Back to resultsDeep Vein Thrombosis Treatment With the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients Using a Strong CYP 3A4 Inducer
Primary Purpose
Venous Thrombosis, Deep Vein Thrombosis
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Rivaroxaban (Xarelto, BAY59-7939)
Sponsored by
About this trial
This is an interventional treatment trial for Venous Thrombosis focused on measuring 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
Eligibility 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
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Rivaroxaban (Xarelto, BAY59-7939)
Arm Description
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
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.
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.
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
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
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
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
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.
Full Information
NCT ID
NCT00786422
First Posted
November 5, 2008
Last Updated
October 20, 2015
Sponsor
Bayer
Collaborators
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
1. Study Identification
Unique Protocol Identification Number
NCT00786422
Brief Title
Deep Vein Thrombosis Treatment With the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients Using a Strong CYP 3A4 Inducer
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2015
Overall Recruitment Status
Completed
Study Start Date
May 2009 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
June 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
Collaborators
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Venous Thrombosis, Deep Vein Thrombosis
Keywords
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Rivaroxaban (Xarelto, BAY59-7939)
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Rivaroxaban (Xarelto, BAY59-7939)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Pharmacodynamics - Prothrombin Time (PT), Baseline Value
Description
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.
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
Title
Pharmacodynamics - Prothrombin Time (PT), Slope
Description
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.
Time Frame
Up to 3 months treatment
Title
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
Description
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.
Time Frame
0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Title
Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban
Description
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.
Time Frame
0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Title
Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban
Description
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.
Time Frame
0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Title
Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding)
Description
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.
Time Frame
Up to 3 months treatment and during subsequent 2 days
Secondary Outcome Measure Information:
Title
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
Description
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).
Time Frame
Up to 3 months treatment and during subsequent 30-day observational period for an individual participant
Title
Percentage of Participants With All Deaths
Description
All deaths were adjudicated by a central independent adjudication committee. Participants who died for any reason were counted for this measure.
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
Title
Percentage of Participants With Treatment Emergent Deaths - 7 Days Window
Description
Treatment emergent deaths were adjudicated by a central independent adjudication committee. Participants who died from treatment emergent adverse events were counted for this measure.
Time Frame
Up to 3 months treatment and during subsequent 7 days
Title
Percentage of Participants With Other Vascular Events
Description
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.
Time Frame
Up to 3 months treatment and during subsequent 1 day
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
City
Redcliffe
State/Province
Queensland
ZIP/Postal Code
4020
Country
Australia
City
Wien
ZIP/Postal Code
1090
Country
Austria
City
São Paulo
State/Province
Sao Paulo
ZIP/Postal Code
01323-001
Country
Brazil
City
München
State/Province
Bayern
ZIP/Postal Code
80331
Country
Germany
City
Debrecen
ZIP/Postal Code
4032
Country
Hungary
City
Ashkelon
ZIP/Postal Code
7830604
Country
Israel
City
Holon
ZIP/Postal Code
58100
Country
Israel
City
Pavia
ZIP/Postal Code
27100
Country
Italy
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2132
Country
South Africa
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2193
Country
South Africa
City
Pretoria
State/Province
Gauteng
ZIP/Postal Code
0084
Country
South Africa
City
Pretoria
State/Province
Gauteng
ZIP/Postal Code
0157
Country
South Africa
City
Roodepoort
State/Province
Gauteng
ZIP/Postal Code
1724
Country
South Africa
City
Somerset West
State/Province
Western Cape
ZIP/Postal Code
7130
Country
South Africa
City
Worcester
State/Province
Western Cape
ZIP/Postal Code
6850
Country
South Africa
12. IPD Sharing Statement
Links:
URL
http://www.clinicaltrialsregister.eu
Description
Click here and search for information of Bayer products for Europe
Learn more about this trial
Deep Vein Thrombosis Treatment With the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients Using a Strong CYP 3A4 Inducer
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