Mild Traumatic Brain Injury
Conditions
Brief summary
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
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.
Interventions
DRUGOmega-3 Polyunsaturated Fatty Acids (Fish Oil 1000 mg (contains 500 mg DHA & 100 mg EPA)) or placebo capsules.
Participants will be randomized to receive fish oil 1000 mg (contains 500 mg DHA & 100 mg EPA) or placebo capsules.
DRUGPlacebo - Cap
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).
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biomarker Endpoint (Neurogenesis) | 3 months | Serum levels of brain derived neurotrophic factor (BDNF) |
| Biomarker Endpoint (Inflammation) | 3 months | We will measure serum levels of high sensitivity C-Reactive Protein (CRP) |
| Biomarker Endpoints (NFL) | Baseline,3 months | Neuronal injury measured by Neurofilament Light Chain (NFL). Samples will be analyzed using a digital immunoassay based on a single molecule counting technology. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinically Significant Bleeding | 3 months | Clinically significant bleeding distress is measured by number of individuals who experienced it. |
| Delayed Functional Recovery | 3 months | 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 |
| Gastrointestinal Distress | 3 months | GI distress is measured by number of individuals who experienced it. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Impairment | 3 months | Cognitive impairment will be defined by a battery of neurocognitive tests including the Montreal Cognitive Assessment (MOCA), Hopkins Verbal Learning Test (HVLT), Trails A and B, Brief Visuospatial Memory Test (BVMT), Stroop Test, Wechsler Test of Adult Reading (WTAR), Brief Test of Attention, (BTA), Wisconsin Card Sorting Test (WCST) and COWAT (Controlled Oral Word Association Test). The WTAR will be used as an estimate of IQ and the neurocognitive test T-scores of interest will be compared against the subject's IQ T-score. The standard deviation (SD) of each T-score is 10. Each of the subject's neurocognitive tests is considered aberrant if it is more than 2 SD below the subject's IQ T-score. A subject is considered cognitively impaired if at least 2 (based on the .05 rule; 5 out of every 100 test scores will be outside of expected range by chance alone) out of the T-scores are aberrant. |
| Moderate/Severe Post-Concussive Symptoms | 3 months | Moderate/severe post-concussive symptoms will be defined as the presence of any one or more of the following: headaches, dizziness, general malaise, excessive fatigue, or noise intolerance, irritability, emotional lability, depression, or anxiety, subjective complaints of concentration or memory difficulty, insomnia, reduced tolerance to alcohol, preoccupation with these symptoms and fear of permanent brain damage. These will be self-reported by the patient. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm Participants randomized to this study arm received 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.
Omega-3 Polyunsaturated Fatty Acids (Fish Oil 1000 mg (contains 500 mg DHA & 100 mg EPA)) or placebo capsules.: Participants were randomized to receive fish oil 1000 mg (contains 500 mg DHA & 100 mg EPA) or placebo capsules. | 22 |
| Placebo Arm Participants randomized to this study arm received placebo drug for 3 months.
Placebo - Cap: Participants were 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). | 22 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 4 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Total | Placebo Arm |
|---|---|---|---|
| Age, Continuous | 37.5 years | 30.5 years | 26.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 41 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 33 Participants | 14 Participants |
| Race (NIH/OMB) White | 1 Participants | 5 Participants | 4 Participants |
| Region of Enrollment United States | 22 participants | 44 participants | 22 participants |
| Sex: Female, Male Female | 16 Participants | 30 Participants | 14 Participants |
| Sex: Female, Male Male | 6 Participants | 14 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 3 / 22 | 0 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 |
Outcome results
Primary
Biomarker Endpoint (Inflammation)
We will measure serum levels of high sensitivity C-Reactive Protein (CRP)
Time frame: 3 months
Population: While serum was collected no CRP data or measurements were made or can be made now or in the future.
Primary
Biomarker Endpoint (Neurogenesis)
Serum levels of brain derived neurotrophic factor (BDNF)
Time frame: 3 months
Population: While serum was collected, no BDNF data or measurements were collected or can be made now or in the future.
Primary
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.
