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Trial record 24 of 226 for:    warfarin AND International

Switching Study From Warfarin to Rivaroxaban

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ClinicalTrials.gov Identifier: NCT01507051
Recruitment Status : Completed
First Posted : January 10, 2012
Results First Posted : April 26, 2012
Last Update Posted : February 9, 2015
Sponsor:
Collaborator:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Participant)
Condition Venous Thrombosis
Interventions Drug: Warfarin (Coumadin)
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Drug: Placebo
Drug: Vitamin K (Konakion)
Enrollment 96
Recruitment Details 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 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).
Arm/Group Title 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
Hide Arm/Group Description 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 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 Days 0 to 3: 20 mg rivaroxaban once daily Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR
Period Title: Overall Study
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
Reason Not Completed
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
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939) Warfarin Alone Total
Hide Arm/Group Description 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 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 Days 0 to 3: 20 mg rivaroxaban once daily Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR Total of all reporting groups
Overall Number of Baseline Participants 28 28 28 7 91
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 28 participants 28 participants 28 participants 7 participants 91 participants
31.3  (7.2) 30.7  (7.5) 34.8  (8.0) 34.6  (6.9) 32.4  (7.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants 28 participants 28 participants 7 participants 91 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Male
28
 100.0%
28
 100.0%
28
 100.0%
7
 100.0%
91
 100.0%
1.Primary Outcome
Title Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)
Hide Description Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax on PT was measured as the ratio of maximum PT (measured in seconds) divided by PT (measured in seconds) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
4.393
(18.03%)
1.884
(10.35%)
1.573
(9.98%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939), Rivaroxaban (Xarelto, BAY59-7939)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS-Mean Ratio
Estimated Value 2.793
Confidence Interval 90%
2.633 to 2.962
Estimation Comments [Not Specified]
2.Primary Outcome
Title Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test)
Hide Description Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax,BA on PT was measured as maximum PT (measured in seconds) minus PT (measured in seconds) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: seconds
44.98
(20.84%)
11.59
(19.52%)
7.31
(23.72%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939), Rivaroxaban (Xarelto, BAY59-7939)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS-Mean Ratio
Estimated Value 6.151
Confidence Interval 90%
5.598 to 6.759
Estimation Comments [Not Specified]
3.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)
Hide Description Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT was the area under the measurement (PT [measured in seconds] at different time-points divided by PT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
55.36
(13.36%)
37.89
(9.92%)
20.41
(33.52%)
4.Secondary Outcome
Title 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)
Hide Description Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUCBA(0-tn) of PT was the area under the measurement (PT [measured in seconds] at different time-points minus PT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: s*h
413.4
(19.87%)
179.9
(26.58%)
33.06
(55.70%)
5.Secondary Outcome
Title Emax on PT (Measured as INR=International Normalized Ratio)
Hide Description Prothrombin time – INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. Emax on PT (INR) was measured as the ratio of maximum INR divided by baseline INR.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
6.655
(23.39%)
2.250
(13.19%)
1.793
(12.87%)
6.Secondary Outcome
Title 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)
Hide Description Prothrombin time – INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT (INR) was the area under the measurement (PT measured as INR at different time-points divided by PT measured as INR at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
72.30
(17.35%)
43.60
(12.81%)
23.21
(30.63%)
7.Secondary Outcome
Title Emax on Factor Xa Activity
Hide Description Test to measure the activity of endogenous Factor Xa. Emax on Factor Xa activity was calculated as 100*(Factor Xa activity at baseline [measured as activity per mL] - minimum of Factor Xa activity [measured as activity per mL]) / Factor Xa activity at baseline [measured as activity per mL].
