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

Deep Vein Thrombosis Clinical Trial

Official title:

The EINSTEIN CYP Cohort Study Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep-vein Thrombosis or Pulmonary Embolism Using a Strong CYP 3A4 Inducer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00786422
• Other study ID #: 13238
• Secondary ID: 2008-003303-31
• Status: Completed
• Phase: Phase 2
• First received: November 5, 2008
• Last updated: October 20, 2015
• Start date: May 2009
• Est. completion date: June 2011

Study information

• Verified date: October 2015
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationSouth Africa: Medicine Control Council
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: June 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

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

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Deep Vein Thrombosis
• Pulmonary Embolism
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• Rivaroxaban (Xarelto, BAY59-7939)
Participants received 30 mg rivaroxaban bid (twice-daily) orally for the first 3 weeks followed by 20 mg rivaroxaban bid for the remainder of the 3-month treatment period.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Bayer	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Countries where clinical trial is conducted

Australia,  Austria,  Brazil,  Germany,  Hungary,  Israel,  Italy,  Netherlands,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacodynamics - Prothrombin Time (PT), Baseline Value	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.	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	No
Primary	Pharmacodynamics - Prothrombin Time (PT), Slope	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.	Up to 3 months treatment	No
Primary	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	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.	0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban	No
Primary	Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) 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.	0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban	No
Primary	Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) 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.	0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban	No
Primary	Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding)	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.	Up to 3 months treatment and during subsequent 2 days	Yes
Secondary	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	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).	Up to 3 months treatment and during subsequent 30-day observational period for an individual participant	No
Secondary	Percentage of Participants With All Deaths	All deaths were adjudicated by a central independent adjudication committee. Participants who died for any reason were counted for this measure.	Up to 3 months and on-treatment (up to 2 days after stop of study drug) plus an observational period planned for one month	Yes
Secondary	Percentage of Participants With Treatment Emergent Deaths - 7 Days Window	Treatment emergent deaths were adjudicated by a central independent adjudication committee. Participants who died from treatment emergent adverse events were counted for this measure.	Up to 3 months treatment and during subsequent 7 days	Yes
Secondary	Percentage of Participants With Other Vascular Events	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.	Up to 3 months treatment and during subsequent 1 day	Yes

External Links

•   Click here and search for drug information provided by the FDA.
•   Click here and search for information of Bayer products for Europe
•   Click here and search for information on any recalls, market or product safety alerts by the FDA which might have occurred with this product.
•   Click here to find results for studies related to Bayer Healthcare products.