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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fish Oil Capsules | Experimental | 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. |
|
| Safflower Oil Capsules | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fish Oil (DPA+EPA 2:1 ratio) Capsules | Dietary Supplement | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Baseline, Week 17, Week 26 |
| 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). | Baseline ans Week 26 |
| 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) | Baseline; Week 17; Week 26 |
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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:
Age: 18-25 Gender: Male Ethnicity: All races and ethnicities
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| Name | Affiliation | Role |
|---|---|---|
| Floyd Chilton, Ph.D. | University of Arizona | Principal Investigator |
| Roberta Brinton, Ph.D. | University of Arizona | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Arizona | Tucson | Arizona | 85721 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36188406 | Derived | Raikes AC, Hernandez GD, Mullins VA, Wang Y, Lopez C, Killgore WDS, Chilton FH, Brinton RD. Effects of docosahexaenoic acid and eicosapentaoic acid supplementation on white matter integrity after repetitive sub-concussive head impacts during American football: Exploratory neuroimaging findings from a pilot RCT. Front Neurol. 2022 Sep 15;13:891531. doi: 10.3389/fneur.2022.891531. eCollection 2022. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
NCAA football participants
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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) | Posted | Mean | 95% Confidence Interval | pg/ml | Baseline, Week 17, Week 26 |
|
6 months
Adverse events were reported to study staff daily when supplements were delivered.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Respiratory Infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Common cold |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Floyd H. Chilton | University of Arizona | 520-621-5327 | fchilton@arizona.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 18, 2020 | Apr 24, 2025 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 29, 2019 | Apr 24, 2025 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000070642 | Brain Injuries, Traumatic |
| D000070627 | Chronic Traumatic Encephalopathy |
| D001924 | Brain Concussion |
| C537987 | Charcot-Marie-Tooth disease, Type 1F |
| ID | Term |
|---|---|
| D001930 | Brain Injuries |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D005395 | Fish Oils |
| D002214 | Capsules |
| ID | Term |
|---|---|
| D009821 | Oils |
| D008055 | Lipids |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
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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.
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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.
|
| High Oleic Safflower Oil Capsules | Dietary Supplement | 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. |
|
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | 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. |
|
|
| 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). | Posted | Mean | 95% Confidence Interval | pg/ml | Baseline ans Week 26 |
|
|
|
| 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) | Posted | Mean | 95% Confidence Interval | pg/ml | Baseline; Week 17; Week 26 |
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| 12 |
| 12 |
| EG001 | 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. | 0 | 17 | 0 | 17 | 11 | 17 |
|
| Acne | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| GI distress | Gastrointestinal disorders | Systematic Assessment | Stomach upset |
|
| Halitosis | Gastrointestinal disorders | Systematic Assessment | Bad breath |
|
| Concussion | Nervous system disorders | Systematic Assessment |
|
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| D006259 |
| Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D020208 | Brain Injury, Chronic |
| D019636 | Neurodegenerative Diseases |
| D001925 | Brain Damage, Chronic |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D016489 | Head Injuries, Closed |
| D014949 | Wounds, Nonpenetrating |
| Week 26 |
|