Switching Study From Warfarin to Rivaroxaban

NCT01507051 | Completed Phase 1 Results

• 2 other identifiers: 108492008-005540-16
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 2

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.

Conditions

Venous Thrombosis

Keywords

Rivaroxaban; Xa-Factors; Warfarin; Thrombosis; Embolism

Outcome Measures

Primary Outcomes (2)

• Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)

  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.

  0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

• Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test)

  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.

  0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Secondary Outcomes (40)

• 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

• 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

• 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

• Emax on Factor Xa Activity

  0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Study Arms (3)

Warfarin followed by Rivaroxaban (Xarelto, BAY59-7939)

EXPERIMENTAL

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

Drug: Warfarin (Coumadin); Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Vitamin K (Konakion)

Warfarin followed by Placebo

PLACEBO COMPARATOR

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

Drug: Warfarin (Coumadin); Drug: Placebo; Drug: Vitamin K (Konakion)

Rivaroxaban (Xarelto, BAY59-7939)

ACTIVE COMPARATOR

Days 0 to 3: 20 mg rivaroxaban once daily

Drug: Rivaroxaban (Xarelto, BAY59-7939)

Interventions

Warfarin (Coumadin) DRUG

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

Warfarin followed by Placebo; Warfarin followed by Rivaroxaban (Xarelto, BAY59-7939)

Rivaroxaban (Xarelto, BAY59-7939) DRUG

Days 0 to 3: 20 mg rivaroxaban once daily

Rivaroxaban (Xarelto, BAY59-7939); Warfarin followed by Rivaroxaban (Xarelto, BAY59-7939)

Placebo DRUG

Days 0 to 3: 1 tablet placebo, identical to active tablet

Warfarin followed by Placebo

Vitamin K (Konakion) DRUG

Day 5: 10 mg vitamin K (Konakion) once daily

Warfarin followed by Placebo; Warfarin followed by Rivaroxaban (Xarelto, BAY59-7939)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Bayer: lead
• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: collaborator

Study Sites (2)

Unknown Facility

Cologne, North Rhine-Westphalia, 51063, Germany

Location

Unknown Facility

Mönchengladbach, North Rhine-Westphalia, 41061, Germany

Location

Related Publications (1)

• 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.

  PMID: 24528331 RESULT

Related Links

• Click here and search for results posted for EMA

MeSH Terms

Conditions

Venous Thrombosis; Thrombosis; Embolism

Interventions

Warfarin; Rivaroxaban; Vitamin K; Vitamin K 1

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Naphthoquinones; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phytol; Diterpenes; Terpenes; Polycyclic Compounds; Quinones

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: BAYER

clinical-trials-contact@bayerhealthcare.com

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2011
• First Posted: January 10, 2012
• Study Start: November 1, 2008
• Primary Completion: November 1, 2009
• Study Completion: November 1, 2009
• Last Updated: February 9, 2015
• Results First Posted: April 26, 2012

Record last verified: 2015-01

Locations

DE (2)