Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 2008-005540-16 | EudraCT Number |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Johnson & Johnson Pharmaceutical Research & Development, L.L.C. | INDUSTRY |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The study objective is to investigate the pharmacodynamics (effects of a drug product) when switching the treatment from warfarin to rivaroxaban.
84 young, healthy subjects will participate; they will be treated following a randomized, parallel-group (Treatments A, B, and C), placebo-controlled (Treatment B), and single-blind (Treatments A and B) design.
The first two groups (A, B) will receive warfarin for approximately one week to adjust their blood coagulation values to a specific level, i.e. to maintain an INR (international normalized ratio) of 2.0 - 3.0. This range is commonly used for long-term anticoagulant treatment.
The first group (A) will receive rivaroxaban for four days, the second group (B) will take placebo. On the last day, all subjects in groups A and B will receive vitamin K to neutralize the effects of warfarin. The third group (C) will not undergo prior treatment with warfarin but will receive rivaroxaban for four days.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Warfarin followed by Rivaroxaban (Xarelto, BAY59-7939) | Experimental | Days -6 and -5: 10 mg warfarin once daily or lower depending on international normalized ratio (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 | Placebo Comparator | 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) | Active Comparator | Days 0 to 3: 20 mg rivaroxaban once daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Warfarin (Coumadin) | Drug | Days -6 and -5: 10 mg warfarin (Coumadin) once daily, dosage lower if the INR is already high on day -5; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin (Coumadin) once daily, dosage depending on INR |
| Measure | Description | Time Frame |
|---|---|---|
| Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Measure | Description | Time Frame |
|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 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. |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Bayer Study Director | Bayer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cologne | North Rhine-Westphalia | 51063 | Germany | |||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24528331 | Result | Kubitza D, Becka M, Muck W, Kratzschmar J. Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects. Br J Clin Pharmacol. 2014 Aug;78(2):353-63. doi: 10.1111/bcp.12349. |
| Label | URL |
|---|---|
| Click here and search for results posted for EMA | View source |
Not provided
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).
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).
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| FG002 | Group C: Rivaroxaban Without Any Pre-treatment With Warfarin | Days 0 to 3: 20 mg rivaroxaban once daily |
| FG003 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
Not provided
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | RG1: Warfarin Followed by Rivaroxaban | 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. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bradycardia | Cardiac disorders | MedDRA (12.1) | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Therapeutic Area Head | BAYER | clinical-trials-contact@bayerhealthcare.com |
Not provided
| ID | Term |
|---|---|
| D020246 | Venous Thrombosis |
| D013927 | Thrombosis |
| D004617 | Embolism |
| ID | Term |
|---|---|
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D014859 | Warfarin |
| D000069552 | Rivaroxaban |
| D014812 | Vitamin K |
| D010837 | Vitamin K 1 |
| ID | Term |
|---|---|
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Rivaroxaban (Xarelto, BAY59-7939) | Drug | Days 0 to 3: 20 mg rivaroxaban once daily |
|
| Placebo | Drug | Days 0 to 3: 1 tablet placebo, identical to active tablet |
|
| Vitamin K (Konakion) | Drug | Day 5: 10 mg vitamin K (Konakion) once daily |
|
| 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| 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) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax on PT (Measured as INR=International Normalized Ratio) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| 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) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax on Factor Xa Activity | 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]. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on Anti-Factor Xa Activity | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on HepTest (Coagulation Test) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time) | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC | 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). | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| 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 | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak | 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). | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| 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 | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on Factor VIIa Activity | 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). | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Emax (Maximum Effect) on Factor IIa Activity | 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). | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose | 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). | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
| Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
| Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin | 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. | Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin |
| Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin | 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. | Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin |
| 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 | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
| Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
| Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose | 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. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
| Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | Cpeak refers to the time after dosing when the drug concentration is expected to reach its maximum (peak) concentration. | Always 3 h after second, third, and fourth dose |
| Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | Ctrough refers to the time after dosing when the drug concentration is expected to reach its minimum (trough) concentration. | Always 24 h after the second, third, and fourth dose |
| Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose | 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. | 3, 24, 48, and 72 h after the last administration of rivaroxaban |
| 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 | Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration. | 0 h (predose) and 24 h after the last administration of warfarin |
| 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 | 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. | 0 h (predose) and 24 h after the last administration of warfarin |
| 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 | Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration. | 0 h (predose) and 24 h after the last administration of warfarin |
| 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 | 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. | 0 h (predose) and 24 h after the last administration of warfarin |
| Mönchengladbach |
| North Rhine-Westphalia |
| 41061 |
| Germany |
| Physician Decision |
|
| Adverse Event |
|
| 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 |
| BG002 | Rivaroxaban (Xarelto, BAY59-7939) | Days 0 to 3: 20 mg rivaroxaban once daily |
| BG003 | Warfarin Alone | Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | 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 |
| OG002 | Rivaroxaban (Xarelto, BAY59-7939) | Days 0 to 3: 20 mg rivaroxaban once daily |
|
|
|
| Primary | Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | seconds | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
|
| Secondary | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | s*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax on PT (Measured as INR=International Normalized Ratio) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax on Factor Xa Activity | 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]. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Percentage of inhibition | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Percentage of inhibition*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on Anti-Factor Xa Activity | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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) | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on HepTest (Coagulation Test) | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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) | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC | 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). | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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 | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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 | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak | 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). | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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 | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| 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 | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on Factor VIIa Activity | 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). | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Emax (Maximum Effect) on Factor IIa Activity | 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). | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio*h | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo |
|
|
|
| Secondary | Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose | 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). | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | microg*h/L | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
|
|
|
|
| Secondary | Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | microg/L | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
|
|
|
|
| Secondary | Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin |
|
|
|
|
| Secondary | Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin |
|
|
|
|
| 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 | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Kg*h/L | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
|
|
|
| Secondary | Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Kg/L | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
|
|
|
| Secondary | Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose | 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. | PK/PD set | Posted | Median | Full Range | hours | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban |
|
|
|
| Secondary | Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | Cpeak refers to the time after dosing when the drug concentration is expected to reach its maximum (peak) concentration. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Microg/L | Always 3 h after second, third, and fourth dose |
|
|
|
| Secondary | Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | Ctrough refers to the time after dosing when the drug concentration is expected to reach its minimum (trough) concentration. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Microg/L | Always 24 h after the second, third, and fourth dose |
|
|
|
| Secondary | Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose | 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. | PK/PD set; derived parameter could not be evaluated for all participants. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | 3, 24, 48, and 72 h after the last administration of rivaroxaban |
|
|
|
| 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 | Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Microg/L | 0 h (predose) and 24 h after the last administration of warfarin |
|
|
|
| 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 | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | 1/Liter | 0 h (predose) and 24 h after the last administration of warfarin |
|
|
|
| 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 | Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | Microg/L | 0 h (predose) and 24 h after the last administration of warfarin |
|
|
|
| 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 | 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. | PK/PD set | Posted | Geometric Mean | Geometric Coefficient of Variation | 1/Liter | 0 h (predose) and 24 h after the last administration of warfarin |
|
|
|
| 0 |
| 28 |
| 14 |
| 28 |
| EG001 | RG2: Warfarin Followed by Placebo | 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. | 0 | 28 | 12 | 28 |
| EG002 | RG3: Rivaroxaban | 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. | 0 | 28 | 10 | 28 |
| EG003 | RG4: Warfarin Alone | 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. | 0 | 63 | 21 | 63 |
| Dry eye | Eye disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Eructation | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Gingival bleeding | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Lip dry | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Tongue ulceration | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Application site erythema | General disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Asthenia | General disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Chest pain | General disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Injection site haematoma | General disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Catheter site pain | General disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (12.1) | Non-systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA (12.1) | Non-systematic Assessment |
|
| Febrile infection | Infections and infestations | MedDRA (12.1) | Non-systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA (12.1) | Non-systematic Assessment |
|
| Muscle strain | Injury, poisoning and procedural complications | MedDRA (12.1) | Non-systematic Assessment |
|
| Tooth fracture | Injury, poisoning and procedural complications | MedDRA (12.1) | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (12.1) | Non-systematic Assessment |
|
| Blood amylase increased | Investigations | MedDRA (12.1) | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (12.1) | Non-systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA (12.1) | Non-systematic Assessment |
|
| C-reactive protein increased | Investigations | MedDRA (12.1) | Non-systematic Assessment |
|
| Lipase increased | Investigations | MedDRA (12.1) | Non-systematic Assessment |
|
| Urine output increased | Investigations | MedDRA (12.1) | Non-systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Muscle tightness | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Musculoskeletal stiffness | Musculoskeletal and connective tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Sleep disorder | Psychiatric disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Spontaneous penile erection | Reproductive system and breast disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (12.1) | Non-systematic Assessment |
|
| Thrombophlebitis | Vascular disorders | MedDRA (12.1) | Non-systematic Assessment |
|
Any disclosure of study results by the Principal Investigator or investigators has to be in agreement with the sponsor.
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D009025 | Morpholines |
| D010078 | Oxazines |
| D009285 | Naphthoquinones |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D010836 | Phytol |
| D004224 | Diterpenes |
| D013729 | Terpenes |
| D011083 | Polycyclic Compounds |
| D011809 | Quinones |
| fourth dose |
|
| fourth dose |
|