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Percentage of inhibition
75.95
(6.56%)
43.41
(12.67%)
49.73
(13.86%)
8.Secondary Outcome
Title AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity
Hide Description Test to measure the activity of endogenous Factor Xa. AUC(0-tn) of Factor Xa activity was the area under the inverse measurement [100*(Factor Xa activity at baseline (measured as activity per mL) - Factor Xa activity (measured as activity per mL) at different time-points) / Factor Xa activity at baseline (measured as activity per mL)] versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Percentage of inhibition*h
1238
(12.28%)
834.8
(19.44%)
514.1
(27.90%)
9.Secondary Outcome
Title Emax (Maximum Effect) on Anti-Factor Xa Activity
Hide Description This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. Emax on anti-Factor Xa activity was measured as the ratio of maximum anti-Factor Xa activity (measured in U/L) divided by anti-Factor Xa activity (measured in U/L) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 12 27
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
15.83
(56.06%)
2.281
(112.7%)
18.57
(42.99%)
10.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity
Hide Description This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. AUC(0-tn) of anti-Factor Xa activity was the area under the measurement (anti-Factor Xa activity [measured in U/L] at different time-points divided by anti-Factor Xa activity [measured in U/L] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 12 27
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
124.9
(68.84%)
19.63
(202.0%)
151.6
(38.88%)
11.Secondary Outcome
Title Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time)
Hide Description The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. Emax on aPTT was measured as the ratio of maximum aPTT (measured in seconds) divided by aPTT (measured in seconds) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
1.843
(10.55%)
1.304
(15.07%)
1.409
(6.19%)
12.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time)
Hide Description The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of aPTT was the area under the measurement (aPTT [measured in seconds] at different time-points divided by aPTT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
32.48
(9.41%)
22.55
(56.41%)
21.82
(42.67%)
13.Secondary Outcome
Title Emax (Maximum Effect) on HepTest (Coagulation Test)
Hide Description This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on HepTest was measured as the ratio of maximum HepTest (measured in seconds) divided by HepTest (measured in seconds) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 23 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
2.148
(14.20%)
1.163
(19.78%)
2.009
(12.13%)
14.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test)
Hide Description This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of HepTest was the area under the measurement (HepTest [measured in seconds] at different time-points divided by HepTest [measured in seconds] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 20 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
27.37
(32.90%)
15.08
(125.9%)
28.25
(29.31%)
15.Secondary Outcome
Title Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time)
Hide Description This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on PiCT was measured as the ratio of maximum PiCT (measured in seconds) divided by PiCT (measured in seconds) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 18 27
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
3.158
(27.20%)
1.139
(21.36%)
2.723
(20.69%)
16.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time)
Hide Description This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PiCT was the area under the measurement (PiCT [measured in seconds] at different time-points divided by PiCT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 12 26
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
37.36
(38.40%)
4.221
(429.5%)
39.20
(8.91%)
17.Secondary Outcome
Title Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC
Hide Description ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP AUC was measured as the ratio of ETP AUC (measured in nm*min as integral of fluorescence measurements) at baseline divided by minimum ETP AUC (measured in nm*min as integral of fluorescence measurements).
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
4.257
(24.41%)
2.610
(22.05%)
1.813
(25.45%)
18.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC
Hide Description ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP AUC was the area under the measurement (ETP AUC [measured in nm*min as integral of fluorescence measurements] at baseline divided by ETP AUC [measured in nm*min as integral of fluorescence measurements] at different time-points) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
69.69
(25.83%)
51.28
(17.90%)
18.06
(78.12%)
19.Secondary Outcome
Title Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time
Hide Description ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP lag time was measured as the ratio of maximum ETP lag time (in minutes as measure for the start of coagulation) divided by ETP lag time (in minutes as measure for the start of coagulation) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
3.954
(19.02%)
1.748
(18.49%)
2.569
(9.83%)
20.Secondary Outcome
Title 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
Hide Description ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP lag time was the area under the measurement (ETP lag time [in minutes as measure for the start of coagulation] at different time-points divided by ETP lag time [in minutes as measure for the start of coagulation] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
63.75
(17.88%)
34.93
(20.83%)
42.79
(9.54%)
21.Secondary Outcome
Title Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak
Hide Description ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak was measured as the ratio of ETP peak (measured in nm as maximum coagulation activity) at baseline divided by minimum ETP peak (measured in nm as maximum coagulation activity).
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
18.73
(44.08%)
2.523
(44.17%)
6.758
(33.31%)
22.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak
Hide Description ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak was the area under the measurement (ETP peak [measured in nm as maximum coagulation activity] at baseline divided by ETP peak measured [in nm as maximum coagulation activity] at different time-points) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
166.8
(45.97%)
46.75
(19.22%)
74.67
(27.40%)
23.Secondary Outcome
Title Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time
Hide Description ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak time was measured as the ratio of maximum ETP peak time (measured in minutes as time to reach the maximum coagulation activity) divided by ETP peak time (measured in minutes as time to reach the maximum coagulation activity) at baseline.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
4.164
(33.95%)
1.375
(20.87%)
3.790
(15.75%)
24.Secondary Outcome
Title 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
Hide Description ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak time was the area under the measurement (ETP peak time [measured in minutes as time to reach the maximum coagulation activity] at different time-points divided by ETP peak time [measured in minutes as time to reach the maximum coagulation activity] at baseline) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
49.14
(28.10%)
19.83
(143.9%)
55.58
(12.47%)
25.Secondary Outcome
Title Emax (Maximum Effect) on Factor VIIa Activity
Hide Description Factor VII is a coagulation factor that is required for the coagulation process. Emax on Factor VIIa activity was measured as the ratio of Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma) at baseline divided by minimum Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma).
