E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 10049909 |
E.1.2 | Term | Venous thromboembolism prophylaxis |
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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 |
The objective of this study is to evaluate the safety and efficacy of a single administration of TB-402 for the prevention of VTE in patients undergoing knee replacement surgery. |
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E.2.2 | Secondary objectives of the trial | |
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 |
A PK/PD sub study will be performed at selected sites, to develop a more detailed understanding of the pharmacokinetics (TB-402 levels) and pharmacodynamics of TB- 402 (PT, APTT, FVIII). PK/PD blood samples will be collected in 60 patients (15 per treatment arm) at screening, day 1, post-infusion day 2, day 7-11, day 35 and day 90. For the patients randomised to enoxaparin, 1 blood sample is to be taken on Day 1; for the patients randomized to TB-402, 2 blood samples are to be taken on Day 1: 1 sample pre- infusion and 1 sample at 2 hours +/- 1 hour after the end of infusion. |
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E.3 | Principal inclusion criteria |
1. Male or female patients aged > 18 and < 80 years old 2. Female patients should be post menopausal 3. Patients undergoing primary elective total knee replacement surgery 4. Written informed consent obtained from the patient (or legally acceptable representative) prior to inclusion in the study 5. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures |
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E.4 | Principal exclusion criteria |
1. Body weight < 50 kg or > 100 kg 2. Patients undergoing a hemiarthroplasty, surface repair or revisionary surgery of the knee 3. Confirmed symptomatic deep vein thrombosis or pulmonary embolism within the past year 4. Anticipated use of indwelling intrathecal or epidural catheter for more than 4 h after surgery or during the entire study 5. Uncontrolled hypertension (SBP>160 mm Hg or DBP > 100 mm Hg) 6. History of intracranial or intraocular bleeding. History of gastrointestinal and/or endoscopically verified ulcer disease within the past year 7. Patients at increased risk of bleeding because of personal history of increased bleeding tendency or any other condition that in the opinion of the investigator increases risk of bleeding (e.g. documented angiodysplasia, recurrent gastrointestinal ulcer) 8. Clinical laboratory evidence at screening of anemia (haemoglobin level < 10.0 g/dL) or thrombocytopenia (platelet count < 100X103/μL) or prolonged activated partial thromboplastin time (APTT) or prothrombin time (PT) as per local lab ranges 9. Excessive peroperative bleeding and/or active significant postoperative wound bleeding as per the investigator’s judgement 10. Antiplatelet agents other than low dose aspirin < 160mg. The use of antithrombotic therapy within 7 days before surgery except for a thromboprophylactic dose of LMWH or unfractionated heparin. The use of intermittent pneumatic compression. 11. Patients who require long-term anticoagulant treatment for a comorbid condition. 12. History of significant adverse reaction (e.g. Heparin- or LMWH- induced thrombocytopenia) to an anticoagulant 13. Creatinin clearance <30 mL/min, hypersensitivity to contrast media, hypersensitivity to enoxaparin sodium 14. Active hepatic disease (defined as transaminase >3 X ULN or bilirubin > 1.5 ULN) or history of hepatic insufficiency 15. Known drug or alcohol abuse 16. Active malignant disease or current cytostatic treatment 17. Participation in an investigational drug study within the past 30 days or previous participation in this trial 18. Any condition which in the opinion of the investigator would put the patient at increased risk from participating in the study 19. Scheduled invasive or surgical procedure within 8 weeks after surgery 20. Brain, spinal, or ophthalmological invasive surgery within the previous 3 months before enrolment |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is; Composite of the occurrence of asymptomatic DVT as detected by bilateral venography and symptomatic VTE, i.e. DVT or fatal or non-fatal PE, up to hospital discharge at D 7 – 11.
The following definitions are applied to assess suspected episodes of PE/DVT: Clinically suspected DVT with one of the following findings: • an intraluminal filling defect on venography or , an extension of an intraluminal filling defect, or a new intraluminal filling defect or an extension of non-visualization of veins in the presence of a sudden cut-off on venography, or • abnormal compression ultrasound (CUS) Clinically suspected PE with one of the following findings: • an intraluminal filling defect in segmental or more proximal branches on sCT (spiral CT) • an intraluminal filling defect or an extension of an existing defect or a new sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram, • a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scintigraphy • inconclusive sCT, pulmonary angiography or lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasound or venography. Fatal PE • PE based on objective diagnostic testing, autopsy, or • death which cannot be attributed to a documented cause and for which PE/DVT cannot be ruled out (unexplained death).
The primary safety endpoint is: The occurrence of total bleeding defined as major and/or clinically relevant non-major bleeding events, from randomisation until the end of the study. Major bleeding is defined as acute clinically overt bleeding: • associated with a fall in hemoglobin of 2 g/dL (i.e 1.25 mmol/L) or more, or • leading to a transfusion of 2 or more units of packed red blood cells or whole blood. A red cell unit is defined as the quantity of red cells obtained from or corresponding to approximately 500 mL of whole blood, or • in a critical site: intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or • that is fatal, or • leading to surgical intervention. Clinically relevant non-major bleeding is defined as acute clinically overt bleeding not meeting the criteria for major bleeding but associated with: • excessive wound hematoma or excessive wound bleeding, or • medical intervention, or • the need for unscheduled contact (visit or telephone call) with a physician, or • temporary cessation of a study drug, or • discomfort for the patient such as pain or impairment of activities of daily life. |
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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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 | No |
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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The end of the trial is defined as the last visit of the last patient. |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |