OPTIMA-TBI Pilot Study

Study Overview
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Brief Summary
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This is a double-blind, randomized controlled trial comparing the effect of omega-3 fatty acid versus placebo on blood biomarkers of brain injury, inflammation and neurogenesis.

Detailed Description
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Primary brain injury, the initial physical injury to brain tissue post-trauma, responds only to measures that prevent TBI from occurring in the first place. However, secondary brain injury, a complex cascade of events causing additional brain injury following primary brain injury, is more amenable to pharmacologic treatment. Neuroinflammation is one of the recognized mechanisms of secondary brain injury. In response to primary brain injury, activated microglia and injured neurons both release signaling proteins including cytokines and chemokines. Ω-3 and ω-6 fatty acids are major components of immune cells and neuronal cell membranes. They are also precursors to neuromodulatory lipids such as eicodanoids, endovanilloids and endocannabinoids that have antinociceptive and anxiolytic properties. Docosahexaenoic acid (DHA) is one of the most abundant fatty acid components of brain cell membrane phospholipids. In rodent model studies, dietary supplementation with omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) decreased secondary axonal injury, attenuated endoplasmic reticulum stress response, decreased neuroinflammation post-TBI, and improved short and long-term neurologic outcomes. Additionally, DHA supplementation post-TBI enhances neurogenesis by counteracting reductions in neuroplasticity biomarkers such as brain-derived neurotrophic factor. Furthermore, DHA deficient rodents are more likely to have a greater amount of axonal injury and slower recovery neurologic recovery post-TBI. To our knowledge there are no human studies examining the effect of omega-3 fatty acid supplementation post-TBI on functional, symptomatic and neurologic outcomes. However, a study of collegiate football players who were randomized to 2, 4 or 6g/day of DHA or placebo for a total of 189 days (including 80 pre-season days). Irrespective of the dose of DHA supplementation, those receiving DHA had lower values of serum neurofilament light chain, a biomarker of axonal injury, than those receiving placebo.

Official Title
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Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI Pilot)

Conditions
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Mild Traumatic Brain Injury

Intervention / Treatment
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* Drug: Omega-3 Polyunsaturated Fatty Acids (Fish Oil 1000 mg (contains 500 mg DHA & 100 mg EPA)) or placebo capsules.
* Drug: Placebo - Cap


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals presenting to the emergency department (ED) within 24 hours of injury, who meet the American Congress of Rehabilitation Medicine (ACRM)'s definition of having mild traumatic brain injury (mTBI) will be eligible The ACRM defines mTBI as a traumatically-induced physiological disruption of brain function as a consequence of the head being struck, striking an object, or undergoing an acceleration/deceleration movement without direct external head trauma and resulting in at least one of the following: any period of loss of consciousness (LOC) any loss of memory for events immediately before or after the injury any alteration in mental state at the time of the injury (eg, feeling dazed, disoriented, or confused) focal neurological deficit(s) that may or may not be transient Exclusion Criteria: GCS<13 at any time during ED stay. Significant polytrauma including: bony fracture or solid organ injury Study medication cannot be administered within 24 hours of injury Patient cannot be relied on to complete follow-up (i.e. no reliable telephone number, substance dependence, homeless) Cannot communicate in English Take an anticoagulant (coumadin or a novel oral anticoagulant) daily Age less than 18 years or greater than 65 years Patients already taking fish oil supplements daily History of cognitive impairment Allergic to fish/fish oil Pregnant women (self-reported)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omega-3 Polyunsaturated Fatty Acid Treatment Arm<br>Participants randomized to this study arm will receive 6g DHA+EPA for one month followed by 1.2 g DHA+EPA for two months. Capsules contain fish oil 1000 mg (contains 500 mg DHA & 100 mg EPA) or placebo capsules. | Drug: Omega-3 Polyunsaturated Fatty Acids (Fish Oil 1000 mg (contains 500 mg DHA & 100 mg EPA)) or placebo capsules.<br>* Participants will be randomized to receive fish oil 1000 mg (contains 500 mg DHA & 100 mg EPA) or placebo capsules.<br>|
| Placebo Comparator: Placebo Arm<br>Participants randomized to this study arm will receive placebo drug for 3 months. | Drug: Placebo - Cap<br>* Participants will be randomized to receive fish oil 1000 mg (contains 500 mg DHA & 100 mg EPA) or placebo capsules (olive oil capsules that look identical to the intervention DHA+EPA).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarker Endpoints (NFL) | Neuronal injury measured by Neurofilament Light Chain (NFL). Samples will be analyzed using a digital immunoassay based on a single molecule counting technology. | Baseline,3 months | 
| Biomarker Endpoint (Inflammation) | We will measure serum levels of high sensitivity C-Reactive Protein (CRP) | 3 months | 
| Biomarker Endpoint (Neurogenesis) | Serum levels of brain derived neurotrophic factor (BDNF) | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delayed Functional Recovery | Delayed functional recovery will be defined as a Glasgow Outcome Scale Extended (GOSE) <8 at 3 months. Scores range from 1-8. 8 is Upper good recovery and 1 is death | 3 months | 
| Gastrointestinal Distress | GI distress is measured by number of individuals who experienced it. | 3 months | 
| Clinically Significant Bleeding | Clinically significant bleeding distress is measured by number of individuals who experienced it. | 3 months |