| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of Venous Thromboembolic Events |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10014523 |
| E.1.2 | Term | Embolism and thrombosis |
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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 estimate the dose of PD 0348292 that is equivalent to enoxaparin 30 mg BID for VTE in subjects undergoing an elective, unilateral TKR;
• To characterize the dose-response of PD 0348292 in subjects undergoing an elective, unilateral TKR with respect to efficacy and safety endpoints; and
• To characterize the pharmacokinetics of PD 0348292 in subjects undergoing an elective, unilateral TKR.
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Age ≥18 years;
2. Male or female; if male, must agree to use an acceptable method of birth control (eg, using condoms) if sexually active during study treatment; if female must meet at least 1 of the following criteria:
• Greater than or equal to 2 years postmenopausal or
• Surgically sterilized (women who have had bilateral oophorectomy or bilateral tubal ligation may participate in this study).
3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
4. Scheduled for an elective, unilateral TKR;
5. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial.
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Females with a total body weight <45 kg or males with a total body weight <57 kg;
2. Subjects scheduled for a hemiarthroplasty, surface repair or revisionary surgery of the knee;
3. History within the past year of DVT, PE, suspected postthrombotic state, intracranial or intraocular bleeding, gastrointestinal bleeding and/or endoscopically verified ulcer disease;
4. History of, or in the opinion of the investigator, potential risk for traumatic or repeated epidural or spinal puncture (refer to spinal/epidural hematomas warning in enoxaparin sodium injection package insert);
5. Anticipated use of indwelling epidural catheters for more than 6 hours after surgery or within 2 hours of administration of the first dose of study medication;
6. Positive urine dipstick for blood (≥ moderate and confirmed by central lab) or significant proteinuria (4+) at screening;
7. Uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic >100 mm Hg) (at time of randomization);
8. Clinical laboratory evidence of anemia (hemoglobin level <10.0 g/dL) or thrombocytopenia (platelet count <100 × 103/µL);
9. Constitutional or acquired coagulation disorders that in the investigator’s judgment puts the subject at excessive risk for bleeding.
10. Severe renal dysfunction, nephrotic syndrome or dysproteinemias (defined as on dialysis or serum creatinine ≥1.8 mg/dL, blood urea nitrogen [BUN] >40 or creatinine clearance <30 mL/min);
11. Active hepatic disease (defined as transaminase ≥ 3 × ULN or bilirubin ≥ 1.5 × ULN) or history of hepatic insufficiency;
12. DSM-IV or local standard diagnosis of drug or alcohol abuse (meets criteria within the preceding past year);
13. Cancer (except for non melanoma skin cancer) or cytotoxic treatment for active malignancy (cancer includes blood dyscrasias, eg, acute or chronic leukemia);
14. An immunocompromised status (eg, receiving immunosuppressive therapy, a documented immunohumoral or cellular immune deficiency state, AIDS, or a history of being HIV positive);
15. Ischemic stroke or myocardial infarction (MI) within the 3 months prior to randomization;
16. Surgery/trauma within 6 months or a diagnostic arthroscopy within 6 weeks of surgery prior to randomization;
17. Immobilization (mainly confined to bed during waking hours/nonambulatory) for 3 or more days prior to randomization;
18. In the opinion of the clinical investigator, subjects potentially at risk of bleeding after minor interventions such as dental treatment, mole removal, or similar interventions within 6 weeks prior to randomization;
19. Significant within the previous year, potential bleeding risks such as recurrent gastrointestinal ulcers, epistaxis, and cystitis;
20. Subjects with any condition possibly affecting drug absorption (eg, gastrectomy);
21. Anticoagulation/direct thrombin inhibitors/thrombolytic therapy administered or completed within 7 days before surgery or during the study treatment period. Subjects having an existing condition requiring long-term anticoagulation therapy should not be included;
• Medications known to affect platelet function or coagulation including: Vitamin K antagonists, unfractionated heparin and derivatives, low molecular weight heparins (LMWH) (except those investigated in the study or used in connection with the intraoperative salvage of RBCs), fondaparinux, desirudin, thrombolytic agents, dipyridamole, sulphinpyrazone, GP IIb/IIIa receptor antagonists, clopidogrel, ticlopidine, nonsteroidal anti-inflammatory drugs (NSAIDs) with half-life >20 hours, acetyl salicylic acid, and dextran.
22. History of significant adverse reaction (eg, heparin or LMWH-induced thrombocytopenia) to an anticoagulant;
23. Hypersensitivity to enoxaparin sodium, heparin, or pork products;
24. Known allergy to contrast media or iodine;
25. 12 lead ECG demonstrating QTc >450 msec and/or clinically significant abnormalities at screening;
26. Previous participation in this study;
27. Use of any other investigational agent within 30 days of randomization;
28. Any condition, which in the opinion of the investigator, would put the subject at increased risk from participating in the study; or
29. Any medical, social, logistical, or psychological reason, which would preclude successful completion of the study protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the incidence of total venous thromboembolic events (VTE) (proximal or distal deep vein thrombosis DVT, and/or pulmonary embolism PE) as determined by a central laboratory. VTE is defined as any postoperative lower extremity deep vein thrombus, or pulmonary embolism, occurring anytime during the treatment period in a symptomatic subject or within 12 hours of the last treatment dose in an asymptomatic subject.
The primary safety endpoint is the incidence of total bleeding (defined as major and/or minor bleeding) during the study treatment period (as defined in Section 3.1.1). Using guidance from the European Agency for the Evaluation of Medicinal Products (EMEA) and the International Society on Thrombosis and Haemostasis, bleeding will be categorized as major or minor, as follows:
• Major bleeding is defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin ≥20 g/L, clinically overt bleeding leading to transfusion of ≥2 units of whole blood or red cells, or symptomatic bleeding in areas of special concern (such as intracranial, retroperitoneal, intraocular, intraspinal, pericardial, intramuscular with compartmental syndrome, or intraarticular).
• Minor bleeding is defined as bleeding that does not meet the definition of major bleeding.
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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) | 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 | 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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