Venous Thrombosis
Conditions
Keywords
Rivaroxaban, Xa-Factors, Warfarin, Thrombosis, Embolism
Brief summary
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.
Interventions
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
DRUGRivaroxaban (Xarelto, BAY59-7939)
Days 0 to 3: 20 mg rivaroxaban once daily
DRUGPlacebo
Days 0 to 3: 1 tablet placebo, identical to active tablet
DRUGVitamin K (Konakion)
Day 5: 10 mg vitamin K (Konakion) once daily
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* 18 to 45 years of age; * Normal body weight: BMI (body mass index) between 18 and 29 kg/m2; * Pharmacogenetics: subjects who are homozygous for the wildtype allele 2C9\*1 and who are carriers of the C-allele at positions 6484 and 7566 of the VKORC1 (vitamin K epoxide reductase) gene, respectively
Exclusion criteria
* Relevant deviation from the normal range in the clinical examination; * Relevant deviation from the normal range in clinical chemistry, hematology or urinalysis; * Resting heart rate in the awake subject below 45 BPM (beats per minute) or above 90 BPM; * Systolic blood pressure below 100 mmHg or above 140 mmHg; and Diastolic blood pressure above 85 mmHg; * Relevant pathological changes in the ECG (electrocardiogram) such as a second or third-degree AV block, prolongation of the QRS (QRS complex in ECG) complex over 120 msec or of the QT / QTc-interval over 450 msec (QT interval in ECG, QTc interval corrected for heart rate); * Subject is tested to be HIV-1/2Ab, p24Ag, HbsAg or HCV-Ab positive; * Known coagulation disorders (e.g. von Willebrand's disease, haemophiliac); * Known disorders with increased bleeding risks (e.g. periodontosis, hemorrhoids, acute gastritis, peptic ulcer); * Known sensitivity to common causes of bleeding (e.g. nasal); * Recent or planned surgical or diagnostic procedures at the central nervous system (CNS) or eye; * Subjects with hyperlipidemia (Coumadin / warfarin warning)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Emax on PT (Measured as INR=International Normalized Ratio) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| 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) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax on Factor Xa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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 \[measured as activity per mL\]. |
| AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on Anti-Factor Xa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on HepTest (Coagulation Test) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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). |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| 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 | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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). |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| 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 | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on Factor VIIa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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). |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Emax (Maximum Effect) on Factor IIa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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). |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban | 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). |
| Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban | 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. |
| Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin | Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration 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. |
| Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin | Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration 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. |
| 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 | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban | 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. |
| Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban | 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 to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban | 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. |
| Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | Always 3 h after second, third, and fourth dose | Cpeak refers to the time after dosing when the drug concentration is expected to reach its maximum (peak) concentration. |
| Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | Always 24 h after the second, third, and fourth dose | Ctrough refers to the time after dosing when the drug concentration is expected to reach its minimum (trough) concentration. |
| Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose | 3, 24, 48, and 72 h after the last administration of rivaroxaban | 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. |
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
| 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 | 0 h (predose) and 24 h after the last administration 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. |
| 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 | 0 h (predose) and 24 h after the last administration 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. |
| 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 | 0 h (predose) and 24 h after the last administration 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. |
| 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 | 0 h (predose) and 24 h after the last administration 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. |
| 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) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo | 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. |
Countries
Germany
Participant flow
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).
Participants by arm
| Arm | Count |
|---|---|
| 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 | 28 |
| 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 | 28 |
| Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily | 28 |
| Warfarin Alone Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR | 7 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 1 | 6 |
Baseline characteristics
| Characteristic | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Alone | Total |
|---|---|---|---|---|---|
| Age, Continuous | 31.3 years STANDARD_DEVIATION 7.2 | 30.7 years STANDARD_DEVIATION 7.5 | 34.8 years STANDARD_DEVIATION 8 | 34.6 years STANDARD_DEVIATION 6.9 | 32.4 years STANDARD_DEVIATION 7.6 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 28 Participants | 28 Participants | 28 Participants | 7 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 28 | 12 / 28 | 10 / 28 | 21 / 63 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 63 |
Outcome results
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) | 44.98 seconds | Geometric Coefficient of Variation 20.84 |
| Warfarin Followed by Placebo | Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) | 11.59 seconds | Geometric Coefficient of Variation 19.52 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) | 7.31 seconds | Geometric Coefficient of Variation 23.72 |
p-value: <0.000190% CI: [5.598, 6.759]ANOVA
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) | 4.393 ratio | Geometric Coefficient of Variation 18.03 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) | 1.884 ratio | Geometric Coefficient of Variation 10.35 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) | 1.573 ratio | Geometric Coefficient of Variation 9.98 |
p-value: <0.000190% CI: [2.633, 2.962]ANOVA
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).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose | 1639 microg*h/L | Geometric Coefficient of Variation 29.46 |
| Warfarin Followed by Placebo | Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose | 1722 microg*h/L | Geometric Coefficient of Variation 26.19 |
p-value: 0.500895% CI: [82.2, 110.2]ANOVA
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | 6.569 Kg*h/L | Geometric Coefficient of Variation 27.55 |
| Warfarin Followed by Placebo | 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 | 6.901 Kg*h/L | Geometric Coefficient of Variation 31.63 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity | 1238 Percentage of inhibition*h | Geometric Coefficient of Variation 12.28 |
| Warfarin Followed by Placebo | AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity | 834.8 Percentage of inhibition*h | Geometric Coefficient of Variation 19.44 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity | 514.1 Percentage of inhibition*h | Geometric Coefficient of Variation 27.9 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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) | 72.30 ratio*h | Geometric Coefficient of Variation 17.35 |
| Warfarin Followed by 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) | 43.60 ratio*h | Geometric Coefficient of Variation 12.81 |
| Rivaroxaban (Xarelto, BAY59-7939) | 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) | 23.21 ratio*h | Geometric Coefficient of Variation 30.63 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity | 124.9 ratio*h | Geometric Coefficient of Variation 68.84 |
| Warfarin Followed by Placebo | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity | 19.63 ratio*h | Geometric Coefficient of Variation 202 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity | 151.6 ratio*h | Geometric Coefficient of Variation 38.88 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time) | 32.48 ratio*h | Geometric Coefficient of Variation 9.41 |
| Warfarin Followed by 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) | 22.55 ratio*h | Geometric Coefficient of Variation 56.41 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time) | 21.82 ratio*h | Geometric Coefficient of Variation 42.67 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC | 69.69 ratio*h | Geometric Coefficient of Variation 25.83 |
| Warfarin Followed by 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 | 51.28 ratio*h | Geometric Coefficient of Variation 17.9 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC | 18.06 ratio*h | Geometric Coefficient of Variation 78.12 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | 63.75 ratio*h | Geometric Coefficient of Variation 17.88 |
| Warfarin Followed by 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 | 34.93 ratio*h | Geometric Coefficient of Variation 20.83 |
| Rivaroxaban (Xarelto, BAY59-7939) | 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 | 42.79 ratio*h | Geometric Coefficient of Variation 9.54 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak | 166.8 ratio*h | Geometric Coefficient of Variation 45.97 |
| Warfarin Followed by 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 | 46.75 ratio*h | Geometric Coefficient of Variation 19.22 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak | 74.67 ratio*h | Geometric Coefficient of Variation 27.4 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | 49.14 ratio*h | Geometric Coefficient of Variation 28.1 |
| Warfarin Followed by 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 | 19.83 ratio*h | Geometric Coefficient of Variation 143.9 |
| Rivaroxaban (Xarelto, BAY59-7939) | 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 | 55.58 ratio*h | Geometric Coefficient of Variation 12.47 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity | 62.26 ratio*h | Geometric Coefficient of Variation 18.2 |
| Warfarin Followed by Placebo | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity | 58.60 ratio*h | Geometric Coefficient of Variation 15.18 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity | 3.908 ratio*h | Geometric Coefficient of Variation 117.7 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity | 134.2 ratio*h | Geometric Coefficient of Variation 44.7 |
| Warfarin Followed by Placebo | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity | 94.83 ratio*h | Geometric Coefficient of Variation 41.07 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity | 9.283 ratio*h | Geometric Coefficient of Variation 70.62 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) | 27.37 ratio*h | Geometric Coefficient of Variation 32.9 |
| Warfarin Followed by Placebo | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) | 15.08 ratio*h | Geometric Coefficient of Variation 125.9 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) | 28.25 ratio*h | Geometric Coefficient of Variation 29.31 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time) | 37.36 ratio*h | Geometric Coefficient of Variation 38.4 |
| Warfarin Followed by 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) | 4.221 ratio*h | Geometric Coefficient of Variation 429.5 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time) | 39.20 ratio*h | Geometric Coefficient of Variation 8.91 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 55.36 ratio*h | Geometric Coefficient of Variation 13.36 |
| Warfarin Followed by Placebo | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 37.89 ratio*h | Geometric Coefficient of Variation 9.92 |
| Rivaroxaban (Xarelto, BAY59-7939) | AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 20.41 ratio*h | Geometric Coefficient of Variation 33.52 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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) | 413.4 s*h | Geometric Coefficient of Variation 19.87 |
| Warfarin Followed by 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) | 179.9 s*h | Geometric Coefficient of Variation 26.58 |
| Rivaroxaban (Xarelto, BAY59-7939) | 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) | 33.06 s*h | Geometric Coefficient of Variation 55.7 |
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.
