Microvascular Injury and Blood-brain Barrier Dysfunction as Novel Biomarkers and Targets for Treatment in Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability around the world. The social and economic burden of TBI is tremendous and the cost of TBI is estimated at $1 billion per year in Canada- $650 million in care and $580 million in lost productivity. Novel interventions aimed at TBI-linked molecular targets have been successful in limiting injury and improving neurologic recovery in animal models, thus providing compelling evidence that effective intervention is possible after injury. This study proposes to investigate traumatic microvascular injury (TMI) and specifically blood-brain barrier dysfunction (BBBD) as a candidate biomarker and therapeutic target in TBI.

Study Overview

• Status: Unknown
• Conditions: Traumatic Brain Injury; Blood Brain Barrier Defect

• Study Type: Observational
• Enrollment (Anticipated): 120

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Recruiting
      • Halifax Infirmary
      • Contact: David B. Clarke, MDCM, PhD, FRCSC, DABNS, FACS; Phone Number: 902-473-4591; Email: d.clarke@dal.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

We will recruit mild (n=40), moderate (n=40) and severe (n=40) TBI patients with a TBI-linked abnormality (e.g. epidural & subdural hematomas, subarachnoid hemorrhage, contusions). TBI will be classified by severity using the Glasgow Coma Scale (GCS); mild TBI (GCS13-15), moderate TBI (GCS 9-12), and severe TBI (GCS <8).

Description

Inclusion Criteria:

• Age 18 - 85 inclusive
• Clinically diagnosed TBI or evidence of TBI

• For mild TBI, as defined by the American Congress on Rehabilitation Medicine (1993), clear evidence and/or documentation of blunt head injury and any one of the following:

  • any loss of consciousness up to 30 min
  • any loss of memory for events immediately before or after the injury as much as 24 h
  • any alteration of mental state at the time of the injury
  • focal neurologic deficits that might or might not be transient

but where the severity of the injury does not exceed oss of consciousness exceeding 30 min, posttraumatic amnesia longer than 24 h, a Glasgow Coma Scale score falling below 13 after 30 min.

• For moderate TBI (GCS 9-12) and severe TBI (GCS 4-8) CT evidence of TBI-linked abnormality (intracranial lesion including traumatic SAH, contusion, extra-axial hematoma). For patients who are intubated, use best documented GCS within first 48 hours of injury.
• Stable respiratory or hemodynamic status allowing MRI within 2-4 days of TBI as determined by the attending physician
• Patient or substitute decision maker can provide consent

Exclusion Criteria:

• Pre-existing known neurologic, psychiatric disease (dementia, prior severe TBI, schizophrenia, uncontrolled epilepsy, major depressive disorder, stroke, multiple sclerosis, brain tumor)
• Serious infection, complications (sepsis, multilobe pneumonia, etc.) < 4 days after TBI
• Acute ischemic heart disease (MI or unstable angina)
• SBP < 100 mm Hg, DBP < 60 mm Hg
• MRI contraindications; patient has metal implant, pacemaker, biostimulator, neurostimulator, internal defibrillator, history of metal in eye, inner ear implant, cerebral aneurism clip, joint replacement, any known metal in their body, or are pregnant or breast feeding
• History or evidence of active malignancy
• History or evidence of serious kidney (GFR =<60) , heart, or liver disease
• Pregnant or breast-feeding women
• Inability to complete follow up visits (e.g. tourists)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in brain volume with blood brain barrier dysfunction	Measurement of change in brain volume with BBBD and extent of permeability change as measured by DCE-MRI	At < 4, 10 ± 2, and 90 ± 10 days post-injury
Change in serum biomarkers of blood brain barrier dysfunction	Measurement of change in serum biomarkers of BBBD / neural injury (vWF, BDNF, GFAP, S100β, sTau, and sNFL)	At < 4, 10 ± 2, and 90 ± 10 days post-injury
Change in Glasgow Outcome Scale-Extended (GOS-E)	The GOS-E is intended to provide a general index of overall outcome that is sensitive to small but clinically relevant treatment effects in people who sustain TBI.	At 10 ± 2 days, 90 ± 10 days, and 1 year post-injury
Change in Rivermead Post Concussion Symptom Questionnaire (RPSQ)	The RPSQ is a 16-item self-report measure administered to individual(s) who sustained a TBI in order to measure the severity of symptoms and assess progress.	At 10 ± 2 days, 90 ± 10 days, and 1 year post-injury
Change in Patient-Reported Outcomes Measurement Information System (PROMIS)	PROMIS is a set of person-centered measures that evaluates and monitors domains such as physical, mental and social health in adults and children. For this study, we will utilize the following domains: depression, fatigue, and pain interference.	At 10 ± 2 days, 90 ± 10 days, and 1 year post-injury
Change in post-traumatic epilepsy	Screening for post-traumatic epilepsy	At 10 ± 2 days, 90 ± 10 days, 1 year, and 2 years post-injury

Collaborators and Investigators

• Sponsor: Nova Scotia Health Authority
• Investigators: Principal Investigator: David B. Clarke, MD, PhD, Nova Scotia Health Authority

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2017
• Primary Completion (Anticipated): August 3, 2019
• Study Completion (Anticipated): August 3, 2020

Study Registration Dates

• First Submitted: April 26, 2017
• First Submitted That Met QC Criteria: May 1, 2017
• First Posted (Actual): May 4, 2017

Study Record Updates

• Last Update Posted (Actual): February 6, 2019
• Last Update Submitted That Met QC Criteria: February 5, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic
• Other Study ID Numbers: TMI_BBBD_2017

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No