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

This study has been completed.
Sponsor:
Collaborator:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT00786422
First received: November 5, 2008
Last updated: August 7, 2014
Last verified: August 2014

November 5, 2008
August 7, 2014
May 2009
May 2011   (final data collection date for primary outcome measure)
  • Pharmacodynamics - Prothrombin Time (PT), Baseline Value [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 3 months treatment ] [ Designated as safety issue: No ]
    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 - 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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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.
  • Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban [ Time Frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban ] [ Designated as safety issue: No ]
    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.
  • Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding) [ Time Frame: Up to 3 months treatment and during subsequent 2 days ] [ Designated as safety issue: Yes ]
    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.
To characterize the population PK/PD of an adapted rivaroxaban dose regimen in patients with acute, proximal deep-vein thrombosis (DVT) or acute pulmonary embolism (PE) and concomitant use of a strong CYP 3A4 inducer. [ Time Frame: 3 month study treatment period ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00786422 on ClinicalTrials.gov Archive Site
  • 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 [ Time Frame: Up to 3 months treatment and during subsequent 30-day observational period for an individual participant ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 3 months and on-treatment (up to 2 days after stop of study drug) plus an observational period planned for one month ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 3 months treatment and during subsequent 7 days ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 3 months treatment and during subsequent 1 day ] [ Designated as safety issue: Yes ]
    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.
  • Symptomatic recurrent VTE [ Time Frame: 3 month study treatment period ] [ Designated as safety issue: No ]
  • Clinically relevant bleeding (i.e., major bleeding and clinically relevant non-major bleeding) [ Time Frame: 3 month study treatment period ] [ Designated as safety issue: No ]
  • All deaths and other vascular events [ Time Frame: 3 month study treatment period ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Deep Vein Thrombosis Treatment With the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients Using a Strong CYP 3A4 Inducer
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

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.

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.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Venous Thrombosis
  • Deep Vein Thrombosis
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.
Experimental: Rivaroxaban (Xarelto, BAY59-7939)
Intervention: Drug: Rivaroxaban (Xarelto, BAY59-7939)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
25
June 2011
May 2011   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Austria,   Brazil,   Germany,   Hungary,   Israel,   Italy,   Netherlands,   South Africa
 
NCT00786422
13238, 2008-003303-31
Yes
Bayer
Bayer
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study Director: Bayer Study Director Bayer
Bayer
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP