Deep Vein Thrombosis Treatment With the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients Using a Strong CYP 3A4 Inducer

Phase 2

Completed

• Conditions: Venous Thrombosis; Deep Vein Thrombosis
• Interventions: Drug: Rivaroxaban (Xarelto, BAY59-7939)

• Registration Number: NCT00786422
• Lead Sponsor: Bayer

Brief Summary

This is a multicenter, cohort study evaluating an adapted rivaroxaban dose regimen in patients with acute, proximal deep-vein thrombosis (DVT) or acute pulmonary embolism (PE) who concomitantly use a strong cytochrome P450 isoenzyme 3A4 (CYP 3A4) inducer for the entire 3-month study duration.

Detailed Description

The following laboratory variables were determined at baseline at the local laboratories: Hemoglobin, platelets, activated partial thromboplastin time (aPTT), international normalized ratio (INR), alanine aminotransferase (ALT), and creatinine.

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study First Submitted: 2008-11-05
• Study First Submitted QC: 2008-11-05
• Study First Posted: 2008-11-06
• Study Start: 2009-05
• Primary Completion: 2011-05
• Study Completion: 2011-06
• Disposition First Submitted: 2012-05-15
• Disposition First Submitted QC: 2012-05-15
• Disposition First Posted: 2012-05-16
• Results First Submitted: 2013-12-20
• Results First Submitted QC: 2014-05-14
• Results First Posted: 2014-06-13
• Status Verified: 2015-10
• Last Update Submitted: 2015-10-20
• Last Update Posted: 2015-11-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

• Confirmed acute symptomatic proximal deep- vein thrombosis and/or pulmonary embolism
• Concomitant use of a strong CYP 3A4 inducer, (i.e., carbamazepine, phenytoin, rifampicin/rifampin, and rifabutin)

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Exclusion Criteria

• Legal lower age limitations (country specific)
• Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of deep -vein thrombosis and/or pulmonary embolism
• Other indication for vitamin K antagonist (VKA) than deep -vein thrombosis and/or pulmonary embolism
• Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors, systemic ketoconazole)
• Use of the strong CYP 3A4 inducers phenobarbital/primidone or St John's Wort

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Rivaroxaban (Xarelto, BAY59-7939)	Rivaroxaban (Xarelto, BAY59-7939)	-

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding)	Up to 3 months treatment and during subsequent 2 days	All events were adjudicated and confirmed by a central independent adjudication committee. Clinically relevant bleeding included major bleeding (overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death) and non-major bleeding associated with medical intervention, unscheduled physician contact, (temporary) cessation of study treatment, discomfort for the participants such as pain, or impairment of activities of daily life.
Pharmacodynamics - Prothrombin Time (PT), Baseline Value	The baseline value of prothrombin time is measured or calculated at a rivaroxaban concentration of 0 µg/L and is based on the observations that were made during the 3 months treatment period	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. Mean and standard deviation (SD) values are presented for PT baseline.
Pharmacodynamics - Prothrombin Time (PT), Slope	Up to 3 months treatment	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 of PT is in seconds. The PT slope describes the linear increase of PT for one unit increase in concentration, thus the unit of PT slope is s\*(µg/L)\^-1. The final population PK/PD model included a fixed slope that was fitted to the data of the 19 patients that were eligible for evaluation. The estimated mean value (fixed/ the same for all patients in this study) is presented for PT slope.
Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban	0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban	Cmin,ss was predicted for each individual participant from rivaroxaban plasma concentrations and was only considered for the time period during which participants concomitantly received rivaroxaban and a strong CYP3A4 inducer.
Pharmacokinetics - AUC(0-24)ss (Area Under the Measurement Versus Time Curve From Time 0 to 24 Hours After First Dosing on a Day at Steady State) of Rivaroxaban	0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban	AUC(0-24)ss was predicted from rivaroxaban plasma concentrations for each individual participant and was only considered for the time period during which participants concomitantly received rivaroxaban and a strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inducer.
Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban	0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban	Cmax,ss was predicted from rivaroxaban plasma concentrations for each individual participant and was only considered for the time period during which participants concomitantly received rivaroxaban and a strong CYP3A4 inducer.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Non-fatal or Fatal Pulmonary Embolism [PE]) Until the Intended End of Study Treatment	Up to 3 months treatment and during subsequent 30-day observational period for an individual participant	All events were adjudicated and confirmed by a central independent adjudication committee. The composite efficacy outcome symptomatic recurrent VTE was analyzed descriptively, with the components: Death due to PE, death for which PE cannot be excluded, symptomatic PE and DVT, symptomatic recurrent PE only, and symptomatic recurrent DVT only up to the end of intended treatment period (3 months; 98 study days) and on-treatment (up to 2 days after stop of study drug).
Percentage of Participants With All Deaths	Up to 3 months and on-treatment (up to 2 days after stop of study drug) plus an observational period planned for one month	All deaths were adjudicated by a central independent adjudication committee. Participants who died for any reason were counted for this measure.
Percentage of Participants With Treatment Emergent Deaths - 7 Days Window	Up to 3 months treatment and during subsequent 7 days	Treatment emergent deaths were adjudicated by a central independent adjudication committee. Participants who died from treatment emergent adverse events were counted for this measure.
Percentage of Participants With Other Vascular Events	Up to 3 months treatment and during subsequent 1 day	All events were adjudicated and confirmed by a central independent adjudication committee. Other vascular events comprised ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI), unstable angina (UA), ischemic stroke, transient ischemic attack (TIA), non-central nervous system systemic embolism and vascular death.