Heart Failure, Infectious Diseases, Respiratory Insufficiency, Rheumatic Diseases, Stroke Acute
Conditions
Keywords
Heart Failure, Respiratory Insufficiency, Stroke Acute, Infectious Diseases, Rheumatic Diseases, Medically ill Patient, Rivaroxaban, Thromboembolism, Prophylactic Anti-Coagulation
Brief summary
The purpose of this study is to evaluate the efficacy and safety of rivaroxaban compared with placebo in the prevention of symptomatic venous thromboembolism (VTE) events and VTE-related death post-hospital discharge in high-risk, medically ill patients.
Detailed description
This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect)-controlled, event-driven, multicenter study in patients who are hospitalized for a specific acute medical illness and have other risk factors for venous thromboembolism (VTE). The study is designed to evaluate rivaroxaban in the prevention of symptomatic VTE events and VTE-related deaths for a period of 45 days post-hospital discharge. The study will consist of a screening phase, a 45-day double-blind treatment phase, and a 30-day follow-up phase. Study drug will start at randomization (Day 1), and will continue until Day 45 (inclusive). A total of approximately 12000 patients will be randomly assigned to either rivaroxaban or placebo in a 1:1 ratio. The total duration for a patient who completes the study after randomization is expected to be 75 days.
Interventions
DRUGRivaroxaban, 10 mg
Patients, randomly allocated to the rivaroxaban arm, with a creatinine clearance at screening greater than or equal to (\>=)50 mL/min will receive 10 mg rivaroxaban tablet with or without food.
DRUGRivaroxaban, 7.5 mg
Patients, randomly allocated to the rivaroxaban arm, with a creatinine clearance at screening from \>=30 to less than (\<)50 mL/min will receive 7.5 mg rivaroxaban tablet with or without food.
DRUGPlacebo
All patients, randomly allocated to the placebo arm, will receive one placebo tablet with or without food.
Sponsors
Bayer
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * The duration of the index hospitalization must have been at least 3 and no more than 10 consecutive days * Must meet venous thromboembolism (VTE) risk criteria with a total modified Improve VTE Risk Score of: greater than or equal 4, or 3 with D-dimer \> 2\* upper limit of normal (ULN), or 2 with D-dimer \> 2\*ULN Key
Exclusion criteria
* Any serious bleeding within 3 months prior to randomization or occurring during index hospitalization * Serious trauma (including head trauma) within 4 weeks before randomization * History of hemorrhagic stroke at any time in the past * Any medical condition that requires chronic use of any parenteral or oral anticoagulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to First Occurrence of Composite of All Symptomatic Venous Thromboembolism (VTE) and VTE Related Death Adjudicated by Clinical Event Committee (CEC) | Up to Day 45 | Symptomatic VTE included lower extremity deep vein thrombosis (DVT) and non-fatal pulmonary embolism (PE). Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45. |
| Event Rate Based on Time From Randomization to the First Occurrence of Major Bleeding Adjudicated by CEC | From randomization to 2 days after the last dose (Day 45) | A major bleeding event was defined using validated International Society on Thrombosis and Haemostasis (ISTH) bleeding criteria. A major bleeding event was defined as overt bleeding that was associated with a fall in hemoglobin of 2 gram per deciliter (g/dL) or more, or a transfusion of 2 or more units of packed red blood cells or whole blood, or a critical site defined as intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or a fatal outcome. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or last dose + 2 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE and All-Cause Mortality (ACM) Adjudicated by CEC | Up to Day 45 | Event rate based on time from randomization to the first occurrence of a composite of symptomatic VTE and ACM (adjudicated by CEC) was assessed. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45. |
| Event Rate Based on Time From Randomization to First Occurrence of VTE-Related Death Adjudicated by CEC | Up to Day 45 | Event rate based on time from randomization to first occurrence of VTE-related death (adjudicated by CEC) was assessed. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45. |
| Event Rate Based on Time From Randomization to First Occurrence of All-Cause Mortality (ACM) Adjudicated by CEC | Up to Day 45 | Event rate based on time from randomization to first occurrence of ACM (adjudicated by CEC) was assessed. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45. |
| Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE, Myocardial Infarction (MI), Non-Hemorrhagic Stroke, and Cardiovascular (CV) Death Adjudicated by CEC | Up to Day 45 | Event rate based on time from randomization to the first occurrence of a composite of symptomatic VTE (lower extremity DVT and non-fatal PE), MI, non-hemorrhagic stroke, and CV death (death due to a known CV cause and death in which a CV cause cannot be ruled out; by this definition, a VTE-related death was considered a CV death) as adjudicated by CEC was reported. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45. |
| Event Rate Based on Time From Randomization to the First Occurrence of a Symptomatic Venous Thromboembolism Event (VTE) Adjudicated by CEC | Up to Day 45 | Event rate based on time from randomization to the first occurrence of a symptomatic VTE (adjudicated by CEC) was assessed. Symptomatic VTE included lower extremity DVT and non-fatal PE. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45. |
Countries
Argentina, Australia, Austria, Belarus, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Colombia, Croatia, Czechia, Denmark, Estonia, Georgia, Germany, Greece, Hungary, Israel, Latvia, Lithuania, Mexico, Netherlands, North Macedonia, Peru, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, Slovakia, South Africa, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
12024 participants were randomized (rivaroxaban-6007;placebo-6017). 5 participants in placebo were excluded(2 invalid consent,3 randomized before Health Authority approval).
