| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophylaxis of venous thromboembolism |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prevention of blood clots |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049909 |
| E.1.2 | Term | Venous thromboembolism prophylaxis |
| E.1.2 | System Organ Class | 100000004865 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Demonstrate the superiority of extended duration (35 days + 7 day window, i.e. 35-42 days allowed) anticoagulation with betrixaban as compared to the standard of care (10 ± 4 days) with enoxaparin for prevention of VTE in patients who are at risk due to acute medical illness |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female (non-pregnant, non-breastfeeding women) ages 40 years and older anticipated to be severely immobilized for at least 24 hours after randomization hospitalized with:
- one of the following Primary Risk Criteria for VTE documented as the cause of the acute hospitalization:
o congestive heart failure,
o acute respiratory failure,
o acute infection without septic shock,
o acute rheumatic disorders,
o acute ischemic stroke with lower extremity hemiparesis or hemiparalysis
3. Signed informed consent form must be present.
4. Patients must be:
•Severely Immobilized for 24 hours during the current hospitalization either before randomization or anticipated to be Severely Immobilized for a total period of 24 hours after randomization*, and
•Are anticipated to be either Severely or Moderately Immobilized for a total of ≥ 4 days following randomization in any type of care setting (e.g., hospital, intermediate care or rehabilitation center, managed care in home, etc.), and
•Are anticipated to be Mildly Immobilized after hospital discharge.
*If the 24 hour period of severe immobility occurs before randomization, the patient must still be at least moderately immobilized at randomization.
Severe immobilization – Patient is totally confined by illness to bed or chair for 100% of time. The patient may be able to use a bedside commode or the hospital room toilet with assistance only.
Moderate immobilization – Patient is confined by illness to bed for more than 50% of the time during daytime hours, but may spend up to 50% of the time in bedside chair. Patient cannot walk distance of 10 meters in 1 attempt or is only able to do so with assistance. Independent mobility is restricted to use of the hospital room toilet.
Mild immobilization - Patient is expected to remain in bed or chair during daytime hours more than was usual prior to their hospitalization.
|
|
| E.4 | Principal exclusion criteria |
a condition requiring and receiving prolonged anticoagulation or anti-platelets
active bleeding or at high risk of bleeding
unable to take oral medication
contraindication to anticoagulant therapy
general conditions in which subjects are not suitable to participate in the study
20. Known uncontrolled human immunodeficiency virus (HIV) infection (i.e., severely neutropenic (ANC < 500/mm3) or anticipated to develop severe neutropenia during the study treatment period due to prior or planned chemotherapy, or have HIV with CD4 count < 100/mm3 within 6 months prior to enrollment) or known complication of HIV infection (e.g., pneumocystis carinii pneumonia, Kaposi’s sarcoma, etc.) at screening. Patients with stable HIV infection on adequate antiviral medication are eligible for enrollment although they may require the reduced dose of betrixaban if their antiviral therapy includes a strong P-gp inhibitor (See Appendix B).
25. Concomitant dual anti-platelet therapy daily [any 2 of the following: aspirin, dipyridamole, or any thienopyridine (i.e., clopidogrel, prasugrel, ticlopidine, ticagrelor)]. Fixed combination of very low dose aspirin (≤ 50 mg) and persantine products (e.g., Aggrenox®) will not be considered dual anti-platelet therapy for the purposes of this protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
The primary (composite) outcome is the occurrence of any of the following events through the Day 35 visit:
Asymptomatic proximal DVT (as detected by ultrasound), symptomatic DVT (proximal or distal), non-fatal PE, or VTE related death
Safety:
The primary safety outcome will be the occurrence of major bleeding through 7 days after discontinuation of all study medication. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
There will be a single interim efficacy and futility analysis of
the primary and secondary outcomes when approximately 50% of the primary-endpoint evaluable patients have data (i.e., 2568 patients with an evaluable primary outcome).
Efficacy and safety outcomes will be reviewed by the IDMC at the following defined intervals:
• After 250 patients have completed follow-up
• After 750 patients have completed follow-up
• After 1500 patients have completed follow-up
• After 3000 patients have completed follow-up
• After 4500 patients have completed follow-up
• After 2568 patients have evaluable primary outcome data. This may occur simultaneously with one of the above meetings if the meeting criteria coincide. |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
The key secondary (composite) outcome is the occurrence of any of the following events through the end of the parenteral treatment period:
Asymptomatic proximal DVT (as detected by ultrasound), symptomatic DVT (proximal or distal), non-fatal PE, or VTE related death
Other Secondary Efficacy Outcomes:
The following other secondary composite outcomes will be examined:
• Symptomatic VTE: The occurrence of symptomatic VTE through the Day 35 visit (VTE-related death, nonfatal PE or symptomatic DVT)
• The occurrence of asymptomatic proximal DVT, symptomatic DVT (proximal or distal), non-fatal PE, or allcause mortality through the Day 35 visit
Safety:
Secondary safety outcomes include the following:
• Occurrence of clinically relevant non-major bleeding (CRNM bleeding) through 7 days after discontinuation of all study medication
• Occurrence of major bleeding through the time of parenteral study medication discontinuation
• Occurrence of CRNM bleeding through the time of parenteral study medication discontinuation
• Occurrence of major bleeding from the time of parenteral study medication discontinuation through Day 35
• Occurrence of CRNM bleeding from the time of parenteral study medication discontinuation through Day 35
• Occurrence of major bleeding through the time of parenteral study medication discontinuation in patientswith severe renal insufficiency (creatinine clearance <
30 ml/min)
• Occurrence of CRNM bleeding through the time of parenteral study medication discontinuation in patients with severe renal insufficiency
• Occurrence of major bleeding through 7 days after discontinuation of all study medication in patients with severe renal insufficiency
• Occurrence of CRNM bleeding through 7 days after discontinuation of all study medication in patients with severe renal insufficiency
• Occurrence of stroke, as adjudicated by the CEC
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
There will be a single interim efficacy and futility analysis of
the primary and secondary outcomes when approximately 50% of the primary-endpoint evaluable patients have data (i.e., 2568 patients with an evaluable primary outcome).
Efficacy and safety outcomes will be reviewed by the IDMC at the following defined intervals:
• After 250 patients have completed follow-up
• After 750 patients have completed follow-up
• After 1500 patients have completed follow-up
• After 3000 patients have completed follow-up
• After 4500 patients have completed follow-up
• After 2568 patients have evaluable primary outcome data. This may occur simultaneously with one of the above meetings if the meeting criteria coincide. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 136 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Croatia |
| Czech Republic |
| Denmark |
| Estonia |
| France |
| Germany |
| Hungary |
| India |
| Italy |
| Latvia |
| Lithuania |
| Spain |
| Israel |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| South Africa |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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