Switching Study From Warfarin to Rivaroxaban

This study has been completed.
Sponsor:
Collaborator:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01507051
First received: December 5, 2011
Last updated: May 8, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Venous Thrombosis
Drug: Warfarin (Coumadin)
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Drug: Placebo
Drug: Vitamin K (Konakion)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Official Title: Randomized, Placebo-controlled, Parallel-group Study in Healthy Male Subjects to Investigate the Pharmacodynamics During the Switching Procedure From Warfarin to Rivaroxaban

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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.

  • AUCBA(0-tn) (Baseline Adjusted Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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.

  • Emax on PT (Measured as INR=International Normalized Ratio) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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 [ Time Frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin ] [ Designated as safety issue: No ]
    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 [ Time Frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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 [ Time Frame: Always 3 h after second, third, and fourth dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Always 24 h after the second, third, and fourth dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 3, 24, 48, and 72 h after the last administration of rivaroxaban ] [ Designated as safety issue: No ]
    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.

  • Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of R-warfarin After the Last Dose of Warfarin [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ] [ Designated as safety issue: No ]
    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 R-warfarin After the Last Dose of Warfarin [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 h (predose) and 24 h after the last administration of warfarin ] [ Designated as safety issue: No ]
    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.


Enrollment: 96
Study Start Date: November 2008
Study Completion Date: November 2009
Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Warfarin followed by Rivaroxaban (Xarelto, BAY59-7939)
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
Drug: Warfarin (Coumadin)
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
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Days 0 to 3: 20 mg rivaroxaban once daily
Drug: Vitamin K (Konakion)
Day 5: 10 mg vitamin K (Konakion) once daily
Placebo Comparator: 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
Drug: Warfarin (Coumadin)
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
Drug: Placebo
Days 0 to 3: 1 tablet placebo, identical to active tablet
Drug: Vitamin K (Konakion)
Day 5: 10 mg vitamin K (Konakion) once daily
Active Comparator: Rivaroxaban (Xarelto, BAY59-7939)
Days 0 to 3: 20 mg rivaroxaban once daily
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Days 0 to 3: 20 mg rivaroxaban once daily

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01507051

Locations
Germany
Köln, Nordrhein-Westfalen, Germany, 51063
Mönchengladbach, Nordrhein-Westfalen, Germany, 41061
Sponsors and Collaborators
Bayer
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Investigators
Study Director: Bayer Study Director Bayer
  More Information

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

Keywords provided by Bayer:
Rivaroxaban
Xa-Factors
Warfarin
Thrombosis
Embolism

Additional relevant MeSH terms:
Thrombosis
Venous Thrombosis
Venous Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Thromboembolism
Vitamins
Vitamin K
Rivaroxaban
Warfarin
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Anticoagulants
Hematologic Agents
Therapeutic Uses
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants

ClinicalTrials.gov processed this record on September 30, 2014