Venous Thromboembolism (VTE)
Conditions
Keywords
Phase III
Brief summary
The purpose of this study is to evaluate whether extended prophylaxis with oral betrixaban can prevent blood clots in the leg and lung that sometime occur in patients hospitalized for an acute medical illness and to compare these results with standard of care enoxaparin. The safety of betrixaban will also be studied.
Interventions
DRUGBetrixaban
Betrixaban 80 mg PO once daily (QD) for 35 day + 7 days. Enoxaparin Placebo: Once daily, 6-14 days
DRUGEnoxaparin
Enoxaparin 40 mg subcutaneous (SC) QD for 10 ± 4 days. Betrixaban Placebo: once daily, 35 days
Sponsors
Portola Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* men and non-pregnant, non-breastfeeding women * anticipated to be severely immobilized for at least 24 hours after randomization * hospitalized with one of the following * congestive heart failure * acute respiratory failure, * acute infection without septic shock, * acute rheumatic disorders * acute ischemic stroke with lower extremity hemiparesis or hemi paralysis
Exclusion criteria
* a condition requiring prolonged anticoagulation or anti-platelets * active bleeding or at high risk of bleeding * contraindication to anticoagulant therapy * general conditions in which subjects are not suitable to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Intent-to-Treat (mITT) Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic Deep Vein Thrombosis (DVT), Non-fatal Pulmonary Emboli (PE), VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | mITT Cohort 1: Between randomization and Day 47 (max) | mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, venous thromboembolism (VTE) related death adjudicated by a blinded independent Clinical Events Committee (CEC) between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1). |
| mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | mITT Cohort 2: Between randomization and Day 47 (max) | mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1). |
| mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | mITT: Between randomization and Day 47 (max) | mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1). |
| Percentage of Participants Experiencing Major Bleeding Through Seven Days After Discontinuation of All Study Medication | Between randomization and Day 49 (max) | Percentage of participants experiencing at least one major bleeding adjudicated by a blinded independent CEC between randomization (day 1) and up to seven days after discontinuation of all study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | mITT Cohort 2: Between randomization and Day 42 (max) | mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1). |
| mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | mITT: Between randomization and Day 42 (max) | mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1). |
| mITT Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | mITT Cohort 1: Between randomization and Day 42 (max) | mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Croatia, Czechia, Denmark, Estonia, Finland, France, Georgia, Germany, Hungary, Israel, Italy, Latvia, Lithuania, Montserrat, Peru, Poland, Romania, Russia, Serbia, Singapore, Slovakia, South Africa, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
First patient was enrolled on 3/29/2012 and last patient completed the study on 1/15/2016. Patients meeting the inclusion and none of the exclusion criteria at screening were randomized 1:1 to either the betrixaban or enoxaparin treatment group.
Pre-assignment details
To maintain the blind, patients either received betrixaban capsules for 35 to 42 days and daily subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days, or received daily SQ injections of enoxaparin for 10 ± 4 days and betrixaban placebo capsules for 35 to 42 days.
Participants by arm
| Arm | Count |
|---|---|
| Betrixaban Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days | 3,759 |
| Enoxaparin Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days | 3,754 |
| Total | 7,513 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse event or serious adverse event | 3 | 3 |
| Overall Study | Cannot contact patient directly | 1 | 2 |
| Overall Study | Death | 206 | 211 |
| Overall Study | Lost to Follow-up | 11 | 17 |
| Overall Study | Patient deemed ineligible after random | 2 | 0 |
| Overall Study | Patient did not wish to attend visits | 0 | 1 |
| Overall Study | Patient /Family decision | 3 | 0 |
| Overall Study | Patient randomized but not dosed | 17 | 16 |
| Overall Study | Patient was assessed via phone in person | 1 | 0 |
| Overall Study | Patient was early terminated from study | 0 | 1 |
| Overall Study | Patient was randomized due to mistake | 1 | 0 |
| Overall Study | SOURCE DOCUMENT/COORDINATOR MISSING | 0 | 2 |
| Overall Study | THE SUBJECT MOVED TO ANOTHER PROVINCE | 0 | 1 |
| Overall Study | Withdrawal by Subject | 43 | 29 |
| Overall Study | Withdraw of consent on day of random | 1 | 0 |
Baseline characteristics
| Characteristic | Betrixaban | Enoxaparin | Total |
|---|---|---|---|
| Age, Continuous | 76.6 years STANDARD_DEVIATION 8.46 | 76.2 years STANDARD_DEVIATION 8.31 | 76.4 years STANDARD_DEVIATION 8.39 |
| Age, Customized <75 years | 1184 Participants | 1237 Participants | 2421 Participants |
| Age, Customized >=75 years | 2575 Participants | 2517 Participants | 5092 Participants |