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
12.80
(47.88%)
6.769
(53.51%)
1.346
(7.51%)
26.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity
Hide Description Factor VII is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor VIIa activity was the area under the measurement (Factor VIIa activity [measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma] at baseline divided by Factor VIIa activity [measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma] at different time-points) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
134.2
(44.70%)
94.83
(41.07%)
9.283
(70.62%)
27.Secondary Outcome
Title Emax (Maximum Effect) on Factor IIa Activity
Hide Description Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. Emax on Factor IIa activity was measured as the ratio of Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma) at baseline divided by minimum Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma).
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
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Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio
3.166
(16.09%)
2.958
(12.31%)
1.126
(5.08%)
28.Secondary Outcome
Title AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity
Hide Description Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor IIa activity was the area under the measurement (Factor IIa activity [measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma] at baseline divided by Factor IIa activity [measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma] at different time-points) versus time curve from time 0 to the last data point.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28 26
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ratio*h
62.26
(18.20%)
58.60
(15.18%)
3.908
(117.7%)
29.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose
Hide Description The AUC is a measure of systemic drug exposure which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample ([AUC(0-24)] is defined as area under the concentration vs. time curve from zero to 24 hours after first (single) dose).
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
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PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microg*h/L
1639
(29.46%)
1722
(26.19%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939), Rivaroxaban (Xarelto, BAY59-7939)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5008
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS-Mean Ratio (%)
Estimated Value 95.17
Confidence Interval 95%
82.20 to 110.2
Estimation Comments [Not Specified]
30.Secondary Outcome
Title Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose
Hide Description Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microg/L
219.8
(30.94%)
221.0
(26.65%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939), Rivaroxaban (Xarelto, BAY59-7939)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9429
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS-Mean Ratio (%)
Estimated Value 99.46
Confidence Interval 95%
85.47 to 115.7
Estimation Comments [Not Specified]
31.Secondary Outcome
Title Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin
Hide Description Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
Time Frame Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo
Hide Arm/Group Description:
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
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
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
40.08
(19.63%)
40.24
(29.43%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939), Warfarin Followed by Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9525
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS-Mean Ratio (%)
Estimated Value 100.4
Confidence Interval 95%
88.00 to 114.5
Estimation Comments [Not Specified]
32.Secondary Outcome
Title Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin
Hide Description Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
Time Frame Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo
Hide Arm/Group Description:
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
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
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
28.24
(17.95%)
27.08
(22.79%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939), Warfarin Followed by Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4397
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS-Mean Ratio (%)
Estimated Value 95.87
Confidence Interval 95%
85.99 to 106.9
Estimation Comments [Not Specified]
33.Secondary Outcome
Title 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
Hide Description The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; [AUC(0-24)norm] is defined as AUC divided by dose per kg body weight from zero to 24 hours after first (single) dose.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Kg*h/L
6.569
(27.55%)
6.901
(31.63%)
34.Secondary Outcome
Title Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose
Hide Description Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Kg/L
0.8812
(27.83%)
0.8857
(31.79%)
35.Secondary Outcome
Title Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose
Hide Description Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time Frame 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28
Median (Full Range)
Unit of Measure: hours
3.008
(1.000 to 4.000)
3.000
(1.000 to 4.067)
36.Secondary Outcome
Title Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose
Hide Description Cpeak refers to the time after dosing when the drug concentration is expected to reach its maximum (peak) concentration.
Time Frame Always 3 h after second, third, and fourth dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Microg/L
second dose
211.2
(28.72%)
206.7
(35.62%)
third dose
206.1
(30.66%)
201.0
(30.65%)
fourth dose
201.4
(77.43%)
214.5
(27.35%)
37.Secondary Outcome
Title Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose
Hide Description Ctrough refers to the time after dosing when the drug concentration is expected to reach its minimum (trough) concentration.
