Clinical trial NCT01814527
Conditions: Mild Concussion Brain Concussion Cerebral Concussion
Keywords: Fish oil Omega 3 Fatty acids Docosahexaenoic acid Mild Concussion Brain Concussion Cerebral Concussion
Sponsor: East Carolina University
Start date: 2013-07-01; Completion date: 2017-07-01
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Concussions are defined as a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces. Currently the standard of care in the treatment for concussions is cognitive and physical rest until symptoms resolve with a graduated return to activity. High dose omega-3 fatty acids have shown to have anti-inflammatory, anti-oxidant, and membrane stabilizing properties. They have also been used in treatment of severe traumatic brain injury. The purpose of this study is to determine if early high dose omega-3 fatty acid supplementation in Division I National Collegiate Athletic Association (NCAA) athletes that have sustained a concussion will decrease the number of days out of competitive sports with a quicker symptom resolution, return to baseline neurocognitive functioning and postural stability using a randomized double blind placebo controlled study design. Once an athlete is identified as having sustained a concussion by the East Carolina University Sports Medicine staff and qualifies for the study, he/she will randomly be assigned to either high dose omega-3 fatty acid or placebo. Both groups will undergo standard and usual care for concussed athletes at East Carolina University. The number of days it takes the athlete to return to competitive athletics will be recorded, along with time to symptom resolution, normalization of their computerized neurocognitive testing (ImPact) and computerized postural stability testing (Biodex BioSway).

Detailed description:
In the United States, an estimated 1.7 million people sustain a traumatic brain injury (TBI) annually; associated with 1.365 million emergency room visits and 275,000 hospitalizations annually with associated direct and indirect cost estimated to have been 4 billion in the United States in 2000. Furthermore, the US Center for Disease Control and Prevention estimates that 1.6 to 3.8 million concussions occur in sports and recreational activities annually.3 However, these figures grossly underestimate the total burden of traumatic brain injuries (TBIs) and concussions, because many individuals suffering from mild to moderate TBIs do not seek medical attention.

Even though concussion is a type of TBI that has been frequently used interchangeably with mild TBI in the medical literature; mild refers to the initial impact rather than the long-term sequelae from the injury. Historically, the definition of concussion has not been well defined, until the 3rd International Conference on Concussion in Sport (Zurich 2008) defined concussion as a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces. Several common features that incorporate clinical, pathological and biomechanical injury constructs that may be utilized in defining the nature of concussive head injury include: Concussion may be caused either by a direct blow to the head, face, neck or elsewhere on the body with an "impulsive" force transmitted to the head. This injury typically results in the rapid onset of short-lived impairment of neurologic function that resolves spontaneously. It may result in neuropathological changes, but the acute clinical symptoms largely reflect a functional disturbance rather than a structural injury. It results in a graded set of clinical signs and symptoms that may or may not involve loss of consciousness. Resolution of the clinical and cognitive symptoms typically follows a sequential course; however, it is important to note that, in a small percentage of cases, post-concussive symptoms may be prolonged. No abnormality on standard structural neuro-imaging studies is seen in concussion. Current data shows that on average 91% of athletes who sustain a concussion have their symptoms and cognitive impairment resolved in 7 ± 1.5 days and balance deficits resolved by day 5.13 Currently the main treatment for concussion is cognitive and physical rest until symptoms resolve with a graduated return to activity.

The neuropathological changes after a concussion result in functional disturbances and the clinical syndrome results from the depolarization and potassium efflux from neurons that trigger the release of excitatory amino-acids like glutamine, which in turn activate N-methyl-D-aspartate (NMDA) receptors and form a pore through which calcium enters the neuron. A large influx of calcium into the cell triggers the lysis of arachidonic acid, calpain activation and initiation of apoptosis, and the formation of reactive oxygen species (ROS). Studies have shown that the incorporation of omega-3 fatty acids into the cell membrane has been associated with decreased generation of intracellular ROS and consequent diminished activation of redox-sensitive transcription factors, such as the nuclear factor- κβ system, modifying the expression of pro-inflammatory genes. Incorporation of omega-3 fatty acids also appears to alter the properties of lipid rafts and caveolae, contributing to membrane fluidity, hormone-receptor binding and the function of membrane associated proteins are affected. Omega-3 fatty acids are also associated with decreased levels of markers and mediators of inflammation such as the cytokines interleukin-1β and tumor necrosis factor (TNF-α).

