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
  Purpose

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.


Condition Intervention Phase
Venous Thrombosis
Deep Vein Thrombosis
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 25
Study Start Date: May 2009
Study Completion Date: June 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rivaroxaban (Xarelto, BAY59-7939) 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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00786422

Locations
Australia, Queensland
Redcliffe, Queensland, Australia, 4020
Austria
Wien, Austria, 1090
Brazil
São Paulo, Sao Paulo, Brazil, 01323-001
Germany
München, Bayern, Germany, 80331
Hungary
Debrecen, Hungary, 4032
Israel
Ashkelon, Israel, 7830604
Holon, Israel, 58100
Italy
Pavia, Italy, 27100
Netherlands
Amsterdam, Netherlands, 1105 AZ
South Africa
Johannesburg, Gauteng, South Africa, 2193
Johannesburg, Gauteng, South Africa, 2132
Pretoria, Gauteng, South Africa, 0157
Pretoria, Gauteng, South Africa, 0084
Roodepoort, Gauteng, South Africa, 1724
Somerset West, Western Cape, South Africa, 7130
Worcester, Western Cape, South Africa, 6850
Sponsors and Collaborators
Bayer
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
No publications provided

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00786422     History of Changes
Other Study ID Numbers: 13238, 2008-003303-31
Study First Received: November 5, 2008
Results First Received: December 20, 2013
Last Updated: August 7, 2014
Health Authority: United States: Food and Drug Administration
South Africa: Medicine Control Council

Keywords provided by Bayer:
Embolism and Thrombosis
Pulmonary Embolism
Embolism
Venous Thrombosis
Thrombosis
Enzyme Inducers
CYP Inducers
Cohort Study
Pharmacologic Actions
Respiratory Tract Diseases
Lung Diseases
Vascular Diseases
Human Immunodeficiency Virus (HIV)
Neurologic disease
Additional relevant MeSH terms:
Fibrin Modulating Agents
Anticoagulants
Therapeutic Uses
Hematologic Agents
Enzyme Inhibitors
Cardiovascular Diseases
Cardiovascular Agents

Additional relevant MeSH terms:
Pulmonary Embolism
Thrombosis
Venous Thromboembolism
Venous Thrombosis
Cardiovascular Diseases
Embolism
Embolism and Thrombosis
Lung Diseases
Respiratory Tract Diseases
Thromboembolism
Vascular Diseases
Rivaroxaban
Anticoagulants
Hematologic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014