Time Frame Always 24 h after the second, third, and fourth dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Microg/L
second dose
13.06
(50.64%)
17.07
(45.32%)
third dose
14.34
(54.05%)
15.85
(47.92%)
fourth dose
12.43
(85.96%)
15.61
(51.52%)
38.Secondary Outcome
Title Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose
Hide Description Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
Time Frame 3, 24, 48, and 72 h after the last administration of rivaroxaban
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set; derived parameter could not be evaluated for all participants.
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939)
Hide Arm/Group Description:
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
Days 0 to 3: 20 mg rivaroxaban once daily
Overall Number of Participants Analyzed 27 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
6.885
(42.48%)
6.931
(36.70%)
39.Secondary Outcome
Title 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
Hide Description Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.
Time Frame 0 h (predose) and 24 h after the last administration of warfarin
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo
Hide Arm/Group Description:
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
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
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Microg/L
before last administration
754.4
(32.70%)
721.8
(25.56%)
after last administration
740.2
(25.88%)
702.8
(28.39%)
40.Secondary Outcome
Title 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
Hide Description Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.
Time Frame 0 h (predose) and 24 h after the last administration of warfarin
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo
Hide Arm/Group Description:
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
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
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/Liter
before last administration
0.07154
(40.86%)
0.07843
(48.55%)
after last administration
0.08633
(44.10%)
0.07915
(46.50%)
41.Secondary Outcome
Title 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
Hide Description Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.
Time Frame 0 h (predose) and 24 h after the last administration of warfarin
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo
Hide Arm/Group Description:
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
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
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Microg/L
before last administration
498.2
(38.93%)
429.9
(31.14%)
after last administration
478.4
(26.17%)
424.9
(29.78%)
42.Secondary Outcome
Title 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
Hide Description Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.
Time Frame 0 h (predose) and 24 h after the last administration of warfarin
Hide Outcome Measure Data
Hide Analysis Population Description
PK/PD set
Arm/Group Title Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) Warfarin Followed by Placebo
Hide Arm/Group Description:
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
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
Overall Number of Participants Analyzed 28 28
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/Liter
before last administration
0.04724
(43.96%)
0.04671
(53.03%)
after last administration
0.05580
(43.11%)
0.04786
(38.96%)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title RG1: Warfarin Followed by Rivaroxaban RG2: Warfarin Followed by Placebo RG3: Rivaroxaban RG4: Warfarin Alone
Hide Arm/Group Description All participants received warfarin and later 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. Note: Safety Data presented here include participants listed in Group A of the Participant Flow section. All participants received warfarin and later 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. Note: Safety Data presented here include participants listed in Group B of the Participant Flow section. All participants received rivaroxaban. Days 0 to 3: 20 mg rivaroxaban once daily. Note: Safety Data presented here include participants listed in Group C of the Participant Flow section. All participants received warfarin in the Run-In Phase, who either received rivaroxaban or placebo afterwards, or discontinued the study. Days -6 to -1(could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR. Note: Safety Data presented here include participants listed in Groups A, B (warfarin run-in only) and D of the Participant Flow section.
