| 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 | 17.0 |
| 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 |
1. General. Male or female patients aged ≥ 40 years.
2. Cause of Acute Hospitalization. At least one of the following as the
cause of the acute hospitalization:
a. Acutely decompensated heart failure with prior symptomatic chronic heart failure
b. Acute respiratory failure in patients with chronic symptomatic lung disease
c. Acute infection without septic shock (e.g., with systolic blood pressure
< 90 mmHg after fluid challenge that requires pressor therapy) at screening and randomization.
d. Acute rheumatic disorders including acute lumbar pain, sciatica, vertebral compression, rheumatoid arthritis, systemic lupus erythematosus, etc.
e. Acute ischemic stroke with lower extremity hemiparesis or hemiparalysis, or with immobility of other origin that satisfies protocol immobility requirements.
3. Eligibility Risk Factors. Any one of the following:
a. ≥ 75 years of age, or
b. 60 through 74 years of age with D-dimer ≥ 2ULN, orc. 40 through 59 years of age with D-dimer ≥ 2ULN and a history of either VTE (DVT or PE) or cancer (excluding non-melanoma carcinoma of the skin)
c. 40 through 59 years of age with D-dimer ≥ 2ULN and a history of either VTE (DVT or PE) or cancer (excluding non-melanoma carcinoma of the skin)
4. Immobilization.
a. Patients have been Severely Immobilized for 24 hours or are anticipated to be Severely Immobilized for 24 hours. Severely Immobilized means patients are confined to a bed or chair for the majority of the day and can only be independently mobile to the in-room toilet. In-bed/chair physical therapy is permitted.
b. After 24 hours of Severe Immobilization, patients are anticipated to be Severely Immobilized or Moderately Immobilized for 3 or more days. Moderately Immobilized means patients can be independently mobile to the in-room or ward toilet; can be mobilized by physical therapy or nursing staff; and can be off-ward with assistance.
5. Hemoglobin.
a. Hgb ≥ 10.0 g/dL during current presentation prior to randomization. A single value of Hgb < 10.0 g/dL does not disqualify a patient. Hgb may be repeated after initial stabilization, e.g., after diuresis in patients with acute decompensated heart failure, or
b. Hgb ≥ 9.5 g/dL from two (2) consecutive blood samples taken on consecutive days with stable or rising (i.e., not falling) values.
6. Length of Hospitalization.
a. Expected total length of current hospitalization ≥ 3 days.
b. Enrollment occurs < 96 hours after hospitalization/presentation (e.g.,
in Emergency Department) for acute medical illness.
7. Contraception.
a. Women of childbearing potential must have a negative serum pregnancy test prior to randomization and must be willing to use an acceptable method of contraception to avoid pregnancy throughout the study. Acceptable methods of contraception include bilateral tubal ligation (women), vasectomy (men), oral contraceptive (women), contraceptive patch, anovulants without estrogen, intradermal contraceptive implant with progesterone, progestagen injections every three months or barrier methods (intra-uterine device, diaphragm,
female condom, male condom).
b. Abstinence (as part of the patient current lifestyle to choose not to
have sex at all) is an acceptable form of contraception, only insofar as
patients agree to use another acceptable method of birth control,
preferably a barrier method, if the patient becomes sexually active,
please refer to 7. a
c. Periodic abstinence (trying to check your chances of becoming
pregnant by the calendar, ovulation, post-ovulation or symptothermal
(checking temperature) methods, and withdrawal are not acceptable
methods of contraception.
8. Informed Consent. Signed informed consent form must be present.
Patients will be consented prior to beginning screening procedures;
however once consent is obtained, a "look back" period is allowable to
assess eligibility criteria (reviewing for tests and evaluations performed
during the current hospitalization up to 96 hours unless otherwise noted
in Section 8.1.2, before randomization. |
|
| E.4 | Principal exclusion criteria |
1. Unable to receive nourishment by enteral administration (e.g., by mouth, feeding tube, PEG tube).
2. Anticipated need for prolonged anticoagulation during the trial.
3. Life expectancy < 8 weeks
4. In the opinion of the Investigator, it will not be possible to obtain an
adequate bilateral compression ultrasound sonography (CUS) evaluation
(e.g., patients with above the knee amputations, some patients withlower limb lymphoedema or obesity that prevents adequate compression)
5. Patients unwilling or unable to comply with study procedures (including the Visit 3 ultrasound procedure) or study medications.
At risk of increased bleeding due to:
6. Low body weight < 45 kg.
7. History of clinically significant bleeding (i.e., requiring medical attention) within 6 months prior to enrollment.
8. History of any significant gastrointestinal, pulmonary or urogenital bleeding, ongoing chronic peptic ulcer disease or ongoing or acute gastritis within 2 years prior to enrollment.
9. Admitting or concomitant diagnosis having resulted in or likely to require major surgery (e.g., one in which a body cavity is surgically entered) within 3 months prior to enrollment or while on study, or other invasive procedure performed within 3 months prior to enrollment or while on study.
10. Ophthalmic surgery or biopsy of a parenchymal organ within 3 months prior to enrollment.
11. Known history of bronchiectasis (as defined by dilation of the bronchi and associated with bloody sputum in patients with chronic pulmonary disease) or active lung cancer; however, lung cancer patients post-treatment who have no evidence of residual disease may be enrolled.
