Switching Study From Warfarin to Rivaroxaban
Condition: Venous Thrombosis
MeSH terms: Thrombosis; Venous Thrombosis
Intervention: Warfarin (Coumadin); Rivaroxaban (Xarelto, BAY59-7939); Placebo; Vitamin K (Konakion)
Intervention description: 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; Days 0 to 3: 20 mg rivaroxaban once daily; Days 0 to 3: 1 tablet placebo, identical to active tablet; Day 5: 10 mg vitamin K (Konakion) once daily
Intervention MeSH terms: Vitamin K; Vitamin K 1; Warfarin; Rivaroxaban
Phase: Phase 1
Study type: Interventional
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 96.0
Sex: Male
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Rivaroxaban; Xa-Factors; Warfarin; Thrombosis; Embolism

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)