Time frame: Baseline,3 months
Population: For some of the assays, some individuals' data was not available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Biomarker Endpoints (NFL) | NFL baseline | 7.9 picograms per ml |
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Biomarker Endpoints (NFL) | NFL 1 month | 6.7 picograms per ml |
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Biomarker Endpoints (NFL) | NFL 3 months | 8.2 picograms per ml |
| Placebo Arm | Biomarker Endpoints (NFL) | NFL baseline | 5.3 picograms per ml |
| Placebo Arm | Biomarker Endpoints (NFL) | NFL 1 month | 8.7 picograms per ml |
| Placebo Arm | Biomarker Endpoints (NFL) | NFL 3 months | 9.7 picograms per ml |
Comparison: Baselinep-value: 0.24Kruskal-Wallis
Comparison: 1 month analysisp-value: 0.43Kruskal-Wallis
Comparison: 3 monthp-value: 0.54Kruskal-Wallis
Secondary
Clinically Significant Bleeding
Clinically significant bleeding distress is measured by number of individuals who experienced it.
Time frame: 3 months
Population: All 22 participants were analyzed on an Intention to Treat analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Clinically Significant Bleeding | 0 Participants |
| Placebo Arm | Clinically Significant Bleeding | 0 Participants |
Secondary
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
Time frame: 3 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Delayed Functional Recovery | Upper good recovery at 3 months (GOSE=8) | 16 Participants |
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Delayed Functional Recovery | Lower good recovery at 3 months (GOSE=7) | 1 Participants |
| Placebo Arm | Delayed Functional Recovery | Upper good recovery at 3 months (GOSE=8) | 17 Participants |
| Placebo Arm | Delayed Functional Recovery | Lower good recovery at 3 months (GOSE=7) | 0 Participants |
p-value: 0.31Chi-squared
Secondary
Gastrointestinal Distress
GI distress is measured by number of individuals who experienced it.
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Gastrointestinal Distress | 3 Participants |
| Placebo Arm | Gastrointestinal Distress | 0 Participants |
Other Pre-specified
Cognitive Impairment
Cognitive impairment will be defined by a battery of neurocognitive tests including the Montreal Cognitive Assessment (MOCA), Hopkins Verbal Learning Test (HVLT), Trails A and B, Brief Visuospatial Memory Test (BVMT), Stroop Test, Wechsler Test of Adult Reading (WTAR), Brief Test of Attention, (BTA), Wisconsin Card Sorting Test (WCST) and COWAT (Controlled Oral Word Association Test). The WTAR will be used as an estimate of IQ and the neurocognitive test T-scores of interest will be compared against the subject's IQ T-score. The standard deviation (SD) of each T-score is 10. Each of the subject's neurocognitive tests is considered aberrant if it is more than 2 SD below the subject's IQ T-score. A subject is considered cognitively impaired if at least 2 (based on the .05 rule; 5 out of every 100 test scores will be outside of expected range by chance alone) out of the T-scores are aberrant.
Time frame: 3 months
Post Hoc
Glial Fibrillary Acidic Protein (GFAP)
Time frame: 3 months
Population: Missing blood samples due to loss of follow-up.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Glial Fibrillary Acidic Protein (GFAP) | Baseline | 77.9 picograms per ml |
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Glial Fibrillary Acidic Protein (GFAP) | 1 month | 51.0 picograms per ml |
| Omega-3 Polyunsaturated Fatty Acid Treatment Arm | Glial Fibrillary Acidic Protein (GFAP) | 3 month | 61.2 picograms per ml |
| Placebo Arm | Glial Fibrillary Acidic Protein (GFAP) | Baseline | 53.7 picograms per ml |
| Placebo Arm | Glial Fibrillary Acidic Protein (GFAP) | 1 month | 87.7 picograms per ml |
| Placebo Arm | Glial Fibrillary Acidic Protein (GFAP) | 3 month | 68.4 picograms per ml |
Other Pre-specified
Moderate/Severe Post-Concussive Symptoms
Moderate/severe post-concussive symptoms will be defined as the presence of any one or more of the following: headaches, dizziness, general malaise, excessive fatigue, or noise intolerance, irritability, emotional lability, depression, or anxiety, subjective complaints of concentration or memory difficulty, insomnia, reduced tolerance to alcohol, preoccupation with these symptoms and fear of permanent brain damage. These will be self-reported by the patient.
Time frame: 3 months