Chronic Traumatic Encephalopathy (CTE), Traumatic Brain Injury (TBI)
Conditions
Keywords
CTE (Chronic Traumatic Encephalopathy), mTBI (Mild Traumatic Brain Injury), Concussion, MRI, Nf-L (Neurofilament Light Chain), Biomarker, Football
Brief summary
Determine if the daily docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) supplement will reduce serum levels of biomarkers of sub-concussion injuries over a course of American football season among collegiate football athletes.
Detailed description
American football is one of the most popular sports in the U.S. Yet this sport is associated with increased risk of concussion (also known as mild traumatic brain injury, or mTBI) and sub-concussive injury from repeated head impacts (RHI) due to the aggressive and high-speed nature of the game. Current protective equipment used by players are not sufficient to reduce concussion incidence and severity, nor are there any therapeutics available to prevent concussion. This study is a randomized, double-blind, placebo controlled trial to determine if an omega-3 polyunsaturated fatty acid (PUFA) fish oil supplement containing 3.0 grams of docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3) can reduce blood biomarkers of sub-concussion injuries compared to placebo (high-oleic safflower oil) over a course of the American football season among collegiate football athletes. The dosage of DHA/EPA used in this study is generally safe, and procedures involved, monthly blood draws, surveys, and Magnetic Resonance Imaging (MRI), pose minimal risks to participants. While this study provides no direct benefit to participants, successful outcomes of this study can benefit the society by shedding light on development of potential preventative therapeutics for sports-induced mTBI and brain injury from RHI. The risk-benefit profile is appropriate for conducting this study. Based on preclinical studies and previous clinical study results, the investigators expect that in comparison to placebo treatment, DHA and EPA treatment throughout the course of one American football season can maintain lower levels of sub-concussion associated biomarkers, inflammatory cytokines, and cardiovascular risk markers. The investigators also expect participants treated with DHA and EPA to have lower brain MRI imaging markers of sub concussion injury.
Interventions
DIETARY_SUPPLEMENTFish Oil (DPA+EPA 2:1 ratio) Capsules
The Treatment Arm intervention consists of providing participants with 3 grams of DHA and EPA (2:1 weight ratio) in capsular form. In order to meet the required 3 grams of DHA and EPA, participants were given 6 capsules to be taken with meals (preferably breakfast, although capsules were provided at lunch when they couldn't be provided at breakfast). Capsules were given 5 times a week during the regular football season.
DIETARY_SUPPLEMENTHigh Oleic Safflower Oil Capsules
The Placebo Arm intervention consists of providing participants with 3 grams of high-oleic safflower oil in a 1:1 allocation ratio in capsular form. In order to maintain the study masking, participants in the Placebo Arm were given 6 capsules (the same as the Treatment Arm) to be taken with meals (preferably breakfast, although capsules were provided at lunch when they couldn't be provided at breakfast). Capsules were given 5 times a week during the regular football season.
Sponsors
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Study personnel will be kept blind to treatment assignments. The treatment assignment for each participant will be available to the investigator in a sealed envelope that may be opened only in the case of a serious adverse event which the investigator feels cannot be adequately treated without knowing the identity of the study medication. Code breakers will be collected and reviewed at the end of the study. If the blinding has been broken, then the investigator will provide documentation regarding the fact and indicate the other staff that received this information.
Intervention model description
Participants will be randomized to treatment (3 grams DHA and EPA (2:1 weight ratio)) or placebo (3 grams high-oleic safflower oil in a 1:1 allocation ratio) based on their position on the football team and roster depth (starter vs. non-starter). Participants will be recruited as a single cohort. After screening, participants will be treated with DHA and EPA or matching placebo for 25 weeks (a full course of an American football season, including summer camp training sessions). A follow-up visit is scheduled 7 weeks after the final dosing at week 32 for recovery and adverse event evaluation.
Eligibility
Sex/Gender
MALE
Age
18 Years to 25 Years
Healthy volunteers
Yes
Inclusion criteria
1\) University of Arizona National Collegiate Athletic Association (NCAA) Division I American football athletes cleared to participate in university athletics as determined by the team physician.
Exclusion criteria
1. Chronic daily anti-inflammatory drugs (\>20 d). 2. Medications for blood lipids. 3. Active fish oil or omega-3 fatty acid supplementation. 4. Consumption of more than two servings of fish per week. 5. Injured and unable to participate in regularly schedule conditioning or competitions. 6. Acute concussion experienced within 30 days of starting the study. 7. Fish allergies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L | Baseline, Week 17, Week 26 | This primary outcome covers the change in the plasma brain biomarker Neurofilament Light Chains (Nf-L) due to sub-concussion injury from baseline to predetermined measurement time points. Nf-L (neuron specific intermediate proteins) are released upon injury to neurons and axons. Measured in picograms per milliliter (pg/ml) |
| Changes in Sub-concussion Injury Related Inflammation Biomarkers - TNF-α | Baseline ans Week 26 | This primary outcome covers the change in the plasma inflammation biomarker Tumor Necrosis Factor-alpha (TNF-α), a cytokine and mediator of inflammation, due to sub-concussion injury from baseline to predetermined measurement time points. TNF-α is measured in picograms per milliliter (pg/ml). |
| Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6 | Baseline; Week 17; Week 26 | This primary outcome covers the change in the plasma inflammation biomarker Interleukin-6 (IL-6), a cytokine and mediator of inflammation, due to sub-concussion injury from baseline to predetermined measurement time points. IL-6 is measured in picograms per milliliter (pg/ml) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fish Oil Capsules Participants in the treatment arm will receive 3 grams of DHA and EPA (2:1 weight ratio) 5 times a week for 25-weeks during regular football season.
