Randomized, Placebo-controlled, Parallel-group Study in Healthy Male Subjects to Investigate the Pharmacodynamics During the Switching Procedure From Warfarin to Rivaroxaban
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 96
- 主要终点
- Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
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
干预措施: Warfarin (Coumadin) (Drug)
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
干预措施: Rivaroxaban (Xarelto, BAY59-7939) (Drug)
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
干预措施: Vitamin K (Konakion) (Drug)
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
干预措施: Warfarin (Coumadin) (Drug)
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
干预措施: Placebo (Drug)
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
干预措施: Vitamin K (Konakion) (Drug)
Rivaroxaban (Xarelto, BAY59-7939)
Days 0 to 3: 20 mg rivaroxaban once daily
干预措施: Rivaroxaban (Xarelto, BAY59-7939) (Drug)
结局指标
主要结局
Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)
时间窗: 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)
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Emax on Factor Xa Activity(0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo)
- Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time)(0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo)
- AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity(0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo)
- AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Lag Time(0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo)
- Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak(0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo)
- Emax (Maximum Effect) on Factor VIIa Activity(0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo)
- Emax (Maximum Effect) on Factor IIa Activity(0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)