A Study to Explore the Pharmacodynamic Changes When Transitioning From Rivaroxaban to Warfarin in Healthy Volunteers

Janssen (J&J Innovative Medicine)

Status and phase: Completed; Phase 1

Conditions: Healthy

Treatments: Drug: Vitamin K; Drug: Rivaroxaban; Drug: Warfarin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01400646

2011-002890-46 (EudraCT Number)

CR018664

RIVAROXAFL1004 (Other Identifier)

Details and patient eligibility

About

The purpose of this study is to explore the pharmacodynamic (what the drug does to the body) changes when transitioning from rivaroxaban 20 mg once daily to warfarin dosed to a therapeutic level as measured by the International Normalized Ratio (INR) range of 2.0 to 3.0 in healthy volunteers. In addition, the pharmacokinetics (what the body does to the drug), safety and tolerability of rivaroxaban during the transition to warfarin will be investigated. The INR is obtained from a blood test, and is a measure for the clotting tendency of the blood used for safe and adequate dosing of warfarin.

Full description

This is a single-center, open-label (study staff and healthy volunteers will know the identity of treatment assigned), sequential 2-treatment period study in healthy adult volunteers to explore the pharmacodynamic changes (changes drugs have on the body), specifically in regard to blood coagulation (blood clotting) when healthy volunteers take oral (by mouth) rivaroxaban followed by warfarin. Treatment Period 1: Rivaroxaban 20 mg/day for 5 days then Rivaoxaban 20 mg/day + Warfarin 10 mg/day for 2-4 days then warfarin 0-15 mg/day for 4 days. Treatment Period 2: Warfarin 10 mg/day for 2-4 days, then 0-15 mg/day for 4 days. Treatment periods 1 and 2 will be separated by a washout period of at least 14 days. In Treatment Periods 1 and 2, the dose of warfarin may be adjusted as specified by the protocol and the last dose of warfarin in each Treatment period will be followed by a single dose of Vitamin K. The approximate total study length for healthy adult volunteers enrolled is approximately 72 days (includes a 28-day Screening Period, a 30-day Open-label Treatment Phase, which includes the 7 days for a follow-up visit, and at least a 14-day washout between treatment periods).

Enrollment: 46 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Volunteers must agree to provide a blood sample for pharmacogenomic testing and must have less than 3 of the variant CYP2C9 and VKORC1 gene alleles associated with increased warfarin sensitivity if their genetic status regarding these alleles is not previously known
• Have coagulation test results (INR, PT, and activated partial thromboplastin time (aPTT) within clinically acceptable limits, blood pressure (after the volunteer is supine for 5 minutes) between 90 and 140 mmHg systolic, inclusive, and between 50 and 90 mmHg diastolic
• Have a body mass index (BMI) between 18 and 30 kg/m2 (inclusive), and body weight of not less than 50 kg
• Be a Non-smoker (Volunteers may not use nicotine-containing products within 3 months prior to study drug administration

Exclusion criteria

• Have a history or current clinically significant medical illness, including (but not limited to) of intracranial tumor or aneurysm
• Have history of gastrointestinal disease (e.g., Crohn's disease) which could result in impaired absorption of the study drugs or history of clinically significant hemoptysis, excessive bruising, bleeding from nose or gums or known disorders with increased bleeding risk (e.g., acute gastritis, acute peptic ulcer) or history of any bleeding diathesis. Concomitant use (also within the last 2 weeks before start of the study) of drugs that influenced the coagulation system, e.g., antiplatelet drugs (e.g., acetylsalicylic acid, ticlopidine and clopidogrel
• abciximab, tirofiban and integrelin) or other anticoagulants (antithrombins, unfractionated heparins, low molecular weight heparins and hirudin, coumadin-type anticoagulants phenprocoumon, warfarin, dabigatran, probenecide)
• Use of medications known to affect the metabolic pathways (CYP3A4, or P-gp) within 14 days of study admission

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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46 participants in 2 patient groups

Rivaroxaban + Warfarin Concomitant Therapy Phase

Experimental group

Description:

Rivaroxaban monotherapy 20 mg/day for 5 days followed by Rivaroxaban 20 mg/day + Warfarin. 10 mg/day for \>= 2 to \<= 4 days concomitant therapy, then Warfarin monotherapy 0-15 mg/day for 4 days (Treatment Period 1). A 14-day washout period will separate Treatment Periods 1 and 2.

Treatment:

Drug: Warfarin

Drug: Warfarin

Drug: Warfarin

Drug: Rivaroxaban

Drug: Vitamin K

Drug: Vitamin K

Drug: Warfarin

Warfarin Monotherapy Phase

Experimental group

Description:

Warfarin monotherapy 10 mg/day for \>=2 to \<=4 days, then Warfarin 0-15 mg/day for 4 days (Treatment Period 2). A 14-day washout period will separate Treatment Periods 1 and 2.

Treatment:

Drug: Warfarin

Drug: Warfarin

Drug: Warfarin

Drug: Vitamin K

Drug: Vitamin K

Drug: Warfarin