Trial Outcomes & Findings for Deep Vein Thrombosis Treatment With the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients Using a Strong CYP 3A4 Inducer (NCT NCT00786422)

NCT ID: NCT00786422

Last Updated: 2015-11-18

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

25 participants

Primary outcome timeframe

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

Results posted on

2015-11-18

Participant Flow

Participants with confirmed acute proximal symptomatic deep vein thrombosis (DVT) or acute pulmonary embolism (PE) were recruited at specialized study sites.

Out of 25 participants screened, 25 participants were assigned to treatment.

Participant milestones

Participant milestones
Measure	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.
Rivaroxaban Treatment STARTED	25
Rivaroxaban Treatment COMPLETED	14
Rivaroxaban Treatment NOT COMPLETED	11
Follow-up Period STARTED	20
Follow-up Period COMPLETED	17
Follow-up Period NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
Rivaroxaban Treatment Death	2
Rivaroxaban Treatment Final visit earlier than planned	3
Rivaroxaban Treatment Lack of Efficacy	1
Rivaroxaban Treatment Physician Decision	1
Rivaroxaban Treatment Withdrawal by Subject	1
Rivaroxaban Treatment Non-compliance with study drug treatment	1
Rivaroxaban Treatment Adverse Event	2
Follow-up Period Death	1
Follow-up Period End-of-study done up to 4 days early	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 Participants 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.
Age, Customized < 65 years	23 Participants n=5 Participants
Age, Customized 65 - 75 years	1 Participants n=5 Participants
Age, Customized > 75 years	1 Participants n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants
Race White	1 Participants n=5 Participants
Race Black	23 Participants n=5 Participants
Race Other (mixed South African descent)	1 Participants n=5 Participants
Creatinine clearance <30 mL/min	0 Participants n=5 Participants
Creatinine clearance 30 - <50 mL/min	0 Participants n=5 Participants
Creatinine clearance 50 - <80 mL/min	4 Participants n=5 Participants
Creatinine clearance > 80 mL/min	21 Participants n=5 Participants
Region of recruitment South Africa - Yes	25 Participants n=5 Participants
Region of recruitment South Africa - No	0 Participants n=5 Participants
Participants with history of tuberculosis History of tuberculosis	20 Participants n=5 Participants
Participants with history of tuberculosis No history of tuberculosis	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=19 Participants 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.	Rivaroxaban Extended Treatment Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
Pharmacodynamics - Prothrombin Time (PT), Baseline Value	15.8 Seconds Standard Deviation 1.49	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=19 Participants 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.	Rivaroxaban Extended Treatment Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
Pharmacodynamics - Prothrombin Time (PT), Slope	0.0389 s*(µg/L)^-1 NA	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=19 Participants 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.	Rivaroxaban Extended Treatment n=18 Participants Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
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 Interval 1259.0 to 6877.0	2319 (µg*h)/L Interval 1059.0 to 5782.0

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=19 Participants 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.	Rivaroxaban Extended Treatment n=18 Participants Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban	200 µg/L Interval 150.0 to 386.0	167 µg/L Interval 126.0 to 324.0

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=19 Participants 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.	Rivaroxaban Extended Treatment n=18 Participants Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban	42 µg/L Interval 1.0 to 170.0	35 µg/L Interval 1.0 to 143.0

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 Participants 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.	Rivaroxaban Extended Treatment Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
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	—
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	—
Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding) Trivial bleeding	8.0 Percentage of participants	—

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 Participants 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.	Rivaroxaban Extended Treatment Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
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	—
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	—
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	—

SECONDARY outcome

Timeframe: 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

All deaths were adjudicated by a central independent adjudication committee. Participants who died for any reason were counted for this measure.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 Participants 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.	Rivaroxaban Extended Treatment Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
Percentage of Participants With All Deaths	12.0 Percentage of participants	—

SECONDARY outcome

Timeframe: Up to 3 months treatment and during subsequent 7 days

Population: All participants

Treatment emergent deaths were adjudicated by a central independent adjudication committee. Participants who died from treatment emergent adverse events were counted for this measure.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 Participants 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.	Rivaroxaban Extended Treatment Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
Percentage of Participants With Treatment Emergent Deaths - 7 Days Window	8.0 Percentage of participants	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 Participants 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.	Rivaroxaban Extended Treatment Participants received 20 mg rivaroxaban bid (twice-daily) orally for the remainder of the 3-month treatment period.
Percentage of Participants With Other Vascular Events	0.0 Percentage of participants	—

Adverse Events

Rivaroxaban (Xarelto, BAY59-7939)

Serious events: 5 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 participants at risk 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.
General disorders Death	8.0% 2/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
General disorders Sudden death	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Hepatobiliary disorders Hepatitis	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Infections and infestations Meningitis cryptococcal	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Nervous system disorders Vascular dementia	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)

Other adverse events

Other adverse events
Measure	Rivaroxaban (Xarelto, BAY59-7939) n=25 participants at risk 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.
Blood and lymphatic system disorders Neutropenia	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Cardiac disorders Tachycardia	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Gastrointestinal disorders Haemorrhoids	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
General disorders Oedema	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
General disorders Oedema peripheral	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Infections and infestations Cellulitis	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Infections and infestations Urinary tract infection	12.0% 3/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Investigations HIV test positive	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Musculoskeletal and connective tissue disorders Arthralgia	8.0% 2/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Musculoskeletal and connective tissue disorders Pain in extremity	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Reproductive system and breast disorders Vaginal haemorrhage	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Respiratory, thoracic and mediastinal disorders Epistaxis	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Respiratory, thoracic and mediastinal disorders Haemoptysis	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Respiratory, thoracic and mediastinal disorders Pharyngeal haemorrhage	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Respiratory, thoracic and mediastinal disorders Upper-airway cough syndrome	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Skin and subcutaneous tissue disorders Skin ulcer	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Vascular disorders Haematoma	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)
Vascular disorders Vein pain	4.0% 1/25 • For the whole study, adverse event (AE) data were collected during the study course of 25 months. For the individual patient, AE were collected during a treatment period planned for three months plus an observational period planned for one month. Abbreviations used:Human Immunodeficiency Virus (HIV)

Additional Information

Therapeutic Area Head

BAYER

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator, whilst free to utilize data derived from the study for scientific purposes, must discuss any publication with Bayer prior to release and obtain written consent of Bayer on the intended publication. The investigator must send a draft manuscript of the publication or abstract to Bayer thirty days in advance of submission in order to obtain approval prior to submission of the final version for publication.
Publication restrictions are in place

Restriction type: OTHER