Clinical trial NCT01507051: Switching Study From Warfarin to Rivaroxaban
Official title: Randomized, Placebo-controlled, Parallel-group Study in Healthy Male Subjects to Investigate the Pharmacodynamics During the Switching Procedure From Warfarin to Rivaroxaban
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Venous Thrombosis
Keywords: Rivaroxaban
Xa-Factors
Warfarin
Thrombosis
Embolism
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
First posted: 2012-01-10
Enrollment: 96
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL

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.


Eligibility 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)

Primary outcomes:
measure: Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Secondary outcomes:
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: 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)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax on PT (Measured as INR=International Normalized Ratio)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: 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)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax on Factor Xa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on Anti-Factor Xa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on HepTest (Coagulation Test)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time)
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: 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
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: 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
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on Factor VIIa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Emax (Maximum Effect) on Factor IIa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
measure: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
measure: Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
measure: Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin
timeFrame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
measure: Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin
timeFrame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
measure: 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
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
measure: Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
measure: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose
timeFrame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
measure: Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose
timeFrame: Always 3 h after second, third, and fourth dose
measure: Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose
timeFrame: Always 24 h after the second, third, and fourth dose
measure: Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose
timeFrame: 3, 24, 48, and 72 h after the last administration of rivaroxaban
measure: 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
timeFrame: 0 h (predose) and 24 h after the last administration of warfarin
measure: 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
timeFrame: 0 h (predose) and 24 h after the last administration of warfarin
measure: 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
timeFrame: 0 h (predose) and 24 h after the last administration of warfarin
measure: 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
timeFrame: 0 h (predose) and 24 h after the last administration of warfarin
Other outcomes:
Locations:
city: Köln
country: Germany
state: Nordrhein-Westfalen
city: Mönchengladbach
country: Germany
state: Nordrhein-Westfalen
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Kubitza D, Becka M, Muck W, Kratzschmar J. Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects. Br J Clin Pharmacol. 2014 Aug;78(2):353-63. doi: 10.1111/bcp.12349.