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

• ClinicalTrials.gov Identifier: NCT00786422
• Recruitment Status: Completed
• First Posted: November 6, 2008
• Results First Posted: June 13, 2014
• Last Update Posted: November 18, 2015
• Sponsor: Bayer
• Collaborator: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• Information provided by (Responsible Party): Bayer

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.

Condition or disease	Intervention/treatment	Phase
Venous Thrombosis; Deep Vein Thrombosis	Drug: Rivaroxaban (Xarelto, BAY59-7939)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: May 2009
• Actual Primary Completion Date: May 2011
• Actual Study Completion Date: June 2011

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   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.
2. Pharmacodynamics - Prothrombin Time (PT), Slope [ Time Frame: 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.
3. 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 ]
   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.
4. 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 ]
   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.
5. 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 ]
   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.
6. 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 ]
   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 :

1. 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 ]
   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).
2. 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 ]
   All deaths were adjudicated by a central independent adjudication committee. Participants who died for any reason were counted for this measure.
3. Percentage of Participants With Treatment Emergent Deaths - 7 Days Window [ Time Frame: 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.
4. Percentage of Participants With Other Vascular Events [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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, 2132

Johannesburg, Gauteng, South Africa, 2193

Pretoria, Gauteng, South Africa, 0084

Pretoria, Gauteng, South Africa, 0157

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:

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• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00786422
• Other Study ID Numbers: 13238; 2008-003303-31 ( EudraCT Number )
• First Posted: November 6, 2008
• Results First Posted: June 13, 2014
• Last Update Posted: November 18, 2015
• Last Verified: October 2015

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:

Thrombosis; Venous Thrombosis; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Rivaroxaban; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anticoagulants