.  Primary:   Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)   [ 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 ]

6.  Primary:   Warfarin S-enantiomers: Maximum Measured Concentration (Cmax)   [ 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 ]

7.  Secondary:   Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N)   [ Time Frame: 24 hours after dose 4 or 6 respectively (day 5 and day 7) ]

8.  Secondary:   Empagliflozin: Terminal Rate Constant at Steady State (λz,ss)   [ 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. ]

9.  Secondary:   Empagliflozin: Terminal Half-life at Steady State (t1/2,ss)   [ 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. ]

10.  Secondary:   Empagliflozin: Time to Maximum Plasma Concentration at Steady State (Tmax,ss)   [ 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 ]

11.  Secondary:   Empagliflozin: Mean Residence Time at Steady State After Oral Administration (MRTpo,ss)   [ 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. ]

12.  Secondary:   Empagliflozin: Apparent Clearance at Steady State (CL/F,ss)   [ 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. ]

13.  Secondary:   Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss)   [ 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 ]

14.  Secondary:   Warfarin R-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)   [ 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 ]

15.  Secondary:   Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax)   [ 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 ]

16.  Secondary:   Warfarin R-enantiomers: Terminal Rate Constant (λz)   [ 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 ]

17.  Secondary:   Warfarin R-enantiomers: Terminal Half-life (t1/2)   [ 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 ]

18.  Secondary:   Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo)   [ 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 ]

19.  Secondary:   Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)   [ 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 ]

20.  Secondary:   Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)   [ 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 ]

21.  Secondary:   Warfarin S-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)   [ 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 ]

22.  Secondary:   Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax)   [ 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 ]

23.  Secondary:   Warfarin S-enantiomers: Terminal Rate Constant (λz)   [ 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 ]

24.  Secondary:   Warfarin S-enantiomers: Terminal Half-life (t1/2)   [ 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 ]

25.  Secondary:   Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo)   [ 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 ]

26.  Secondary:   Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)   [ 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 ]

27.  Secondary:   Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)   [ 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 ]

28.  Secondary:   Warfarin: Peak International Normalised Ratio (INRmax)   [ 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 ]

29.  Secondary:   Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point (INR AUEC0-tz)   [ 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 ]

30.  Secondary:   Warfarin: Peak International Normalised Ratio Adjusted to Baseline (INRmax,Base)   [ 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 ]

31.  Secondary:   Warfarin: Peak Prothrombin Time (PTmax)   [ 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 ]

32.  Secondary:   Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base)   [ 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 ]

33.  Secondary:   Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point (PT AUEC0-tz)   [ 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 ]

34.  Secondary:   Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base)   [ 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 ]

35.  Secondary:   Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (PT AUEC0-tz,Base)   [ 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 ]

36.  Secondary:   Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator   [ Time Frame: Drug administration until beginning of next sequence/end of trial, 35 days ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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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
e-mail: clintriage.rdg@boehringer-ingelheim.com


No publications provided


Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01111331     History of Changes
Other Study ID Numbers: 1245.18, 2009-018088-29
Study First Received: April 26, 2010
Results First Received: May 16, 2014
Last Updated: June 25, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices