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

Sponsor

Sunnybrook Health Sciences Centre (Other)

Overall Status

Recruiting

CT.gov ID

NCT03559114

Collaborator

Sunnybrook Research Institute (Other), Canadian Institutes of Health Research (CIHR) (Other)

1,100

Enrollment

Locations

Arms

64.4

Anticipated Duration (Months)

110

Patients Per Site

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Drug: Dalteparin Drug: Saline	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Jul 19, 2018

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

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

Arm

Intervention/Treatment

Active Comparator: Anticoagulant

Dalteparin sodium (at a dose of 5000 IU once daily by subcutaneous injection) for 7 days upon randomization after hospital admission.

Drug: Dalteparin

Dalteparin in prophylactic doses administered daily if screening criteria are satisfied.

Other Names:

Fragmin

Placebo Comparator: Saline

Saline (0.2 mL) once daily by subcutaneous injection for 7 days upon randomization after hospital admission.

Drug: Saline

Saline in prophylactic doses administered daily if screening criteria are satisfied.

Other Names:

Sodium Chloride

Outcome Measures

Primary Outcome Measures

Clinically important VTE [8 days]
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

Secondary Outcome Measures

Clinically-important ICB (Intracranial bleeding) progression [7 days]
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
Objectively confirmed new or progressing ICB on radiology, [8 days]
Assessed by comparing the initial brain CT (Day 0) to that performed within 8±1 days following randomization (or most recent prior to death).
180-day Mortality [180 days]
Mortality at 180 days
7-day Mortality [7 days]
Mortality at 7 days
30-day Mortality [30 days]
Mortality at 30 days
Delayed VTE after day 7 [30 days]
Any clinically important VTE occurring between Day 8 to Day 30 detected by treating clinicians
Functional neurological outcome at day 30 as measured by Glasgow Outcome Scale Extended [30 days]
Glasgow Outcome Scale Extended (GOSE) at Day 30±5 by phone interview.
Functional neurological outcome at day 180 as measured by Glasgow Outcome Scale Extended [180 days]
Glasgow Outcome Scale Extended (GOSE) at Day 180±14 by phone interview.
Quality of life outcome at 30 days as measured by the EuroQol5D [30 days]
EQ-5D (EuroQol 5D) at Day 30±5 by phone interview.
Quality of life outcome at 180 days as measured by the EuroQol5D [180 days]
EQ-5D (EuroQol 5D) at Day 180±14 by phone interview.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

Patients with severe and moderate acute TBI defined as:

GCS of ≤8 or
GCS of 9-12 (moderate) with any intracranial hemorrhage seen on CT scan (patients with only subarachnoid hemorrhage are excluded)

Upon randomization patient can receive the first dose of study drug in the first 3 calendar days of the time of injury
≥ 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:

Known Hypersensitivity to FRAGMIN (Dalteparin), or its constituents including benzyl alcohol or to other low molecular weight heparins and/or heparins or pork products
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
Known septic endocarditis
Uncontrollable active bleeding
Known major blood clotting disorders
Known acute gastroduodenal ulcer (with active bleeding)
Severe uncontrolled hypertension (i.e. BP>210 despite medications)
Known diabetic or hemorrhagic retinopathy
Anticipated to be unable to receive SCD on at least one lower extremity due to nature of injuries for duration of intervention period
Presence of another confounding factor that can adequately explain the poor GCS at time of presentation (e.g. drug toxicity, seizure)
Known presence of irreversible coagulopathies
Known Pregnancy
Participants extremely low weight (<45 kg), or extremely high weight (>120kg)
Not expected to survive more than 48 hours from admission

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Foothills Medical Centre	Calgary	Alberta	Canada	T2N 2T9
2	Royal Alexandra Hospital	Edmonton	Alberta	Canada	T5H 3V9
3	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
4	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
5	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 3A7
6	Hamilton Health Sciences Centre	Hamilton	Ontario	Canada	L8N 3Z5
7	Kingston General Hospital	Kingston	Ontario	Canada	K7N 2V7
8	The Ottawa Hospital	Ottawa	Ontario	Canada	KIH 8L6
9	Sunnybrook Health Science Centre	Toronto	Ontario	Canada	M4N 3M5
10	Royal University Hospital	Saskatoon	Saskatchewan	Canada	S7N 0W8

Sponsors and Collaborators

Sunnybrook Health Sciences Centre
Sunnybrook Research Institute
Canadian Institutes of Health Research (CIHR)

Investigators

Principal Investigator: Farhad Pirouzmand, MD, MSc, FRCSC, Sunnybrook Health Sciences Centre
Principal Investigator: Damon Scales, MD, PhD, FRCPC, Sunnybrook Health Sciences Centre