Mills et al looked at the effects of omega-3 fatty acid supplementation in a head injury model in rats. Docosahexaenoic acid (DHA) was started approximately 24 hours after injury, in the following doses: 10 mg/kg/day for group 1 and 40 mg/kg/day for group 2. The number of beta-amyloid precursor protein (APP)-positive axons was used to measure the level of injury. There was a significant quantitative difference of 182 ± 44.6 APP-positive axons in un-supplemented animals versus sham-injured animals (control animals), which had 4.1 ± 1.3 APP-positive axons per square millimeter. Group 1 showed 26.1 ± 5.3 and group 2 showed 19.6 ± 4.7, APP-positive axons. It is notable that the omega-3 fatty acid supplementation groups had a significantly reduced number of APP-positive axons at 30 days after injury to levels similar to those in uninjured animals. This study shows pathologic improvement with high dose omega-3 fatty acid supplementation, specifically DHA, in a head injury rat model. However, there are no current human studies in the medical literature that look at omega-3 fatty acid supplementation in the treatment of concussions. Does high dose omega-3 fatty acid supplementation in Division I NCAA athletes that have sustained a concussion improve time to symptom resolution, neurocognition and postural stability and thus decrease the number of days out of competitive sports? Protocol: Once an athlete qualifies for the study he/she will be randomly be assigned to either high dose omega-3 fatty acid/DHA supplementation or placebo. Demographics of the athlete will be obtained which include: age, gender, sport, academic year, height, weight, BMI, history of prior concussion, migraines, learning disability, or psychiatric diagnosis. Both groups will undergo standard and usual care for concussed athletes at East Carolina University. The physician and the athletic training staff evaluating and clearing the athlete to return to activity will be blinded.

Currently East Carolina University employs a regimented return-to-play protocol for every student-athlete that has sustained a concussion. As part of their pre-participation physical, all student-athletes will have a baseline computerized postural stability test using Biodex BioSway and a computerized neurocognitive test using ImPact. At the time of injury a Sport Concussion Assessment Tool 2 (SCAT2) is administered by a certified athletic trainer, and the student-athlete is withdrawn from participation if they are symptomatic and/or have deficits noted. The same day a concussion is suspected a repeat Biodex postural stability test will also be administered and the student-athlete is given a detailed information sheet on instructions for monitoring and follow-up. A repeat Impact neurocognitive test will then be administered within 24 hours after the injury. The student-athlete is then seen and examined by a sports medicine physician to review the results, perform a clinical exam and confirm the diagnosis. The student-athlete is then evaluated daily with a modified Symptom Evaluation Questionnaire found on the SCAT2 by an athletic trainer. When the student-athlete is asymptomatic with activities of daily living (ADLs) for 24 hours, he/she then begins a non-contact return to play protocol resembling Zurich's beginning with a supervised cardiovascular challenge. This includes 30 minutes of supervised light aerobic activity on a treadmill or stationary bike. If the athlete is asymptomatic with the cardiovascular challenge then he/she can progress to noncontact sport specific drills the subsequent day. If the athlete is still doing well he/she can progress their non-contact training drills and start light resistance training the following day. If the student-athlete remains asymptomatic through the non-contact activity progression, he/she then re-takes the computerized neurocognitive test, postural stability assessment and is re-evaluated by the physician. If the postural stability assessment and neurocognitive test are back to baseline the athlete is then cleared at the discretion of the treating sports medicine physician to return to full unrestricted activity. However, if a student-athlete's symptoms continue by day 7 both Impact and Biodex BioSway evaluation will be re-administered. This will be repeated again at 14 days and 30 days post-injury if the student-athlete continues to be symptomatic.

Arms: arm 1: The experimental group will be given a standardized dose of omega-3 fatty acid containing 2200mg of DHA for 30 days after onset of concussion or longer for those with continued symptomatology. Brain Armor an over the counter DHA supplements that is independently tested and certified by the National Science Foundation Athletic Banned Substance Certified for Sport Program. The Docosahexaenoic acid supplement has 440mg of DHA per capsule and each subject will be given 5 capsules of Brain Armor once daily for a DHA dose of 2200mg/day. arm 2: The placebo group will be given an equal amount of capsules.
Interventions: intervention 1: Docosahexaenoic acid intervention 2: Placebo
Intervention descriptions: intervention 1: 5 capsules containing 440mg of Docosahexaenoic acid (DHA)for total daily dosing of 2200mg of DHA daily intervention 2: 5 capsules that are identical to the treatment.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
Title: High Dose Omega-3 Fatty Acids in the Treatment of Sport Related Concussions 
 
NCT: 01814527 
 
Completion Date: 4/25/2018 
 
 


Methods 
This study obtained IRB approval prior to enrollment of participants through East Carolina 
University and Medical Institutional Review Board. The study design was a randomized double-
blind placebo-controlled trial using student’s T test for analysis of continuous outcome variables.  
This study was conducted at East Carolina University over a 4 year period.  The inclusion 
criteria for each subject were: must be a NCAA Division I student athlete at East Carolina 
University, must be 18 years old, have sustained a sport related concussion with the past 24 
hours, and have a neurological exam not consistent with concern for an intracranial hemorrhage 
or other significant pathology.  The exclusion criteria for each participant was: a recent prior 
concussion within the past 30 days, a history of moderate to severe TBI that has required 
hospitalization or resulted in prolonged signs and/or symptoms (>3 weeks), a known 
neurological diagnosis associated with impaired cognitive function other than attention deficit 
hyperactivity disorder or attention deficit disorder, a known allergy to algae, omega-3 fatty acid, 
or any component of the formulation, a known liver pathology or significantly elevated LFTs 
(greater than 3 x normal), a current lower extremity injury that will affect postural stability 
testing, subjects already routinely using omega-3/DHA supplementation, and subjects currently 
requiring anticoagulants, anti-platelets or any NSAIDs. 
Once a student-athlete was diagnosed with a sport related concussion, and met the inclusion and 
exclusion criteria, the athlete met with the primary investigator and an IRB approved informed 
consent was obtained.  The athlete then was randomly assigned to either high dose omega-3 fatty 
acid/DHA supplementation or placebo.  Demographics of the athlete were obtained and include 
age, gender, sport, academic year, height, weight, BMI, history of prior concussion, migraines, 
learning disability, or psychiatric diagnosis. The experimental group was given a standardized 
dose of 2 grams (4 capsules) of omega-3 fatty acid/DHA for 30 days after onset of concussion.  
The placebo group was given an equal number of capsules.  Both the omega-3 fatty acid/DHA 
capsules and placebo capsules were donated to East Carolina University for the purpose of this 
study by DSM Nutritional Products.  The omega-3 fatty acid/DHA used in this study was derived 
from algae and therefore had no fish odor or after taste.  The physician and the athletic training 
staff evaluating and clearing the athlete to return to activity were blinded.  Each athlete 
underwent daily directly observed therapy by certified athletic trainers and daily symptom 
monitoring using the Symptom Evaluation scale found on the Sport Concussion Assessment 
Tool 2 (SCAT2).  Symptoms were grouped into physical, cognitive, emotional and sleep 
categories with the total number of symptoms and symptoms severity score calculated for each 
category and overall. 
Both groups underwent standard and usual care for concussed athletes at East Carolina 
University. East Carolina University employs a regimented return-to-play protocol for every 
student-athlete that has sustained a concussion (Figure 1).  As part of their pre-participation 
physical, all student-athletes have a baseline computerized neuro-physical postural stability test 
using Biodex SD/BioSway and a computerized neurocognitive test using ImPact.  At the time of 


injury, a SCAT2 is administered by a certified athletic trainer, and the student-athlete is 
withdrawn from participation if they are symptomatic and/or have deficits noted.  The same day 
a concussion is suspected a repeat Biodex postural stability test is administered and the student-
athlete is given a detailed information sheet on instructions for monitoring and follow-up.  A 
repeat Impact neurocognitive test is administered within 24 hours after the injury.  The student-
athlete is then seen and examined by a sports medicine physician to review the results, perform a 
clinical examination, and confirm the diagnosis.  The student-athlete is then evaluated daily with 
a modified Symptom Evaluation Questionnaire found on the SCAT2 by an athletic trainer.  
When the student-athlete is asymptomatic with activities of daily living (ADLs) for 24 hours, 
he/she then begins a non-contact return to play protocol beginning with a supervised 
cardiovascular challenge.  This includes 30 minutes of supervised light aerobic activity on a 
treadmill or stationary bike.  If the athlete is asymptomatic with the cardiovascular challenge, 
then he/she can progress to noncontact sport specific drills the subsequent day.  If the athlete is 
still doing well, he/she can progress their non-contact training drills and start light resistance 
training the following day.  If the student-athlete remains asymptomatic through the non-contact 
activity progression, he/she then re-takes the computerized neurocognitive test, postural stability 
assessment and is re-evaluated by the physician.  If the postural stability assessment and 
neurocognitive test are back to baseline the athlete is then cleared at the discretion of the treating 
sports medicine physician to return to full unrestricted activity.  However, if a student-athlete 
continues to be symptomatic on day 7 both Impact and Biodex SD/BioSway evaluation will be 
re-administered.  This will be repeated at 14 days and 30 days post-injury if the student-athlete 
continues to be symptomatic (Figure 1).  The primary outcome of the study is the total number of 
days from onset of concussion it takes for the athlete to return to unrestricted full participation in 
their respective sport. 
Results 
A total of 62 student-athletes were enrolled and completed the study.  7 student-athletes were 
excluded from the analysis secondary to return to play greater than 30 days.  Of those 7 student-
athletes 6 were in the DHA cohort and 1 was in the placebo cohort.  55 student-athletes (33 male 
and 22 female) were used in the analysis.  The demographics of the DHA cohort were: 19.7±1.4 
years of old, 60.9% male, 39.1% female, and a BMI of 27.7±6.1.  The demographics of the 
placebo cohort were: 19.9±1.4 years of age, 59.4% male, 40.6% female, and a BMI of 28.3±6.1.  
There was no statistically significant difference in age, gender, BMI, and sports distribution in 
the DHA vs the placebo cohort.  Direct observed therapy of the intervention lead to a compliance 
rate of 84.2% in the DHA cohort and 83.0% in the placebo cohort.  A previous history of 
concussion prior to the study was recorded and there was no statistical difference between the 
cohorts with the DHA cohort at 47.8% and the placebo cohort at 50%.  The initial SCAT2 
symptom severity score, an indicator of concussion severity, was recorded.  The DHA cohort’s 
initial SCAT2 symptom severity score was 42.7±27.9 compared to the placebo cohort’s initial 
SCAT2 symptom severity score of 49.9±26.6.  Despite the placebo cohort’s higher symptom 


severity score this was not statistically significant.  The primary outcome of this study was the 
number of days that the athlete required to return to play.  The DHA cohort’s return to play was 
11.0±4.8 days [95% CI 9.1,13.0] and the placebo cohort’s return to play was 11.9±5.4 days [95% 
CI 10.0,13.8], with a P value of 0.558 (Figure 2).  The effect size was calculated to be 0.16 and a 
post hoc power analysis was calculated to be 0.09. 
 
 


 
Figure 1: East Carolina University Concussion Management Standardized Protocol 
 
 
 


Figure 2: Results 
DHA (n= 23) 
Placebo (n=32) 
Age (years) 
19.7 ± 1.4  
19.9 ± 1.4 
Gender (male: female) 
60.9%: 39.1% 
59.4%: 40.6% 
BMI (kg/m²) 
27.7 ± 6.1 
28.3 ± 6.1 
Compliance 
84.20% 
83.02% 
History of Concussion 
47.8% 
50% 
SCAT2 Symptom Severity Score 
42.7±27.9 
49.9±26.6 
Return to Play (days) (P=0.558) 
11.0 ± 4.8 [95% CI 9.1,13.0]  
11.9 ± 5.4 [95% CI 10.0,13.8]  
 
 
 
 
 
 


 
  
 
 
 
East Carolina University 
Informed Consent to Participate in Research 
Information to consider before taking part in research that has more than minimal risk. 
Title of Research Study: High Dose Omega-3 Fatty Acids in the Treatment of Sport Related 
Concussions 
Principal Investigator: Joseph Armen DO 
Institution/Department or Division: Department of Family Medicine and Sports Medicine, Brody 
School of Medicine 
Address:1001 East 5th Street, Greenville, NC 27858 
Telephone #: 252-737-2593 
 
Researchers at East Carolina University (ECU) study problems in society, health problems, 
environmental problems, behavior problems and the human condition.  Our goal is to try to find 
ways to improve the lives of you and others.  To do this, we need the help of volunteers who are 
willing to take part in research. 
Why is this research being done? 
The purpose of this study is to evaluate if Brain Armor, a high-dose omega-3 fatty acid 
supplement, gives added benefit and improve recoverability to athletes who have sustained a 
concussion.  Omega-3 fatty acids is an oil commonly found in fish, there is a growing body of 
evidence that omega-3 fatty acids have antioxidant and anti-inflammatory properties and can 
improve brain function.  A concussion is a self-limiting head injury in which a direct or indirect 
blow to the head causes functional problems without any structural brain damage.  The purpose 
of this study is to determine if omega-3 fatty acids’ antioxidant and anti-inflammatory properties 
can improve symptoms of a concussion and improve brain function.  A potential benefit of this 
study is to reduce the length of time recovering from a concussion and potentially reducing the 
incidence of post-concussion syndrome.   
Why am I being invited to take part in this research? 
You are being invited to take part in this research because you are National Collegiate Athletic 
Association (NCAA) Division I athlete who has sustained a concussion within the last 24 hours.  
If you volunteer to take part in this research, you will be one of 100 people to do so.   
Are there reasons I should not take part in this research?  
You should not volunteer for this study if you are less than 18 years of age.  You must not have a 
history of: 1. Have a recent prior concussion within the past 30 days.  2.  Have a history of 


moderate to severe concussion that has required hospitalization or result in prolonged 
signs/symptoms (greater than 3 weeks).  3.  Have a known neurological problem associated with 
trouble thinking or focusing other than Attention Deficit Disorder or Attention Deficit and 
Hyperactivity Disorder (ADD/ADHD).  4. Already routinely using omega-3/Docosahexaenoic 
Acid (DHA) supplementation.  5. Have a history of allergy to algae (common water plant), 
omega-3 fatty acid, or any component of the formulation.  6. Currently on any blood thinners 
such as Coumadin, aspirin, or Plavix, if you are on an anti-inflammatory (ie Motrin, Aleve) you 
will be asked to stop that medication.  7. If you have known liver problems with significantly 
elevated liver enzymes.  8. A current lower extremity injury that will affect postural stability 
testing (balance testing). 
What other choices do I have if I do not take part in this research? 
You can choose not to participate, at which point you will undergo East Carolina University’s 
standard return to play protocol and still receive the standard of care in the treatment of 
concussions. 
Where is the research going to take place and how long will it last? 
The research procedures will be conducted at Ward Sports Medicine Building.  Once identified 
as a potential subject it will take about 30 minutes for informed consent and medication 
dispensing.  You will then follow a standard return to play protocol with East Carolina 
University Sports Medicine staff. 
What will I be asked to do? 
You are being asked to do the following: 
 