Pre-assignment details
Participants were randomized (1:1) to receive rivaroxaban or placebo. In rivaroxaban, participants were treated with rivaroxaban 10 mg or 7.5 mg as per their creatinine clearance level. Data in the participant flow section is reported for study discontinuation from the disposition data.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban 10 mg or 7.5 mg Participants with a creatinine clearance (CrCl) greater than or equal to (\>=) 50 milliliter per minute (mL/min) received 10 milligram (mg) rivaroxaban tablet once daily orally and participants with a creatinine clearance from \>=30 to less than (\<) 50 mL/min at screening received 7.5 mg rivaroxaban tablet once daily orally for 45 days. | 6,007 |
| Placebo Participants received rivaroxaban matched placebo tablet once daily orally for 45 days. | 6,012 |
| Total | 12,019 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 109 | 120 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Withdrawal by Subject | 20 | 20 |
Baseline characteristics
| Characteristic | Rivaroxaban 10 mg or 7.5 mg | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 69.7 years STANDARD_DEVIATION 10.06 | 69.7 years STANDARD_DEVIATION 10.14 | 69.7 years STANDARD_DEVIATION 10.22 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 499 Participants | 981 Participants | 482 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5490 Participants | 11000 Participants | 5510 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 38 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 16 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 71 Participants | 128 Participants | 57 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 128 Participants | 251 Participants | 123 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) White | 5782 Participants | 11590 Participants | 5808 Participants |
| Region of Enrollment ARGENTINA | 120 Participants | 242 Participants | 122 Participants |
| Region of Enrollment AUSTRALIA | 45 Participants | 88 Participants | 43 Participants |
| Region of Enrollment AUSTRIA | 6 Participants | 14 Participants | 8 Participants |
| Region of Enrollment BELARUS | 67 Participants | 133 Participants | 66 Participants |
| Region of Enrollment BOSNIA-HERZEGOVINA | 298 Participants | 597 Participants | 299 Participants |
| Region of Enrollment BRAZIL | 46 Participants | 92 Participants | 46 Participants |
| Region of Enrollment BULGARIA | 714 Participants | 1428 Participants | 714 Participants |
| Region of Enrollment CANADA | 21 Participants | 43 Participants | 22 Participants |
| Region of Enrollment COLOMBIA | 70 Participants | 140 Participants | 70 Participants |
| Region of Enrollment CROATIA | 135 Participants | 270 Participants | 135 Participants |
| Region of Enrollment CZECH REPUBLIC | 115 Participants | 231 Participants | 116 Participants |
| Region of Enrollment DENMARK | 3 Participants | 7 Participants | 4 Participants |
| Region of Enrollment ESTONIA | 5 Participants | 11 Participants | 6 Participants |
| Region of Enrollment GEORGIA | 880 Participants | 1762 Participants | 882 Participants |
| Region of Enrollment GERMANY | 8 Participants | 17 Participants | 9 Participants |
| Region of Enrollment GREECE | 66 Participants | 131 Participants | 65 Participants |
| Region of Enrollment HUNGARY | 275 Participants | 549 Participants | 274 Participants |
| Region of Enrollment ISRAEL | 55 Participants | 111 Participants | 56 Participants |
| Region of Enrollment ITALY | 74 Participants | 147 Participants | 73 Participants |
| Region of Enrollment LATVIA | 154 Participants | 308 Participants | 154 Participants |
| Region of Enrollment LITHUANIA | 82 Participants | 164 Participants | 82 Participants |
| Region of Enrollment MEXICO | 17 Participants | 32 Participants | 15 Participants |
| Region of Enrollment NETHERLANDS | 8 Participants | 17 Participants | 9 Participants |
| Region of Enrollment PERU | 33 Participants | 65 Participants | 32 Participants |
| Region of Enrollment POLAND | 310 Participants | 619 Participants | 309 Participants |
