| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Venous Thromboembolism (VTE) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051055 |
| E.1.2 | Term | Deep vein thrombosis |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037377 |
| E.1.2 | Term | Pulmonary embolism |
|
| 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 |
| To determine if apixaban is non-inferior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy. |
|
| E.2.2 | Secondary objectives of the trial |
a) To determine if apixaban is superior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE or
• VTE-related death over 6 months of therapy
• All-cause death over 6 months of therapy
b) To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy:
• in the combined endpoint of adjudicated recurrent symptomatic VTE or cardiovascular death over 6 months of therapy
• in the combined endpoint of adjudicated recurrent symptomatic VTE , VTE-related death, or major bleeding over 6 months of therapy
• in adjudicated major bleeding during 6 months of therapy
• in the composite of adjudicated major bleeding and adjudicated clinically relevant nonmajor bleeding during 6 months of therapy
c) To characterize the primary efficacy outcome in the subset of subjects with index
events of DVT only and in the subset of subjects with index events of PE with or
without DVT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a) Acute symptomatic proximal DVT with evidence of proximal thrombosis that involves at least the popliteal vein or a more proximal vein, demonstrated by imaging with:
− compression ultrasound (CUS), including grey-scale or color-coded Doppler,
or
− ascending contrast venography.
Or
b) Acute symptomatic PE with evidence of thrombosis demonstrated by imaging as follows:
− an intraluminal filling defect in segmental or more proximal branches on spiral CT scan; or
− an intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; or
− a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS).
c) Men and women, ages 18 years or greater.
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study.
b) Women who are pregnant or breastfeeding.
c) Women with a positive pregnancy test on enrollment or prior to investigational product administration.
2) Target Disease Exceptions
a) Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of VTE.
b) Active bleeding or high risk for bleeding contraindicating treatment with LMWH and a VKA.
c) Subjects with cancer who will be treated for 6-months or more with low molecular weight heparin therapy.
d) Subjects with contraindications according to the local prescribing information of enoxaparin or warfarin.
3) Medical History and Concurrent Diseases
a) Subjects with an indication, other than VTE, intended for long-term treatment with a VKA such as:
• Mechanical valve
• Atrial fibrillation or atrial flutter with moderate to high risk of systemic thromboembolism. Subjects with atrial fibrillation that appears to be associated with acute PE may participate.
b) Conditions for which serious bleeding may occur and the time of exclusion relative to the time of randomization: see chart list section 4.2.2.3
c) Active and clinically significant liver disease (eg, hepatorenal syndrome);
d) Life expectancy < 6 months;
e) Bacterial endocarditis;
f) Uncontrolled hypertension: systolic blood pressure > 180 mm Hg or diastolic blood pressure > 100 mm Hg; (subjects who have a transient, higher blood pressure elevation associated with acute PE [upper limit: systolic blood pressure 200 mm Hg or diastolic blood pressure 100 mm Hg] may enter the study;) elevated blood pressure that is persistent 1 - 2 days after the index DVT or PE should be treated according to local guidelines);
4) Physical and Laboratory Test Findings
a) Platelet count < 100,000/mm³ or hemoglobin < 9 g/dL
b) Serum creatinine > 2.5 mg/dL [221 umol/L] or a calculated creatinine clearance < 25 ml/min;
c) ALT or AST > 2 times upper limit of normal, or a total bilirubin > 1.5 times upper limit of normal (unless the latter has an alternative causative factor identified [eg, Gilbert’s syndrome]).
5) Allergies and Adverse Drug Reactions
a) Heparin induced thrombocytopenia;
b) Allergic reaction to unfractionated heparin, LMWH, fondaparinux or any VKA.
6) Prohibited Treatments and/or Therapies
a) DVT or PE treatment with more than two doses of fondaparinux or a LMWH that is labeled for once daily dosing, or more than three doses of a LMWH that is labeled for twice daily dosing, or continuous infusion of unfractionated heparin for more than 36 hours, before the first administration of study drug; and/or
b) DVT or PE treatment with more than two doses of oral VKA therapy before the first administration of study drug.
c) Treatment with apixaban in a previous clinical trial.
d) Subjects requiring ASA > 165 mg/day at randomization.
e) Subjects requiring dual anti-platelet therapy (ASA plus clopidogrel or ASA plus ticlopidine) at randomization. Subjects who transition from dual anti-platelet therapy to monotherapy prior to randomization will be eligible for the trial.
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness;
c) Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of study treatment (with the exception of approved medications being used for an approved indication, eg, investigating a new dosing regimen for an approved indication.);
d) Any condition, which in the opinion of the investigator, would put the subject at an unacceptable risk from participating in the study; or
e) Any other medical, social, logistical, or psychological reason, which in the opinion of the investigator, would preclude compliance with, or successful completion of, the study protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The following outcomes will be examined:
- The primary efficacy outcome: the incidence of an adjudicated composite of recurrent symptomatic VTE or VTE-related death during 6 months of therapy.
- The primary safety outcome: the incidence of adjudicated major bleeding during the treatment period.
- Secondary Efficacy Endpoints: the incidence of:
• adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and all-cause death
• adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and CV death
• adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death and major bleeding
• adjudicated symptomatic nonfatal DVT
• adjudicated symptomatic nonfatal PE
• adjudicated VTE-related death
• adjudicated CV death
• all-cause death.
- Secondary Safety Endpoints: the incidence of:
• an adjudicated composite of major and clinically relevant non-major bleeding
Other safety outcome measures will also be assessed, including adjudicated minor bleeding, adjudicated total bleeding, serious and non-serious AEs, and changes in standard clinical laboratory test results.
- Other Endpoints:
Estimates of apixaban population pharmacokinetic parameters. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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.8.3 |
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 | 105 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
Telephone follow-up call 30 days after final treatment visit
|
|
| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