All-Cause Mortality
RG1: Warfarin Followed by Rivaroxaban RG2: Warfarin Followed by Placebo RG3: Rivaroxaban RG4: Warfarin Alone
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
RG1: Warfarin Followed by Rivaroxaban RG2: Warfarin Followed by Placebo RG3: Rivaroxaban RG4: Warfarin Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/28 (0.00%)      0/28 (0.00%)      0/28 (0.00%)      0/63 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
RG1: Warfarin Followed by Rivaroxaban RG2: Warfarin Followed by Placebo RG3: Rivaroxaban RG4: Warfarin Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/28 (50.00%)      12/28 (42.86%)      10/28 (35.71%)      21/63 (33.33%)    
Cardiac disorders         
Bradycardia * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 1/28 (3.57%)  1 0/63 (0.00%)  0
Eye disorders         
Dry eye * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Gastrointestinal disorders         
Abdominal discomfort * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Abdominal pain * 1  0/28 (0.00%)  0 2/28 (7.14%)  2 0/28 (0.00%)  0 1/63 (1.59%)  1
Diarrhoea * 1  2/28 (7.14%)  2 1/28 (3.57%)  1 0/28 (0.00%)  0 3/63 (4.76%)  3
Dyspepsia * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Eructation * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Flatulence * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 2/63 (3.17%)  2
Gingival bleeding * 1  2/28 (7.14%)  2 0/28 (0.00%)  0 0/28 (0.00%)  0 3/63 (4.76%)  3
Lip dry * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Nausea * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Tongue ulceration * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
Toothache * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
General disorders         
Application site erythema * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
Asthenia * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Chest pain * 1  1/28 (3.57%)  2 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
Fatigue * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 3/63 (4.76%)  3
Injection site haematoma * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 1/28 (3.57%)  1 1/63 (1.59%)  1
Catheter site pain * 1  0/28 (0.00%)  0 1/28 (3.57%)  2 0/28 (0.00%)  0 1/63 (1.59%)  1
Infections and infestations         
Nasopharyngitis * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 3/28 (10.71%)  3 1/63 (1.59%)  1
Rhinitis * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 0/28 (0.00%)  0 0/63 (0.00%)  0
Febrile infection * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 0/28 (0.00%)  0 0/63 (0.00%)  0
Oral herpes * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 1/28 (3.57%)  1 0/63 (0.00%)  0
Injury, poisoning and procedural complications         
Muscle strain * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Tooth fracture * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Investigations         
Alanine aminotransferase increased * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
Blood amylase increased * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
Blood bilirubin increased * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Blood creatine phosphokinase increased * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 1/28 (3.57%)  1 0/63 (0.00%)  0
C-reactive protein increased * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 0/28 (0.00%)  0 1/63 (1.59%)  1
Lipase increased * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 2/28 (7.14%)  2 0/63 (0.00%)  0
Urine output increased * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 0/28 (0.00%)  0 0/63 (0.00%)  0
Metabolism and nutrition disorders         
Hypoglycaemia * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Musculoskeletal and connective tissue disorders         
Back pain * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 1/28 (3.57%)  1 1/63 (1.59%)  1
Myalgia * 1  0/28 (0.00%)  0 2/28 (7.14%)  2 0/28 (0.00%)  0 0/63 (0.00%)  0
Neck pain * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 0/28 (0.00%)  0 1/63 (1.59%)  1
Muscle tightness * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 1/28 (3.57%)  1 0/63 (0.00%)  0
Musculoskeletal stiffness * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
Nervous system disorders         
Dizziness * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 1/28 (3.57%)  1 1/63 (1.59%)  1
Headache * 1  2/28 (7.14%)  2 1/28 (3.57%)  1 1/28 (3.57%)  1 4/63 (6.35%)  4
Paraesthesia * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 0/28 (0.00%)  0 0/63 (0.00%)  0
Psychiatric disorders         
Sleep disorder * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Reproductive system and breast disorders         
Spontaneous penile erection * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Cough * 1  1/28 (3.57%)  1 1/28 (3.57%)  1 0/28 (0.00%)  0 0/63 (0.00%)  0
Epistaxis * 1  0/28 (0.00%)  0 1/28 (3.57%)  1 1/28 (3.57%)  1 0/63 (0.00%)  0
Hiccups * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Nasal congestion * 1  0/28 (0.00%)  0 3/28 (10.71%)  3 0/28 (0.00%)  0 0/63 (0.00%)  0
Skin and subcutaneous tissue disorders         
Hyperhidrosis * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 0/28 (0.00%)  0 1/63 (1.59%)  1
Pruritus * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 1/28 (3.57%)  1 0/63 (0.00%)  0
Rash * 1  0/28 (0.00%)  0 0/28 (0.00%)  0 1/28 (3.57%)  1 0/63 (0.00%)  0
Vascular disorders         
Thrombophlebitis * 1  1/28 (3.57%)  1 0/28 (0.00%)  0 0/28 (0.00%)  0 0/63 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (12.1)
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.
Any disclosure of study results by the Principal Investigator or investigators has to be in agreement with the sponsor.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Therapeutic Area Head
Organization: BAYER
EMail: clinical-trials-contact@bayerhealthcare.com
Layout table for additonal information
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01507051     History of Changes
Other Study ID Numbers: 10849
2008-005540-16 ( EudraCT Number )
First Submitted: December 5, 2011
First Posted: January 10, 2012
Results First Submitted: January 30, 2012
Results First Posted: April 26, 2012
Last Update Posted: February 9, 2015