| Sex: Female, Male Female | 2054 Participants | 2034 Participants | 4088 Participants |
| Sex: Female, Male Male | 1705 Participants | 1720 Participants | 3425 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 879 / 3,716 | 779 / 3,716 |
| serious Total, serious adverse events | 657 / 3,716 | 615 / 3,716 |
Outcome results
Primary
mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3
mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
Time frame: mITT Cohort 2: Between randomization and Day 47 (max)
Population: Cohort 2 (encompasses both participants over 75 and participants with baseline D-dimer ≥ 2 x ULN as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban | mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | 4.70 Percentage of Participants |
| Enoxaparin | mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | 6.02 Percentage of Participants |
p-value: 0.01895% CI: [0.041, 0.359]Cochran-Mantel-Haenszel
Primary
mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3
mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
Time frame: mITT: Between randomization and Day 47 (max)
Population: The mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban | mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | 4.43 Percentage of Participants |
| Enoxaparin | mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | 5.99 Percentage of Participants |
p-value: 0.00395% CI: [0.092, 0.387]Cochran-Mantel-Haenszel
Primary
Modified Intent-to-Treat (mITT) Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic Deep Vein Thrombosis (DVT), Non-fatal Pulmonary Emboli (PE), VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3
mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, venous thromboembolism (VTE) related death adjudicated by a blinded independent Clinical Events Committee (CEC) between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
Time frame: mITT Cohort 1: Between randomization and Day 47 (max)
Population: Cohort 1 (participants with baseline D-dimer ≥ 2 x upper limit normal (ULN) as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban | Modified Intent-to-Treat (mITT) Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic Deep Vein Thrombosis (DVT), Non-fatal Pulmonary Emboli (PE), VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | 5.70 Percentage of Participants |
| Enoxaparin | Modified Intent-to-Treat (mITT) Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic Deep Vein Thrombosis (DVT), Non-fatal Pulmonary Emboli (PE), VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 | 7.18 Percentage of Participants |
p-value: 0.03895% CI: [0.013, 0.366]Cochran-Mantel-Haenszel
Primary
Percentage of Participants Experiencing Major Bleeding Through Seven Days After Discontinuation of All Study Medication
Percentage of participants experiencing at least one major bleeding adjudicated by a blinded independent CEC between randomization (day 1) and up to seven days after discontinuation of all study medication.
Time frame: Between randomization and Day 49 (max)
Population: Safety population which consisted of all participants who had taken at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban | Percentage of Participants Experiencing Major Bleeding Through Seven Days After Discontinuation of All Study Medication | 0.67 Percentage of Participants |
| Enoxaparin | Percentage of Participants Experiencing Major Bleeding Through Seven Days After Discontinuation of All Study Medication | 0.57 Percentage of Participants |
p-value: 0.554Chi-squared
Secondary
mITT Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3
mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
Time frame: mITT Cohort 1: Between randomization and Day 42 (max)
Population: Cohort 1 (participants with baseline D-dimer ≥ 2 x ULN as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban | mITT Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | 1.30 Percentage of Participants |
| Enoxaparin | mITT Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | 1.90 Percentage of Participants |
p-value: 0.09295% CI: [-0.069, 0.576]Cochran-Mantel-Haenszel
Secondary
mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3
mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
Time frame: mITT Cohort 2: Between randomization and Day 42 (max)
Population: Cohort 2 (encompasses both participants over 75 and participants with baseline D-dimer ≥ 2 x ULN as determined by the local lab) of the mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban | mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | 1.03 Percentage of Participants |
| Enoxaparin | mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | 1.45 Percentage of Participants |
p-value: 0.1195% CI: [-0.085, 0.542]Cochran-Mantel-Haenszel
Secondary
mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3
mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
Time frame: mITT: Between randomization and Day 42 (max)
Population: The mITT population which consisted of all participants who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy components.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Betrixaban | mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | 0.94 Percentage of Participants |
| Enoxaparin | mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 | 1.45 Percentage of Participants |
p-value: 0.03995% CI: [0.02, 0.58]Cochran-Mantel-Haenszel