Time frame: Always 3 h after second, third, and fourth dose
Population: PK/PD set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | fourth dose | 201.4 Microg/L | Geometric Coefficient of Variation 77.43 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | second dose | 211.2 Microg/L | Geometric Coefficient of Variation 28.72 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | third dose | 206.1 Microg/L | Geometric Coefficient of Variation 30.66 |
| Warfarin Followed by Placebo | Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | fourth dose | 214.5 Microg/L | Geometric Coefficient of Variation 27.35 |
| Warfarin Followed by Placebo | Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | second dose | 206.7 Microg/L | Geometric Coefficient of Variation 35.62 |
| Warfarin Followed by Placebo | Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose | third dose | 201.0 Microg/L | Geometric Coefficient of Variation 30.65 |
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.
Time frame: Always 24 h after the second, third, and fourth dose
Population: PK/PD set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | second dose | 13.06 Microg/L | Geometric Coefficient of Variation 50.64 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | third dose | 14.34 Microg/L | Geometric Coefficient of Variation 54.05 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | fourth dose | 12.43 Microg/L | Geometric Coefficient of Variation 85.96 |
| Warfarin Followed by Placebo | Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | second dose | 17.07 Microg/L | Geometric Coefficient of Variation 45.32 |
| Warfarin Followed by Placebo | Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | third dose | 15.85 Microg/L | Geometric Coefficient of Variation 47.92 |
| Warfarin Followed by Placebo | Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose | fourth dose | 15.61 Microg/L | Geometric Coefficient of Variation 51.52 |
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.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Population: PK/PD set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | before last administration | 754.4 Microg/L | Geometric Coefficient of Variation 32.7 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | after last administration | 740.2 Microg/L | Geometric Coefficient of Variation 25.88 |
| Warfarin Followed by Placebo | 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 | before last administration | 721.8 Microg/L | Geometric Coefficient of Variation 25.56 |
| Warfarin Followed by Placebo | 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 | after last administration | 702.8 Microg/L | Geometric Coefficient of Variation 28.39 |
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.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Population: PK/PD set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | before last administration | 498.2 Microg/L | Geometric Coefficient of Variation 38.93 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | after last administration | 478.4 Microg/L | Geometric Coefficient of Variation 26.17 |
| Warfarin Followed by Placebo | 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 | before last administration | 429.9 Microg/L | Geometric Coefficient of Variation 31.14 |
| Warfarin Followed by Placebo | 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 | after last administration | 424.9 Microg/L | Geometric Coefficient of Variation 29.78 |
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.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Population: PK/PD set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | before last administration | 0.07154 1/Liter | Geometric Coefficient of Variation 40.86 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | after last administration | 0.08633 1/Liter | Geometric Coefficient of Variation 44.1 |
| Warfarin Followed by Placebo | 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 | before last administration | 0.07843 1/Liter | Geometric Coefficient of Variation 48.55 |
| Warfarin Followed by Placebo | 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 | after last administration | 0.07915 1/Liter | Geometric Coefficient of Variation 46.5 |
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.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Population: PK/PD set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | before last administration | 0.04724 1/Liter | Geometric Coefficient of Variation 43.96 |
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | 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 | after last administration | 0.05580 1/Liter | Geometric Coefficient of Variation 43.11 |
| Warfarin Followed by Placebo | 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 | before last administration | 0.04671 1/Liter | Geometric Coefficient of Variation 53.03 |
| Warfarin Followed by Placebo | 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 | after last administration | 0.04786 1/Liter | Geometric Coefficient of Variation 38.96 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Anti-Factor Xa Activity | 15.83 ratio | Geometric Coefficient of Variation 56.06 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on Anti-Factor Xa Activity | 2.281 ratio | Geometric Coefficient of Variation 112.7 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Anti-Factor Xa Activity | 18.57 ratio | Geometric Coefficient of Variation 42.99 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) | 1.843 ratio | Geometric Coefficient of Variation 10.55 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) | 1.304 ratio | Geometric Coefficient of Variation 15.07 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) | 1.409 ratio | Geometric Coefficient of Variation 6.19 |
