E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Venous Thromboembolic Events |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10043565 |
E.1.2 | Term | Thromboembolic event |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051055 |
E.1.2 | Term | Deep vein thrombosis |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037377 |
E.1.2 | Term | Pulmonary embolism |
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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 compare the effect of oral apixaban 2.5 mg BID versus subcutaneous (SC) enoxaparin 40 mg QD on the composite endpoint of adjudicated asymptomatic and symptomatic DVT, non-fatal PE and all cause death through Day 12 of double-blind treatment in subjects undergoing elective unilateral or same day bilateral knee replacement surgery.
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E.2.2 | Secondary objectives of the trial |
To demonstrate that oral apixaban 2.5 mg BID is non-inferior to subcutaneous (SC) enoxaparin 40 mg QD on the event rate on the composite of adjudicated proximal DVT, non-fatal PE and VTE-related death (see Section 6.4.2) through Day 12 of double-blind treatment. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK Substudy Protocol Amendment 03 - Site Specific (v1.0, date 29-Apr-2008)
PK Substudy Objectives: • To characterize the population PK of apixaban and variability in PK parameters in subjects undergoing total knee replacement surgery • To characterize the relationship between plasma anti-Xa activity and apixaban concentration • To quantify the effect of selected covariates on variability in apixaban PK parameters in subjects undergoing total knee replacement surgery • To characterize the exposure-response relationships for primary efficacy endpoints, as well as selected clinically relevant secondary efficacy and safety endpoints. • To assess the impact of selected covariates on the exposure-response relationships.
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E.3 | Principal inclusion criteria |
1) Subjects must be willing and able to give written informed consent. Consent to participate in the study must be obtained prior to any screening procedures. 2) Subjects undergoing elective unilateral or bilateral same day total knee replacement or a revision of at least one component of a total knee replacement. 3) Subject must be willing and able to undergo bilateral ascending contrast venography. 4) Men and women, of any race, at least 18 (or legal age of consent if greater) years of age 5) Women of childbearing potential (WOCBP) must be using an adequate method of contraception. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 48 hours prior to the start of investigational product. |
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E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire treatment period of the study 2) Women who are pregnant or breastfeeding 3) Women with a positive pregnancy test on enrollment or prior to investigational product administration 4) Known or suspected or acquired bleeding or coagulation disorder in the subject or a first degree relative 5) Known or suspected history of heparin-induced thrombocytopenia 6) Known coagulopathy 7) Active bleeding or at high risk for bleeding 8) Brain, spinal, ophthalmologic, or major surgery or trauma within the past 90 days 9) Active hepatobiliary disease 10) Alcohol and/or substance abuse within the past year 11) Any condition, in the opinion of the Investigator, for which surgery or administration of an anticoagulant is contraindicated 12) Two consecutive blood pressure readings within 15-30 minutes with supine SBP > 180 mm Hg or supine DBP > 105 mm Hg 13) Hemoglobin < 10 g/dL 14) Platelet count < 100,000/mm3 15) Creatinine clearance < 30 mL/min as estimated by the method of Cockcroft and Gault (see Section 6.3.4) 16) ALT or AST > 2 x ULN or a Total Bilirubin ≥ 1.5 x ULN (unless an alternative causative factor [eg, Gilbert’s syndrome] is identified) 17) Hypersensitivity to unfractionated heparin (UFH), low molecular weight heparin (LMWH), porcine products, or iodinated contrast medium (for venogram) 18) Need for ongoing treatment with a parenteral or oral anticoagulant (eg, subjects with mechanical valves, warfarin eligible atrial fibrillation) 19) Current use of dextrans or fibrinolytics (but the use of synthetic colloids like pentastarch and hetastarch as blood substitutes is allowed) 20) Treatment with medications affecting coagulation or platelet function as follows: • Unfractionated heparin, LMWH, warfarin (or any other VKA), glycoprotein IIb/IIIa inhibitors (eg, abciximab, eptifibatide, tirofiban) within 4 days before surgery • Acetylsalicylic acid > 165 mg/day within 4 days before surgery • Clopidogrel, ticlopidine, dipyridamole, sulfinpyrazone within 7 days before surgery • Non-selective NSAIDs with a T1/2 greater than 17 hours (eg, Piroxicam and Tinoxican) within 7 days before surgery • Fondaparinux within 7 days before surgery • Anti-fibrinolytics, with exception of the use of tranexamic acid where it represents standard of care for the investigator 21) Planned indwelling intrathecal or epidural catheter that can not be removed at least 5 hours prior to first dose of post-operative study drug. 22) Prisoners or subjects who are involuntarily incarcerated. 23) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. 24) Subjects who have been previously randomized into an apixaban clinical trial. 25) Administration of any investigational drug currently or within 30 days prior to enrollment into this study. 26) Any other contra-indication listed in the country specific labeling for enoxaparin.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the composite of adjudicated asymptomatic and symptomatic DVT, non-fatal PE and all-cause death through Day 12 of double-blind treatment in subjects undergoing elective unilateral or same day bilateral knee replacement surgery. The key secondary efficacy endpoint is the composite of adjudicated asymptomatic and symptomatic proximal DVT, non-fatal PE and all VTE related death through Day 12 of double-blind treatment in subjects undergoing elective total knee replacement surgery.
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | 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 | No |
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 | 73 |
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 |
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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
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |