PROphylaxis for Venous ThromboEmbolism in Severe Traumatic Brain Injury (PROTEST)

Study Overview
=================
Brief Summary
-----------------
This is a pilot study, phase III, multi-centre, double blind, randomized controlled trial of patients with traumatic brain injury (TBI).

Detailed Description
-----------------
Patients with severe brain injury are at risk for developing blood clots in their legs, which can travel to the lungs. This potentially serious complication is known as venous thromboembolism (VTE). Anticoagulants are commonly used to prevent VTE in hospital patients. However, in patients with major head injury, anticoagulant prevention is commonly delayed for the fear that it can potentially lead to further bleeding in the brain. Another method that aims to prevent blood clots involves the use of sequential compression device (SCD) that compress the legs and increase the flow of blood in the leg veins. This study will compare results from patients who receive the SCDs only to those who receive both SCD and anticoagulants. The outcome of this study will provide information about how best to prevent blood clots while not increase brain bleeding after head injury.

Official Title
-----------------
PROTEST Trial - PROphylaxis for Venous ThromboEmbolism in Severe Traumatic Brain Injury, a Double-blind Randomized Controlled Trial

Conditions
-----------------
Traumatic Brain Injury

Intervention / Treatment
-----------------
* Drug: Dalteparin
* Drug: Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria The pragmatic nature of this study seeks to include all consecutive patients presenting with significant TBI, regardless of whether ICB is evident at presentation. Inclusion criteria are the following: i) Patients with severe TBI defined as GCS of ≤8, or ii) Patients with moderate TBI defined as GCS = 9-12, admitted to ICU, with at least some ICB present on initial CT scan and any of the following: Requiring invasive mechanical ventilation at the time of screening Increased ICB on repeat CT scan compared to initial CT scan iii) Upon randomization the patient will be able to receive the first dose of study drug in the first 3 calendar days from the time of injury iv) ≥ 18 years of age Exclusion Criteria All participants meeting any of the following exclusion criteria at baseline will be excluded from participation in this study: i) Known Hypersensitivity to FRAGMIN (Dalteparin), or its constituents including benzyl alcohol or to other low molecular weight heparins and/or heparins or pork products ii) Known history of confirmed or suspected immunologically-mediated heparin-induced thrombocytopenia (delayed-onset severe thrombocytopenia), and/or in patients with a known history of a positive in vitro platelet-aggregation test in the presence of FRAGMIN (Dalteparin) is positive iii) Known septic endocarditis iv) Uncontrollable active bleeding v) Known major blood clotting disorders vi) Known acute gastroduodenal ulcer (with active bleeding) vii) Severe uncontrolled hypertension (i.e. BP>210 despite medications) viii) Known diabetic or hemorrhagic retinopathy ix) Anticipated to be unable to receive SCD on at least one lower extremity due to nature of injuries for duration of intervention period x) Presence of another confounding factor that can adequately explain the poor GCS at time of presentation (e.g. drug toxicity, seizure) xi) Known presence of irreversible coagulopathies xii) Known Pregnancy xiii) Participants extremely low weight (<45 kg), or extremely high weight (>120kg) xiv) Not expected to survive more than 48 hours from admission

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Anticoagulant<br>Dalteparin sodium (at a dose of 5000 IU once daily by subcutaneous injection) for 7 days upon randomization after hospital admission. | Drug: Dalteparin<br>* Dalteparin in prophylactic doses administered daily if screening criteria are satisfied.<br>* Other names: Fragmin;|
| Placebo Comparator: Saline<br>Saline (0.2 mL) once daily by subcutaneous injection for 7 days upon randomization after hospital admission. | Drug: Saline<br>* Saline in prophylactic doses administered daily if screening criteria are satisfied.<br>* Other names: Sodium Chloride;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically important VTE | Composite outcome of clinically-important VTE within 7±1 days after randomization defined as any of: Symptomatic, objectively-confirmed pulmonary embolism (PE), or Symptomatic, objectively-confirmed, proximal leg deep vein thrombosis (DVT), or Proximal (above knee) leg DVT on compression ultrasonography on Day 7±1 | 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically-important ICB (Intracranial bleeding) progression | Clinically-important ICB progression within 7±1 days after randomization , as defined by having (1) any increase in volume of blood in the brain on any CT scan within 7±1 days relative to initial CT scan on Day 0* AND (2) clinical worsening within 24 hours of this CT scan, defined by one or more of the following: Surgical intervention related to increased ICB after Day 0 (craniotomy/craniectomy, ICP monitor, external ventricular drain) Decrease of GCS (Glasgow Coma Scale) by at least 2 points not related to sedation Increase in ICP >5 mmHg on 2 occasions at least 6 hours apart despite medical therapy (if ICP monitor is in place) Death | 7 days | 
| Objectively confirmed new or progressing ICB on radiology, | Assessed by comparing the initial brain CT (Day 0) to that performed within 8±1 days following randomization (or most recent prior to death). | 8 days | 
| 180-day Mortality | Mortality at 180 days | 180 days | 
| 7-day Mortality | Mortality at 7 days | 7 days | 
| 30-day Mortality | Mortality at 30 days | 30 days | 
| Delayed VTE after day 7 | Any clinically important VTE occurring between Day 8 to Day 30 detected by treating clinicians | 30 days | 
| Functional neurological outcome at day 30 as measured by Glasgow Outcome Scale Extended | Glasgow Outcome Scale Extended (GOSE) at Day 30±5 by phone interview. | 30 days | 
| Functional neurological outcome at day 180 as measured by Glasgow Outcome Scale Extended | Glasgow Outcome Scale Extended (GOSE) at Day 180±14 by phone interview. | 180 days | 
| Quality of life outcome at 30 days as measured by the EuroQol5D | EQ-5D (EuroQol 5D) at Day 30±5 by phone interview. | 30 days | 
| Quality of life outcome at 180 days as measured by the EuroQol5D | EQ-5D (EuroQol 5D) at Day 180±14 by phone interview. | 180 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sequential Compression Device, Anticoagulant Thromboprophylaxis, Deep Vein Thrombosis, Sub Cutaneous, VTE