Switching Study From Warfarin to Rivaroxaban

This study has been completed.
Sponsor:
Collaborator:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01507051
First received: December 5, 2011
Last updated: May 8, 2014
Last verified: May 2014
Results First Received: January 30, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Pharmacodynamics Study;   Intervention Model: Parallel Assignment;   Masking: Single Blind (Subject)
Condition: Venous Thrombosis
Interventions: Drug: Warfarin (Coumadin)
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Drug: Placebo
Drug: Vitamin K (Konakion)

  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
Participants were recruited by 2 centers in Germany: ClinPharmCologne - MEDA Manufacturing GmbH, Neurather Ring 1, 51063 Koeln, and CRS Clinical-Research-Services Moenchengladbach GmbH, Hindenburgstrasse 304-306, 41061 Moenchengladbach. 84 participants were planned to participate (n=28 per group; minimum completion target n=75, n=25 per group).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
488 participants were screened, 392 were dropped. 96 participants were included in the study, 55 by Trial Unit 1 ClinPharmCologne, and 41 by Trial Unit 2 CRS Moenchengladbach. 91 participants were included in the safety set, 84 participants were valid for the assessment of pharmacokinetics and pharmacodynamics (PK/PD set).

Reporting Groups
  Description
Group A: Warfarin Followed by Rivaroxaban Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily
Group B: Warfarin Followed by Placebo Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily
Group C: Rivaroxaban Without Any Pre-treatment With Warfarin Days 0 to 3: 20 mg rivaroxaban once daily
Group D: Warfarin Alone Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR

Participant Flow:   Overall Study
    Group A: Warfarin Followed by Rivaroxaban     Group B: Warfarin Followed by Placebo     Group C: Rivaroxaban Without Any Pre-treatment With Warfarin     Group D: Warfarin Alone  
STARTED     29     31     29     7  
Warfarin run-in Phase     28     28     0     7 [1]
Received Placebo or Rivaroxaban     28 [2]   28 [3]   28 [4]   0  
COMPLETED     27     28     28     0  
NOT COMPLETED     2     3     1     7  
Withdrawal by Subject                 1                 3                 1                 6  
Physician Decision                 0                 0                 0                 1  
Adverse Event                 1                 0                 0                 0  
[1] Safety Population: in RG4
[2] Safety Population: in RG1 and in RG4 (RG = Reporting Group for Safety Data)
[3] Safety Population: in RG2 and in RG4
[4] Safety Population: in RG3



  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
Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily
Warfarin Followed by Placebo Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily
Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Warfarin Alone Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR
Total Total of all reporting groups

Baseline Measures
    Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939)     Warfarin Followed by Placebo     Rivaroxaban (Xarelto, BAY59-7939)     Warfarin Alone     Total  
Number of Participants  
[units: participants]
  28     28     28     7     91  
Age  
[units: years]
Mean ± Standard Deviation
  31.3  ± 7.2     30.7  ± 7.5     34.8  ± 8.0     34.6  ± 6.9     32.4  ± 7.6  
Gender  
[units: participants]
         
Female     0     0     0     0     0  
Male     28     28     28     7     91  



  Outcome Measures
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1.  Primary:   Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

2.  Primary:   Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

3.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

4.  Secondary:   AUCBA(0-tn) (Baseline Adjusted Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

5.  Secondary:   Emax on PT (Measured as INR=International Normalized Ratio)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

6.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) for PT (Measured as INR=International Normalized Ratio)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

7.  Secondary:   Emax on Factor Xa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

8.  Secondary:   AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

9.  Secondary:   Emax (Maximum Effect) on Anti-Factor Xa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

10.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

11.  Secondary:   Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

12.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

13.  Secondary:   Emax (Maximum Effect) on HepTest (Coagulation Test)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

14.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

15.  Secondary:   Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

16.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time)   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

17.  Secondary:   Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

18.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

19.  Secondary:   Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

20.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Lag Time   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

21.  Secondary:   Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

22.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

23.  Secondary:   Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

24.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak Time   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

25.  Secondary:   Emax (Maximum Effect) on Factor VIIa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

26.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

27.  Secondary:   Emax (Maximum Effect) on Factor IIa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

28.  Secondary:   AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ]

29.  Secondary:   Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ]

30.  Secondary:   Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ]

31.  Secondary:   Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin   [ Time Frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin ]

32.  Secondary:   Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin   [ Time Frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin ]

33.  Secondary:   Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Divided by Dose Per kg Body Weight [AUC(0-24)Norm] of Rivaroxaban After First Dose   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ]

34.  Secondary:   Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ]

35.  Secondary:   Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose   [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ]

36.  Secondary:   Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose   [ Time Frame: Always 3 h after second, third, and fourth dose ]

37.  Secondary:   Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose   [ Time Frame: Always 24 h after the second, third, and fourth dose ]

38.  Secondary:   Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose   [ Time Frame: 3, 24, 48, and 72 h after the last administration of rivaroxaban ]

39.  Secondary:   Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of R-warfarin After the Last Dose of Warfarin   [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ]

40.  Secondary:   Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of R-warfarin After the Last Dose of Warfarin   [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ]

41.  Secondary:   Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of S-warfarin After the Last Dose of Warfarin   [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ]

42.  Secondary:   Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of S-warfarin After the Last Dose of Warfarin   [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ]


  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:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com


Publications of Results:

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01507051     History of Changes
Other Study ID Numbers: 10849, 2008-005540-16
Study First Received: December 5, 2011
Results First Received: January 30, 2012
Last Updated: May 8, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices