Switching Study From Warfarin to Rivaroxaban

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

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

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 ]