12. End stage renal disease with CrCl <15 mL/min, or requiring dialysis, or likely to require dialysis within 3 months of enrollment.
13. History of: a. spontaneous intracranial (IC) bleeding within 3 years prior to enrollment or concurrent intracranial (IC) bleeding
14. History of severe head trauma or other severe physical trauma within 3 months prior to enrollment
15. Known intracranial lesions, including neoplasm, metastatic disease, arterio-venous malformation or aneurysm
16. Has severe renal insufficiency (i.e., CrCl between ≥ 15 mL/min and <30 mL/min) and requires a concomitant use of a strong P-gp inhibitor (See Appendix B).
17. Contraindication to anticoagulant therapy
18. Known abnormality of liver function tests [ > 3x ULN for serum glutamic-oxaloacetic transaminase (SGOT)/aspartate aminotransferase
(AST), serum glutamate pyruvate transaminase (SGPT)/alanine
transaminase (ALT) or alkaline phosphatase (ALP), or > 2 x ULN for total
bilirubin in the absence of Gilbert's syndrome], active liver disease, or hepatic dysfunction (e.g., cirrhosis).
19. 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 Pgp
inhibitor (See Appendix B).
20. Concurrent or history of alcohol or drug abuse within 1 year prior to
enrollment.
21. Shock with persistent systolic BP < 90 mmHg and/or requiring pharmacological support of blood pressure.
22. History of hypersensitivity to either of the study articles or any component of their formulations (enoxaparin or betrixaban) including heparin induced thrombocytopenia.
23. Pregnancy or breastfeeding or any plan to become pregnant during the study.
24. Concomitant dual anti-platelet therapy daily [any 2 of the following:
aspirin, dipyridamole, or any thienopyridine (i.e., clopidogrel, prasugrel,
ticlopidine, ticagrelor)]. However, patients receiving a fixed combination
of very low dose aspirin (≤ 50 mg) and persantine products (e.g.,Aggrenox®) may be enrolled.
25. Greater than 96 hours of administration of the following anticoagulants immediately prior to receiving study treatment.
26. Cannot have received any oral anticoagulant within 96 hours immediately prior to the beginning of study treatment (e.g., vitamin K
antagonist, direct fXa inhibitors, direct thrombin inhibitors).
27. Indication for fibrinolysis or thrombolysis or having received such therapy within 30 days prior to enrollment.
28. Use of bevacizumab (Avastin®) or similar anti-angiogenic therapy within 6 months prior to enrollment or planned use during the study period.
29. Use of experimental drugs or devices within 30 days prior to screening
30. Patients who were previously randomized in the study cannot be enrolled again at a later date.
31. Unconscious patients will not be enrolled in the trial. |
|
| 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 Visit 3:
Asymptomatic proximal deep vein/venous thrombosis (DVT) as detected by ultrasound), symptomatic DVT (proximal or distal), non-fatal pulmonary embolism (PE), or VTE related death.
All events are as adjudicated by the Clinical Events Committee (CEC) except asymptomatic proximal DVT (as detected by ultrasound) which will be determined by the ultrasound core laboratory.
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 |
Safety outcomes will be reviewed by the IDMC at the following defined
intervals:
• After 250 patients have completed Visit 3 and have data available for review
• After 750 patients have completed Visit 3 and have data available for review
• After 1500 patients have completed Visit 3 and have data available for review
• After 3000 patients have completed Visit 3 and have data available for review
• After 4500 patients have completed Visit 3 and have data available for review
One non-binding futility analysis is planned when approximately 50% of the overall population has evaluable primary outcome data.
The IDMC may also decide to meet and review safety data at other time points as they deem necessary. |
|
| E.5.2 | Secondary end point(s) |
The following other secondary composite outcomes will be examined:
• Symptomatic VTE: The occurrence of symptomatic VTE through the Visit 3 (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 Visit 3
All events are as adjudicated by the CEC except asymptomatic proximal DVT (as detected by ultrasound) which will be determined by the ultrasound core laboratory. mortality through Visit 3
Additionally, the components of the primary endpoint will be examined as secondary efficacy outcomes:
1. The occurrence of asymptomatic proximal DVT (as detected by ultrasound) through Visit 3
2. The occurrence of symptomatic DVT (proximal or distal) through Visit 3
3. The occurrence of non-fatal PE through Visit 3
4. The occurrence of VTE-related death through Visit 3
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
• Time to event (days) for a first occurrence of a major bleeding event through 7 days after discontinuation of all study medication
• Time to event (days) for a first occurrence of a major or CRNM bleeding event through 7 days after discontinuation of all study medication |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety outcomes will be reviewed by the IDMC at the following defined intervals:
• After 250 patients have completed Visit 3 and have data available for review
• After 750 patients have completed Visit 3 and have data available for review
• After 1500 patients have completed Visit 3 and have data available for review
• After 3000 patients have completed Visit 3 and have data available for review
• After 4500 patients have completed Visit 3 and have data available for review
One non-binding futility analysis is planned when approximately 50% of the overall population has evaluable primary outcome data.
The IDMC may also decide to meet nd review safety data at other time points as they deem necessary. |
|
| 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 | Yes |
| 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 | 7 |
| 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 |
| Belarus |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Croatia |
| Czech Republic |
| Denmark |
| Estonia |
| Finland |
| France |
| Georgia |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Latvia |
| Lithuania |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| Slovakia |
| South Africa |
| Spain |
| Turkey |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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