E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Total Venous thromboembolism (VTE), defined as the combination of fatal or nonfatal pulmonary embolism, symptomatic deep vein thrombosis (DVT), and asymptomatic proximal DVT.
Una Enfermedad Tromboembólica Venosa (ETV) total se define como una combinación de embolismo pulmonar mortal y no-mortal, Trombosis Venosa Profunda (TVP) sintomática y TVP proximal asintomática
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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 | 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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049918 |
E.1.2 | Term | Deep venous thrombosis proximal |
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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 demonstrate that oral administration of apixaban 2.5 mg BID for 30 days reduces the rate of total venous thromboembolism (VTE) and VTE-related death compared to standard, subcutaneous administration of enoxaparin 40 mg QD for a recommended minimum period of 6 days, in subjects with acute medical illness. Total VTE is defined as the combination of fatal or nonfatal pulmonary embolism, symptomatic deep vein thrombosis (DVT), and asymptomatic proximal DVT detected by bilateral compression ultrasound. |
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E.2.2 | Secondary objectives of the trial |
Efficacy:
• To demonstrate that oral administration of apixaban 2.5 mg BID is not inferior to subcutaneous administration of enoxaparin 40 mg QD for the prevention of total VTE and VTE-related death occurring up to the time of discontinuation of parenteral therapy. • To demonstrate that oral administration of apixaban 2.5 mg BID for 30 days reduces the rate of total VTE and all cause death compared to subcutaneous administration of enoxaparin 40 mg QD. • To assess the effect of orally-administered apixaban 2.5 mg BID on the incidence and time to occurrence of symptomatic PE and symptomatic DVT. • To assess the effect of orally-administered apixaban 2.5 mg BID on the rate of all-cause mortality at 30 and 90 days after randomization.
Safety
• To demonstrate that orally administered apixaban 2.5 mg BID for 30 days is generally safe and well tolerated in this patient population. |
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E.2.3 | Trial contains a sub-study | No |
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 screening. 2) Subjects hospitalized due to congestive heart failure, acute respiratory failure or with infection (without septic shock), acute rheumatic disorder, or inflammatory bowel disease. 3) Except for subjects with congestive heart failure or respiratory failure, subjects must have one additional factor including: a) age ≥ 75 b) previous documented VTE or history of VTE for which they received anticoagulation for at least 6 weeks c) cancer d) BMI ≥ 30 (See Appendix 4 for BMI chart) e) estrogenic hormone therapy f) chronic heart or respiratory failure 4) Expected hospitalization of ≥ 3 days after randomization 5) Severely or moderately restricted mobility (i.e. bedridden or limited to chair, walking to bathroom or within room; see section 6.9.1) 6) Men and women, of any race, at least 40 years of age
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. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 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 study period 2) WOCBP using a prohibited contraceptive method 3) Women who are pregnant or breastfeeding 4) Women with a positive pregnancy test on enrollment or prior to investigational product administration 5) Subjects with a confirmed VTE 6) Subjects with diseases requiring ongoing treatment with a parenteral or oral anticoagulant, e.g. subjects with mechanical valves, warfarin eligible atrial fibrillation 7) Subjects with conditions requiring treatment with parenteral or oral antiplatelet agents other than aspirin ≤ 165 mg/day 8) Active liver disease as evidenced by abnormal laboratory test findings (see physical and laboratory findings below) 9) Anemia or thrombocytopenia as evidenced by abnormal laboratory test findings (see physical and laboratory findings below) 10) Severe renal disease as evidenced by creatinine clearance < 30 mL/min as estimated by the method of Cockcroft and Gault (see Section 6.3.1.2) 11) Subjects hospitalized more than 48 hours prior to randomization 12) Subjects who are unable to take oral medications 13) Subjects who have had surgery in the past 30 days that may be associated with a risk of bleeding 14) Subjects who have received anticoagulant prophylaxis for VTE in the past 14 days consisting of more than two doses of enoxaparin or another low molecular weight heparin, more than four doses of unfractionated heparin, or more than two doses of an oral anticoagulant 15) Subjects with active bleeding or high risk of bleeding 16) Subjects with planned or scheduled invasive procedures during the treatment period 17) Subjects in whom in the opinion of the Investigator it is not possible to obtain an adequate bilateral compression ultrasound evaluation 18) Subjects with acute shock 19) Subjects with a life expectancy < 1 month 20) Abnormal hematological findings: • Hemoglobin < 10 g/dL • Platelet count < 100,000/mm 21) Abnormal liver function tests: • ALT or AST > 2 X ULN or • bilirubin (direct or total) > 1.5 X ULN (unless in an alternative causative factor [e.g., Gilbert’s syndrome] is identified) 22) Known or suspected allergies to enoxaparin or prior heparin-induced thrombocytopenia 23) Use of bevacizumab (Avastin®) therapy within the previous 6 months or planned use during the study period 24) Presently receiving oral anticoagulant therapy 25) Presently receiving oral antiplatelet therapy other than aspirin at a dose ≤ 165 mg. 26) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious disease) illness must not be enrolled into this study 27) Administration of any investigational drug currently or within 30 days prior to planned enrollment into this study 28) Subjects unwilling or unable to comply with study medication instructions including the use of enoxaparin or matching placebo for the recommended minimum treatment duration of 6 days 29) Subjects unwilling or unable to comply with study procedures (e.g., bilateral compression ultrasound) specified in the protocol 30) Subjects who have previously been randomized in an experimental study of apixaban |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome measure is a composite endpoint of adjudicated total VTE and VTE-related death during 30 days of double-blind treatment, in acutely ill medical subjects during and following hospitalization. |
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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 | 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 | Yes |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 106 |
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 | 1 |
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 | 1 |
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 |