| Region of Enrollment PORTUGAL | 6 Participants | 13 Participants | 7 Participants |
| Region of Enrollment PUERTO RICO | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment REPUBLIC OF MACEDONIA | 451 Participants | 902 Participants | 451 Participants |
| Region of Enrollment ROMANIA | 162 Participants | 324 Participants | 162 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 571 Participants | 1142 Participants | 571 Participants |
| Region of Enrollment SERBIA | 305 Participants | 609 Participants | 304 Participants |
| Region of Enrollment SOUTH AFRICA | 103 Participants | 205 Participants | 102 Participants |
| Region of Enrollment SPAIN | 192 Participants | 383 Participants | 191 Participants |
| Region of Enrollment TURKEY | 35 Participants | 70 Participants | 35 Participants |
| Region of Enrollment UKRAINE | 426 Participants | 854 Participants | 428 Participants |
| Region of Enrollment UNITED KINGDOM | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment UNITED STATES | 145 Participants | 290 Participants | 145 Participants |
| Sex: Female, Male Female | 2877 Participants | 5735 Participants | 2858 Participants |
| Sex: Female, Male Male | 3130 Participants | 6284 Participants | 3154 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 115 / 6,007 | 126 / 6,012 |
| other Total, other adverse events | 250 / 6,007 | 280 / 6,012 |
| serious Total, serious adverse events | 475 / 6,007 | 493 / 6,012 |
Outcome results
Primary
Event Rate Based on Time From Randomization to the First Occurrence of Major Bleeding Adjudicated by CEC
A major bleeding event was defined using validated International Society on Thrombosis and Haemostasis (ISTH) bleeding criteria. A major bleeding event was defined as overt bleeding that was associated with a fall in hemoglobin of 2 gram per deciliter (g/dL) or more, or a transfusion of 2 or more units of packed red blood cells or whole blood, or a critical site defined as intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or a fatal outcome. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or last dose + 2 days.
Time frame: From randomization to 2 days after the last dose (Day 45)
Population: The Safety analysis set included all enrolled participants in the ITT analysis set who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg or 7.5 mg | Event Rate Based on Time From Randomization to the First Occurrence of Major Bleeding Adjudicated by CEC | 0.28 Events per 100 participants in 45 days |
| Placebo | Event Rate Based on Time From Randomization to the First Occurrence of Major Bleeding Adjudicated by CEC | 0.15 Events per 100 participants in 45 days |
p-value: 0.12495% CI: [0.84, 4.23]Cox proportional hazards model
Primary
Time From Randomization to First Occurrence of Composite of All Symptomatic Venous Thromboembolism (VTE) and VTE Related Death Adjudicated by Clinical Event Committee (CEC)
Symptomatic VTE included lower extremity deep vein thrombosis (DVT) and non-fatal pulmonary embolism (PE). Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45.
Time frame: Up to Day 45
Population: Intention-to-treat (ITT) analysis set comprised all randomized participants who signed a valid informed consent, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg or 7.5 mg | Time From Randomization to First Occurrence of Composite of All Symptomatic Venous Thromboembolism (VTE) and VTE Related Death Adjudicated by Clinical Event Committee (CEC) | 0.84 Events per 100 participants in 45 days |
| Placebo | Time From Randomization to First Occurrence of Composite of All Symptomatic Venous Thromboembolism (VTE) and VTE Related Death Adjudicated by Clinical Event Committee (CEC) | 1.11 Events per 100 participants in 45 days |
p-value: 0.13695% CI: [0.52, 1.09]Cox proportional hazards model
Secondary
Event Rate Based on Time From Randomization to First Occurrence of All-Cause Mortality (ACM) Adjudicated by CEC
Event rate based on time from randomization to first occurrence of ACM (adjudicated by CEC) was assessed. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45.
