Deep Vein Thrombosis, Venous Thrombosis
Conditions
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
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.
Interventions
DRUGRivaroxaban (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.
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding) | 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. |
| Pharmacodynamics - Prothrombin Time (PT), Slope | 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. |
| 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 | 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. |
| Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban | 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. |
| Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban | 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. |
| Pharmacodynamics - Prothrombin Time (PT), Baseline Value | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With All Deaths | 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. |
| Percentage of Participants With Treatment Emergent Deaths - 7 Days Window | 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. |
| Percentage of Participants With Other Vascular Events | 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. |
| 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 | 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). |
Countries
Australia, Austria, Brazil, Germany, Hungary, Israel, Italy, Netherlands, South Africa
Participant flow
Recruitment details
Participants with confirmed acute proximal symptomatic deep vein thrombosis (DVT) or acute pulmonary embolism (PE) were recruited at specialized study sites.
Pre-assignment details
Out of 25 participants screened, 25 participants were assigned to treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up Period | Death | 1 |
| Follow-up Period | End-of-study done up to 4 days early | 2 |
| Rivaroxaban Treatment | Adverse Event | 2 |
| Rivaroxaban Treatment | Death | 2 |
| Rivaroxaban Treatment | Final visit earlier than planned | 3 |
| Rivaroxaban Treatment | Lack of Efficacy | 1 |
| Rivaroxaban Treatment | Non-compliance with study drug treatment | 1 |
| Rivaroxaban Treatment | Physician Decision | 1 |
| Rivaroxaban Treatment | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|
| Age, Customized 65 - 75 years | 1 Participants |
| Age, Customized < 65 years | 23 Participants |
| Age, Customized > 75 years | 1 Participants |
| Creatinine clearance 30 - <50 mL/min | 0 Participants |
| Creatinine clearance <30 mL/min | 0 Participants |
| Creatinine clearance 50 - <80 mL/min | 4 Participants |
| Creatinine clearance > 80 mL/min | 21 Participants |
| Participants with history of tuberculosis History of tuberculosis | 20 Participants |
| Participants with history of tuberculosis No history of tuberculosis | 5 Participants |
| Race Black | 23 Participants |
| Race Other (mixed South African descent) | 1 Participants |
| Race White | 1 Participants |
| Region of recruitment South Africa - No | 0 Participants |
| Region of recruitment South Africa - Yes | 25 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 25 |
| serious Total, serious adverse events | 5 / 25 |
Outcome results
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.
Time frame: Up to 3 months treatment and during subsequent 2 days
Population: The safety population consisted of all participants who received at least 1 dose of rivaroxaban.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding) | Any confirmed bleeding | 12.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding) | Clinically relevant non-major bleeding | 8.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding) | Trivial bleeding | 8.0 Percentage of participants |
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.
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
Population: The pharmacokinetics/pharmacodynamics (PK/PD) population included all participants who received at least 1 dose of rivaroxaban and had at least 1 valid PK/PD sample after first administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Pharmacodynamics - Prothrombin Time (PT), Baseline Value | 15.8 Seconds | Standard Deviation 1.49 |
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.
Time frame: Up to 3 months treatment
Population: The pharmacokinetics/pharmacodynamics (PK/PD) population included all participants who received at least 1 dose of rivaroxaban and had at least 1 valid PK/PD sample after first administration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Pharmacodynamics - Prothrombin Time (PT), Slope | 0.0389 s*(µg/L)^-1 |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: The pharmacokinetics/pharmacodynamics (PK/PD) population included all participants who received at least 1 dose of rivaroxaban and had at least 1 valid PK/PD sample after first administration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | 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 | 2836 (µg*h)/L |
| Rivaroxaban Extended Treatment | 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 | 2319 (µg*h)/L |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: The pharmacokinetics/pharmacodynamics (PK/PD) population included all participants who received at least 1 dose of rivaroxaban and had at least 1 valid PK/PD sample after first administration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban | 200 µg/L |
| Rivaroxaban Extended Treatment | Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban | 167 µg/L |
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.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Population: The pharmacokinetics/pharmacodynamics (PK/PD) population included all participants who received at least 1 dose of rivaroxaban and had at least 1 valid PK/PD sample after first administration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban | 42 µg/L |
| Rivaroxaban Extended Treatment | Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban | 35 µg/L |
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.
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
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All Deaths | 12.0 Percentage of participants |
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.
Time frame: Up to 3 months treatment and during subsequent 1 day
Population: The safety population consisted of all participants who received at least 1 dose of rivaroxaban.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Other Vascular Events | 0.0 Percentage of participants |
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).
Time frame: Up to 3 months treatment and during subsequent 30-day observational period for an individual participant
Population: The safety population consisted of all participants who received at least 1 dose of rivaroxaban.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | 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 | symptomatic recurrent VTE (composite) | 8.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | 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 | Death | 4.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | 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 | Symptomatic recurrent deep vein thrombosis only | 4.0 Percentage of participants |
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.
Time frame: Up to 3 months treatment and during subsequent 7 days
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Treatment Emergent Deaths - 7 Days Window | 8.0 Percentage of participants |