Phase 1
N=96
Switching Study From Warfarin to Rivaroxaban
Venous Thrombosis
Bottom Line
View on ClinicalTrials.gov: NCT01507051 ↗Enrolled (actual)
96
Serious AEs
0.0%
Results posted
Apr 2012
Primary outcome: Primary: Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) — 4.393; 1.884; 1.573 ratio — p=<0.0001
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- Warfarin (Coumadin) (Drug); Rivaroxaban (Xarelto, BAY59-7939) (Drug); Placebo (Drug); Vitamin K (Konakion) (Drug)
- Age
- Adult · 18+ yrs
- Sex
- Male
- Sponsor
- Bayer
- Primary completion
- Nov 2009
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) |
4.393; 1.884; 1.573 | <0.0001 sig |
| PRIMARY Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) |
44.98; 11.59; 7.31 | <0.0001 sig |
| SECONDARY 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; 37.89; 20.41 | — |
| 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) |
413.4; 179.9; 33.06 | — |
| SECONDARY Emax on PT (Measured as INR=International Normalized Ratio) |
6.655; 2.250; 1.793 | — |
| 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) |
72.30; 43.60; 23.21 | — |
| SECONDARY Emax on Factor Xa Activity |
75.95; 43.41; 49.73 | — |
| SECONDARY AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity |
1238; 834.8; 514.1 | — |
| SECONDARY Emax (Maximum Effect) on Anti-Factor Xa Activity |
15.83; 2.281; 18.57 | — |
| SECONDARY 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; 19.63; 151.6 | — |
| SECONDARY Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) |
1.843; 1.304; 1.409 | — |
| 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) |
32.48; 22.55; 21.82 | — |
| SECONDARY Emax (Maximum Effect) on HepTest (Coagulation Test) |
2.148; 1.163; 2.009 | — |
| SECONDARY AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) |
27.37; 15.08; 28.25 | — |
| SECONDARY Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) |
3.158; 1.139; 2.723 | — |
| 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) |
37.36; 4.221; 39.20 | — |
| SECONDARY Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC |
4.257; 2.610; 1.813 | — |
| 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 |
69.69; 51.28; 18.06 | — |
| SECONDARY Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time |
3.954; 1.748; 2.569 | — |
| 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 |
63.75; 34.93; 42.79 | — |
| SECONDARY Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak |
18.73; 2.523; 6.758 | — |
| 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 |
166.8; 46.75; 74.67 | — |
| SECONDARY Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time |
4.164; 1.375; 3.790 | — |
| 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 |
49.14; 19.83; 55.58 | — |
| SECONDARY Emax (Maximum Effect) on Factor VIIa Activity |
12.80; 6.769; 1.346 | — |
| SECONDARY AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity |
134.2; 94.83; 9.283 | — |
| SECONDARY Emax (Maximum Effect) on Factor IIa Activity |
3.166; 2.958; 1.126 | — |
| SECONDARY AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity |
62.26; 58.60; 3.908 | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose |
1639; 1722 | 0.5008 |
| SECONDARY Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose |
219.8; 221.0 | 0.9429 |
| SECONDARY Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin |
40.08; 40.24 | 0.9525 |
| SECONDARY Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin |
28.24; 27.08 | 0.4397 |
| 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 |
6.569; 6.901 | — |
| SECONDARY Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose |
0.8812; 0.8857 | — |
| SECONDARY Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose |
3.008; 3.000 | — |
| SECONDARY Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose |
211.2; 206.7; 206.1; 201.0; 201.4; 214.5 | — |
| SECONDARY Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose |
13.06; 17.07; 14.34; 15.85; 12.43; 15.61 | — |
| SECONDARY Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose |
6.885; 6.931 | — |
| 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 |
754.4; 721.8; 740.2; 702.8 | — |
| 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 |
0.07154; 0.07843; 0.08633; 0.07915 | — |
| 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 |
498.2; 429.9; 478.4; 424.9 | — |
| 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 |
0.04724; 0.04671; 0.05580; 0.04786 | — |
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)
Data sourced from ClinicalTrials.gov (NCT01507051). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.