Single Intravenous Administration of TB-402 for the Prophylaxis of Venous Thromboembolic Events (VTE) After Total Knee Replacement Surgery

Study Overview
=================
Brief Summary
-----------------
The purpose 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.

Detailed Description
-----------------
Currently available anticoagulant therapies for the prevention of VTE include low molecular weight heparins, pentasaccharides and vitamin K antagonists, all of which have inherent limitations(1-3). Improved anticoagulant agents are therefore required(4). A novel antithrombotic agent requires demonstration of both efficacy and safety in relevant populations. Phase II studies are frequently performed in patients undergoing total hip replacement and/or total knee replacement because of the high and well documented incidence of deep vein thrombosis in the absence of adequate thromboprophylaxis(5-7). In this study, we assess the safety and efficacy of TB-402, a novel antithrombotic agent that partially inhibits factor VIII, in the prevention of VTE in patients undergoing total knee replacement surgery.

Official Title
-----------------
Single Intravenous Administration of TB-402 for the Prophylaxis of Venous Thromboembolic Events (VTE) After Total Knee Replacement Surgery: A Dose-Escalating, Multicenter, Randomised, Active- Controlled Open Label Study

Conditions
-----------------
Total Knee Replacement Surgery

Intervention / Treatment
-----------------
* Drug: TB-402
* Drug: Enoxaparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients aged > 18 and < 80 years old Female patients should be post menopausal Patients undergoing primary elective total knee replacement surgery Written informed consent obtained from the patient (or a legally acceptable representative) prior to inclusion in the study Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures Exclusion Criteria: Body weight < 50 kg or > 100 kg Patients undergoing a hemiarthroplasty, surface repair or revisionary surgery of the knee Confirmed symptomatic deep vein thrombosis or pulmonary embolism within the past year Anticipated use of indwelling intrathecal or epidural catheter for more than 4 h after surgery or during the entire study Uncontrolled hypertension (SBP>160 mm Hg or DBP > 100 mm Hg) History of intracranial or intraocular bleeding. History of gastrointestinal and/or endoscopically verified ulcer disease within the past year

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>0.3 mg/kg TB-402 | Drug: TB-402<br>* TB-402 administered as single bolus 18-24 post total knee replacement surgery.<br>|
| Experimental: 2<br>0.6 mg/kg TB-402 | Drug: TB-402<br>* TB-402 administered as single bolus 18-24 post total knee replacement surgery.<br>|
| Experimental: 3<br>1.2 mg/kg TB-402 | Drug: TB-402<br>* TB-402 administered as single bolus 18-24 post total knee replacement surgery.<br>|
| Active Comparator: 4<br> | Drug: Enoxaparin<br>* Enoxaparin 40mg/day sc injection for at least 10 days post-surgery<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of total bleeding defined as major and/or clinically relevant non-major bleeding events, from randomisation until the end of the study. |  | All visists from randomization to end of study | 
| Composite of the occurrence of asymptomatic DVT as detected by bilateral venography and symptomatic VTE, i.e. DVT or fatal or non-fatal PE. |  | Prior to hospital discharge Day 7-11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of major bleeding events |  | All visists from randomization to end of study | 
| Incidence of clinically significant non-major bleeding events |  | All visits from randomization to end of study | 
| Incidence of minor bleeding events |  | All visits from randomization to end of study | 
| Incidence of all cause mortality |  | All visits from randomization to end of study | 
| Incidence of adverse events |  | All visists from randomization to end of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TKR, VTE, DVT