Fish Oil (DPA+EPA 2:1 ratio) Capsules: The Treatment Arm intervention consists of providing participants with 3 grams of DHA and EPA (2:1 weight ratio) in capsular form. In order to meet the required 3 grams of DHA and EPA, participants were given 6 capsules to be taken with meals (preferably breakfast, although capsules were provided at lunch when they couldn't be provided at breakfast). Capsules were given 5 times a week during the regular football season. | 19 |
| Safflower Oil Capsules Participants in the treatment arm will receive 3 grams of high-oleic safflower oil (in a 1:1 allocation ratio) 5 times a week for 25-weeks during regular football season.
High Oleic Safflower Oil Capsules: The Placebo Arm intervention consists of providing participants with 3 grams of high-oleic safflower oil in a 1:1 allocation ratio in capsular form. In order to maintain the study masking, participants in the Placebo Arm were given 6 capsules (the same as the Treatment Arm) to be taken with meals (preferably breakfast, although capsules were provided at lunch when they couldn't be provided at breakfast). Capsules were given 5 times a week during the regular football season. | 19 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 7 | 2 |
Baseline characteristics
| Characteristic | Fish Oil Capsules | Safflower Oil Capsules | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 19 Participants | 38 Participants |
| Age, Continuous | 20.9 years STANDARD_DEVIATION 0.7 | 21.2 years STANDARD_DEVIATION 2.07 | 21.05 years STANDARD_DEVIATION 1.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 14 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 19 Participants | 19 Participants | 38 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 19 Participants | 19 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 17 |
| other Total, other adverse events | 12 / 12 | 11 / 17 |
| serious Total, serious adverse events | 0 / 12 | 0 / 17 |
Outcome results
Primary
Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L
This primary outcome covers the change in the plasma brain biomarker Neurofilament Light Chains (Nf-L) due to sub-concussion injury from baseline to predetermined measurement time points. Nf-L (neuron specific intermediate proteins) are released upon injury to neurons and axons. Measured in picograms per milliliter (pg/ml)
Time frame: Baseline, Week 17, Week 26
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Fish Oil Capsules | Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L | Baseline | 5.36 pg/ml |
| Fish Oil Capsules | Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L | Week 17 | 6.05 pg/ml |
| Fish Oil Capsules | Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L | Week 26 | 7.61 pg/ml |
| Safflower Oil Capsules | Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L | Baseline | 4.82 pg/ml |
| Safflower Oil Capsules | Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L | Week 17 | 6.47 pg/ml |
| Safflower Oil Capsules | Changes in Brain Biomarkers Due to Sub-concussion Injury - Nf-L | Week 26 | 6.21 pg/ml |
Primary
Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6
This primary outcome covers the change in the plasma inflammation biomarker Interleukin-6 (IL-6), a cytokine and mediator of inflammation, due to sub-concussion injury from baseline to predetermined measurement time points. IL-6 is measured in picograms per milliliter (pg/ml)
Time frame: Baseline; Week 17; Week 26
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Fish Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6 | Baseline | 2.186 pg/ml |
| Fish Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6 | Week 17 | 2.338 pg/ml |
| Fish Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6 | Week 26 | 2.158 pg/ml |
| Safflower Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6 | Baseline | 1.309 pg/ml |
| Safflower Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6 | Week 17 | 2.107 pg/ml |
| Safflower Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - IL-6 | Week 26 | 1.761 pg/ml |
Primary
Changes in Sub-concussion Injury Related Inflammation Biomarkers - TNF-α
This primary outcome covers the change in the plasma inflammation biomarker Tumor Necrosis Factor-alpha (TNF-α), a cytokine and mediator of inflammation, due to sub-concussion injury from baseline to predetermined measurement time points. TNF-α is measured in picograms per milliliter (pg/ml).
Time frame: Baseline ans Week 26
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Fish Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - TNF-α | Baseline | 1.181 pg/ml |
| Fish Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - TNF-α | Week 26 | 1.039 pg/ml |
| Safflower Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - TNF-α | Baseline | 0.962 pg/ml |
| Safflower Oil Capsules | Changes in Sub-concussion Injury Related Inflammation Biomarkers - TNF-α | Week 26 | 0.918 pg/ml |