After you sign this consent form, you will be randomly assigned, by sealed random envelope, to 
either Brain Armor or placebo.  You are being asked to be compliant with medication 
administration and recommendations given by the team physician and athletic training staff.  
You will undergo standard and usual care for concussed athletes at East Carolina University.  
Demographics of the athlete will be obtained which include: age, gender, sport, academic year, 
height, weight, Body mass index, history of prior concussion, and history of learning disability or 
psychiatric diagnosis.   
What possible harms or discomforts might I experience if I take part in the research? 
It has been determined that the risks associated with this research are potential adverse drug 
reactions that can be experienced with omega-3 fatty acids or with the placebo, such as rash or 
hives.  If this occurs you need to contact the primary investigator immediately and discontinue 
the medication.  More common side effects include gastrointestinal upset, heartburn or nausea.  


What are the possible benefits I may experience from taking part in this research? 
We do not know if you will get any benefits by taking part in this study.  A potential benefit of 
this study is to reduce the length of time recovering from a concussion and potentially reducing 
the incidence of post-concussion syndrome.   
Will I be paid for taking part in this research? 
We will not be able to pay you for the time you volunteer while being in this study.   
What will it cost me to take part in this research?  
It will not cost you any money to be part of the research.  
Who will know that I took part in this research and learn personal information about me? 
To do this research, ECU and the people and organizations listed below may know that you took 
part in this research and may see information about you that is normally kept private.  With your 
permission, these people may use your private information to do this research: 
• Any agency of the federal, state, or local government that regulates human research.  This 
includes the Department of Health and Human Services (DHHS), the North Carolina 
Department of Health, and the Office for Human Research Protections.  
• The University & Medical Center Institutional Review Board (UMCIRB) and its staff, who 
have responsibility for overseeing your welfare during this research, and other ECU staff 
who oversee this research. 
• Additionally, the following people and/or organizations may be given access to your 
personal health information and they are: Joseph Armen DO. 
How will you keep the information you collect about me secure?  How long will you keep 
it? 
All data will be kept for a minimum of 6 years.  For this particular study, you will be assigned a 
case number that is random and cannot be traced back to you by anyone other than the principal 
researcher.  All computer files are securely on remote departmental folder within Piratedrive.  
All paper files will be kept in Joseph Armen’s office in ECU Student Health Center, room 150.   
What if I decide I do not want to continue in this research? 
If you decide you no longer want to be in this research after it has already started, you may stop 
at any time.  You will not be penalized or criticized for stopping.  You will not lose any benefits 
that you should normally receive.  
Who should I contact if I have questions? 
The people conducting this study will be available to answer any questions concerning this 
research, now or in the future.  You may contact Joseph Armen DO 252-737-2593, 7 days a 
week between 9 am and 5 pm. 
If you have questions about your rights as someone taking part in research, you may call the 
UMCIRB Office at phone number 252-744-2914 (days, 8:00 am-5:00 pm).  If you would like to 


report a complaint or concern about this research study, you may call the Director of UMCIRB 
Office, at 252-744-1971. 
Is there anything else I should know? 
N/A 
I have decided I want to take part in this research.  What should I do now? 
The person obtaining informed consent will ask you to read the following and if you agree, you 
should sign this form:   
• I have read (or had read to me) all of the above information.   
• I have had an opportunity to ask questions about things in this research I did not 
understand and have received satisfactory answers.   
• I know that I can stop taking part in this study at any time.   
• By signing this informed consent form, I am not giving up any of my rights.   
• I have been given a copy of this consent document, and it is mine to keep.  
 
 
 
 
 
 
 
 
 
 
 
 
_____________ 
Participant's Name  (PRINT)                                 Signature                           
 
Date   
 
Person Obtaining Informed Consent:  I have conducted the initial informed consent process.  I 
have orally reviewed the contents of the consent document with the person who has signed 
above, and answered all of the person’s questions about the research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Person Obtaining Consent  (PRINT)                      Signature                                    Date   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator   (PRINT)                           Signature                                    Date   
(If other than person obtaining informed consent)