| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Elective unilateral total knee arthroplasty |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10023469 |
| E.1.2 | Term | Knee arthroplasty |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 assess if at least one dose of MAA868 is non-inferior to enoxaparin 40 mg through Day 10 after randomization in terms of incidence of adjudicated total VTE in patients undergoing unilateral TKA. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of MAA868 relative to enoxaparin in terms of the incidence of major and clinically relevant non-major (CRNM) bleeding events through Day 10 and through Day 30.
• To assess if at least one dose of MAA868 is non-inferior to enoxaparin 40 mg through Day 30 and Day 110 (EoS) in terms of the incidence of adjudicated total VTE in patients undergoing unilateral TKA. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to provide written informed consent before any study assessment is performed
2. Male and female patients (≥ 18 years old and < 80 years old)
3. Scheduled to undergo elective unilateral TKA
4. Willing to comply with study requirements including venography at Day 10 ± 2 days
5. Body weight between 50 kg and 130 kg inclusive
6. aPTT, PT, INR within normal limits at screening |
|
| E.4 | Principal exclusion criteria |
1. Use of other investigational drugs within 5 half-lives of enrollment or until the expected pharmacodynamic effect has returned to baseline, whichever is longer
2. History of hypersensitivity to any of the study drugs (including enoxaparin) or its excipients, to drugs of similar chemical classes or drugs issued from the same biologic origin or any contraindication listed in the label for enoxaparin
3. Any medical condition requiring chronic antithrombotic therapy (e.g. atrial fibrillation, VTE, recent coronary intervention) with the exception of low dose aspirin ≤ 100 mg
4. Known or suspected active bleeding at study entry
5. Macroscopic hematuria or urine dipstick positive for blood 2+ or greater during the screening period
6. Patients at increased risk of bleeding because of a history of increased bleeding tendency (e.g.., history of bleeding diathesis, known active gastrointestinal lesions such as angiodysplasia or an endoscopically verified gastrointestinal ulcer or a history of gastrointestinal bleeding within the past year) or any other condition that in the opinion of the Investigator increases risk of bleeding or patients with a history of intracranial or intraocular bleeding
7. Major surgery including brain, spinal, or ophthalmologic surgery within the past 6 months
8. History of a traumatic spinal or epidural anesthesia or excessive intra- or direct postoperative bleeding
9. Major trauma within the past 6 months
10. History of VTE
11. Malignancy within the past year, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
12. Myocardial infarction, stroke, or transient ischemic attack in the past 6 months
13. Uncontrolled hypertension (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg), based on up to 3 readings at screening
14. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m2
15. Clinically significant anemia during screening as defined by hemoglobin level < 10 g/dL for males and < 11 g/dL for females
16. Platelet count <150,000/m3 at screening or a history of heparin-induced thrombocytopenia
17. Unable to undergo venography due to a known allergy to the contrast agent, anticipated poor venous access, impaired renal function, or any other reason identified and specified by the Investigator
18. Anticipated use of intermittent pneumatic compression devices post TKA procedure
19. Liver dysfunction (ALT/AST >3x ULN or total bilirubin >2x ULN), diagnosis of liver cirrhosis, history of hepatic encephalopathy, esophageal varices, or portocaval shunt
20. Positive test for human immunodeficiency virus (HIV), positive hepatitis B (hepatitis B surface antigen [HBsAg]) or hepatitis C (anti hepatitis C antibody [Anti-HCV] and confirmed by a positive HCV nucleic acid test) at Screening
21. Clinically significant abnormal ECG, which precludes the patient from surgery, at screening as judged by the Investigator
22. Recent (within the last 12 months) or current history of alcoholism or drug addiction
23. Pregnant or nursing (lactating) women
24. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception, which comply with the surgical intervention planned during the proposed clinical study, during use of study treatments and for 3 days after last treatment of enoxaparin and 110 days after administration of MAA868.
25. Sexually active males must agree to use a condom during intercourse during their time in the study and should not father a child or donate sperm in this period.
26. Significant illness which has not resolved within two (2) weeks prior to the start of the study drug
27. Any illnesses or other medical conditions which may preclude patients from complying with study requirements
28. Anticipated elective surgery (e.g., contralateral TKA) during the study period |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Occurrence of confirmed composite endpoint of asymptomatic DVT on the protocol required venography, confirmed symptomatic VTE (including confirmed symptomatic DVT of the leg, fatal or non-fatal PE), or unexplained death for which PE could not be ruled-out during treatment through Day 10. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Occurrence of confirmed composite endpoint of major bleeding and CRNM bleeding events through Day 10 and Day 30.
2) Occurrence of confirmed composite endpoint of asymptomatic DVT on the protocol required venography, confirmed symptomatic VTE (including confirmed symptomatic DVT of the leg, fatal or non-fatal PE), or unexplained death for which PE could not be ruled-out during treatment through Day 30 and Day 110. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Day 10 - 30
2) Day 30 - 110 |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 22 |
| 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 | No |
| 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 |
| Belgium |
| Bulgaria |
| Latvia |
| Lithuania |
| Poland |
| Russian Federation |
| Ukraine |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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