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).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC | 4.257 ratio | Geometric Coefficient of Variation 24.41 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC | 2.610 ratio | Geometric Coefficient of Variation 22.05 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC | 1.813 ratio | Geometric Coefficient of Variation 25.45 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time | 3.954 ratio | Geometric Coefficient of Variation 19.02 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time | 1.748 ratio | Geometric Coefficient of Variation 18.49 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time | 2.569 ratio | Geometric Coefficient of Variation 9.83 |
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).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak | 18.73 ratio | Geometric Coefficient of Variation 44.08 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak | 2.523 ratio | Geometric Coefficient of Variation 44.17 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak | 6.758 ratio | Geometric Coefficient of Variation 33.31 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time | 4.164 ratio | Geometric Coefficient of Variation 33.95 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time | 1.375 ratio | Geometric Coefficient of Variation 20.87 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time | 3.790 ratio | Geometric Coefficient of Variation 15.75 |
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).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Factor IIa Activity | 3.166 ratio | Geometric Coefficient of Variation 16.09 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on Factor IIa Activity | 2.958 ratio | Geometric Coefficient of Variation 12.31 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Factor IIa Activity | 1.126 ratio | Geometric Coefficient of Variation 5.08 |
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).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Factor VIIa Activity | 12.80 ratio | Geometric Coefficient of Variation 47.88 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on Factor VIIa Activity | 6.769 ratio | Geometric Coefficient of Variation 53.51 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on Factor VIIa Activity | 1.346 ratio | Geometric Coefficient of Variation 7.51 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on HepTest (Coagulation Test) | 2.148 ratio | Geometric Coefficient of Variation 14.2 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on HepTest (Coagulation Test) | 1.163 ratio | Geometric Coefficient of Variation 19.78 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on HepTest (Coagulation Test) | 2.009 ratio | Geometric Coefficient of Variation 12.13 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) | 3.158 ratio | Geometric Coefficient of Variation 27.2 |
| Warfarin Followed by Placebo | Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) | 1.139 ratio | Geometric Coefficient of Variation 21.36 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) | 2.723 ratio | Geometric Coefficient of Variation 20.69 |
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 \[measured as activity per mL\].
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax on Factor Xa Activity | 75.95 Percentage of inhibition | Geometric Coefficient of Variation 6.56 |
| Warfarin Followed by Placebo | Emax on Factor Xa Activity | 43.41 Percentage of inhibition | Geometric Coefficient of Variation 12.67 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax on Factor Xa Activity | 49.73 Percentage of inhibition | Geometric Coefficient of Variation 13.86 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Emax on PT (Measured as INR=International Normalized Ratio) | 6.655 ratio | Geometric Coefficient of Variation 23.39 |
| Warfarin Followed by Placebo | Emax on PT (Measured as INR=International Normalized Ratio) | 2.250 ratio | Geometric Coefficient of Variation 13.19 |
| Rivaroxaban (Xarelto, BAY59-7939) | Emax on PT (Measured as INR=International Normalized Ratio) | 1.793 ratio | Geometric Coefficient of Variation 12.87 |
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.
Time frame: 3, 24, 48, and 72 h after the last administration of rivaroxaban
Population: PK/PD set; derived parameter could not be evaluated for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose | 6.885 hours | Geometric Coefficient of Variation 42.48 |
| Warfarin Followed by Placebo | Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose | 6.931 hours | Geometric Coefficient of Variation 36.7 |
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.
Time frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin | 40.08 hours | Geometric Coefficient of Variation 19.63 |
| Warfarin Followed by Placebo | Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin | 40.24 hours | Geometric Coefficient of Variation 29.43 |
p-value: 0.952595% CI: [88, 114.5]ANOVA
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.
Time frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin | 28.24 hours | Geometric Coefficient of Variation 17.95 |
| Warfarin Followed by Placebo | Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin | 27.08 hours | Geometric Coefficient of Variation 22.79 |
p-value: 0.439795% CI: [85.99, 106.9]ANOVA
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose | 219.8 microg/L | Geometric Coefficient of Variation 30.94 |
| Warfarin Followed by Placebo | Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose | 221.0 microg/L | Geometric Coefficient of Variation 26.65 |
p-value: 0.942995% CI: [85.47, 115.7]ANOVA
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: PK/PD set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose | 0.8812 Kg/L | Geometric Coefficient of Variation 27.83 |
| Warfarin Followed by Placebo | Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose | 0.8857 Kg/L | Geometric Coefficient of Variation 31.79 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: PK/PD set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose | 3.008 hours |
| Warfarin Followed by Placebo | Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose | 3.000 hours |