Time frame: Up to Day 45
Population: ITT analysis set comprised all randomized participants who signed a valid informed consent, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg or 7.5 mg | Event Rate Based on Time From Randomization to First Occurrence of All-Cause Mortality (ACM) Adjudicated by CEC | 1.19 Events per 100 participants in 45 days |
| Placebo | Event Rate Based on Time From Randomization to First Occurrence of All-Cause Mortality (ACM) Adjudicated by CEC | 1.49 Events per 100 participants in 45 days |
p-value: 0.15695% CI: [0.58, 1.09]Cox proportional hazards model
Secondary
Event Rate Based on Time From Randomization to First Occurrence of VTE-Related Death Adjudicated by CEC
Event rate based on time from randomization to first occurrence of VTE-related death (adjudicated by CEC) was assessed. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45.
Time frame: Up to Day 45
Population: ITT analysis set comprised all randomized participants who signed a valid informed consent, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg or 7.5 mg | Event Rate Based on Time From Randomization to First Occurrence of VTE-Related Death Adjudicated by CEC | 0.72 Events per 100 participants in 45 days |
| Placebo | Event Rate Based on Time From Randomization to First Occurrence of VTE-Related Death Adjudicated by CEC | 0.77 Events per 100 participants in 45 days |
p-value: 0.75195% CI: [0.62, 1.42]Cox proportional hazards model
Secondary
Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE and All-Cause Mortality (ACM) Adjudicated by CEC
Event rate based on time from randomization to the first occurrence of a composite of symptomatic VTE and ACM (adjudicated by CEC) was assessed. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45.
Time frame: Up to Day 45
Population: ITT analysis set comprised all randomized participants who signed a valid informed consent, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg or 7.5 mg | Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE and All-Cause Mortality (ACM) Adjudicated by CEC | 1.31 Events per 100 participants in 45 days |
| Placebo | Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE and All-Cause Mortality (ACM) Adjudicated by CEC | 1.80 Events per 100 participants in 45 days |
p-value: 0.03395% CI: [0.54, 0.97]Cox proportional hazards model
Secondary
Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE, Myocardial Infarction (MI), Non-Hemorrhagic Stroke, and Cardiovascular (CV) Death Adjudicated by CEC
Event rate based on time from randomization to the first occurrence of a composite of symptomatic VTE (lower extremity DVT and non-fatal PE), MI, non-hemorrhagic stroke, and CV death (death due to a known CV cause and death in which a CV cause cannot be ruled out; by this definition, a VTE-related death was considered a CV death) as adjudicated by CEC was reported. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45.
Time frame: Up to Day 45
Population: ITT analysis set comprised all randomized participants who signed a valid informed consent, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg or 7.5 mg | Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE, Myocardial Infarction (MI), Non-Hemorrhagic Stroke, and Cardiovascular (CV) Death Adjudicated by CEC | 1.58 Events per 100 participants in 45 days |
| Placebo | Event Rate Based on Time From Randomization to the First Occurrence of a Composite of Symptomatic VTE, Myocardial Infarction (MI), Non-Hemorrhagic Stroke, and Cardiovascular (CV) Death Adjudicated by CEC | 2.03 Events per 100 participants in 45 days |
p-value: 0.07395% CI: [0.6, 1.02]Cox proportional hazards model
Secondary
Event Rate Based on Time From Randomization to the First Occurrence of a Symptomatic Venous Thromboembolism Event (VTE) Adjudicated by CEC
Event rate based on time from randomization to the first occurrence of a symptomatic VTE (adjudicated by CEC) was assessed. Symptomatic VTE included lower extremity DVT and non-fatal PE. Event rate was defined as number of events per 100 participants in 45 days of follow up. Participants who did not have events were censored on the minimum of last visit before or on death, or Day 45.
Time frame: Up to Day 45
Population: ITT analysis set comprised all randomized participants who signed a valid informed consent, regardless of actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg or 7.5 mg | Event Rate Based on Time From Randomization to the First Occurrence of a Symptomatic Venous Thromboembolism Event (VTE) Adjudicated by CEC | 0.19 Events per 100 participants in 45 days |
| Placebo | Event Rate Based on Time From Randomization to the First Occurrence of a Symptomatic Venous Thromboembolism Event (VTE) Adjudicated by CEC | 0.42 Events per 100 participants in 45 days |
p-value: 0.02395% CI: [0.22, 0.89]Cox proportional hazards model