Study Completed

Venous thrombosis

Bayer Identifier:

10849

ClinicalTrials.gov Identifier:

NCT01507051

EudraCT Number:

2008-005540-16

EU CT Number:

Not Available

Switching study from warfarin to rivaroxaban

Trial 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.

Key Participants Requirements

Sex

Male

Age

18 - 45 Years

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)

Trial summary

Enrollment Goal

Trial Dates

November 2008 - November 2009

Phase

Phase 1

Could I Receive a placebo

Yes

Products

Xarelto (Rivaroxaban, BAY59-7939)

Accepts Healthy Volunteer

Yes

Where to participate

Status	Institution	Location
Completed	MEDA Manufacturing GmbH, ClinPharmCologne	Köln, 51063, Germany
Completed	CRS Clinical-Research-Services Mönchengladbach GmbH	Mönchengladbach, 41061, Germany

Primary Outcome

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
Safety Issue:
No
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
Safety Issue:
No

Secondary Outcome

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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No
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
Safety Issue:
No

Trial design

Randomized, placebo-controlled, parallel-group study in healthy male subjects to investigate the pharmacodynamics during the switching procedure from warfarin to rivaroxaban

Trial Type

Interventional

Intervention Type

Drug

Trial Purpose

Other

Allocation

Randomized

Blinding

Single Blind

Assignment

Parallel Assignment

Trial Arms

Additional Information

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