Clinical trial NCT01903525
Conditions: Concussion Mild Traumatic Brain Injury
Sponsor: University of Texas Southwestern Medical Center
Start date: 2013-09-01; Completion date: 2017-08-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In recent years, media attention has focused on the long-term sequelae of repeated concussive episodes in professional athletes. The growing understanding of the damage done by what was once considered a "ding" during a game or match, and the neurologic consequences of "playing through" or returning to play too soon has led to additional interest in and concern for pediatric athletes (18 or under) who experience sports-related concussions during game or practice play.

Because it has only been in recent years that the full scope of damage done by repeated concussive episodes has come to light, very little research has been done on treatment of concussion in either adults or children. Brain injuries in children can be especially problematic, as the brain may continue to develop until the child reaches the age of 24 or older, so concussion during this time of development may be particularly damaging.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid commonly found in both fish oils and algae. DHA is known to improve development of the eyes and brain in young children. It is thought to be an effective anti-inflammatory and anti-oxidant, and since it occurs naturally and causes very few harmful side effects, it may be a useful compound in the treatment of pediatric concussion.

This is a feasibility trial of DHA for the treatment of sports concussion in a pediatric population. The investigators' primary aim is to determine acceptability of randomization for this compound as well as rate of enrollment given our clinical population. The investigators' secondary aim is to examine preliminary outcomes. The investigators hypothesize that subjects who take 2 g of DHA daily for 3 months will see a shorter time to full recovery and return to play and a shorter time to resolve balance disturbance. These are good, albeit unvalidated, clinical indicators of concussive recovery.

Detailed description:
This is a double-blind, randomized, placebo-controlled feasibility trial of DHA for the treatment of pediatric concussion related to sports-injury. The definition used for concussion is from the Consensus Statement on Concussion in Sport: the 3rd International Conference on Concussion in Sport (Br J Sports Med 2009;43:Suppl 1 i76-i84 doi:10.1136/bjsm.2009.058248) and will meet the following criteria:

1. Direct blow to the head, face, neck or a blow elsewhere on the body with an "impulsive" force transmitted to the head.
2. Rapid onset of short-lived impairment of neurologic function in one or more of the following clinical domains that resolves spontaneously:

   1. symptoms: somatic (eg, headache), cognitive (eg, feeling like in a fog) and/or emotional symptoms (eg, lability).
   2. physical signs (eg, loss of consciousness, amnesia).
   3. behavioural changes (eg, irritability).
   4. cognitive impairment (eg, slowed reaction times).
   5. sleep disturbance (eg, drowsiness).
3. No abnormality on standard structural neuroimaging studies, if such neuroimaging studies are completed for a clinically-indicated reason. Note: neuroimaging is not a part of this study protocol. Study participants will not undergo neuroimaging as part of this study.

Subjects will be randomized in a 1:1 fashion. DHA is an omega-3 fatty acid that occurs naturally in fish oil and algae. There are many dietary supplements containing DHA available in the marketplace. Martek Biosciences provides an algae-based DHA compound which minimizes the side effects of "fishiness" in both flavor and "fish burps." The DHA produced by Martek Biosciences is also used for many infant formula companies in the US. DHA and identical placebo will be provided by Martek Biosciences.

The DHASCO capsules are supplied as 950 mg capsules with an effective dose of 500 mg DHA per capsule. The placebo capsules are supplied as 950 mg capsules consisting of 475 mg corn oil and 475 mg soy oil. Both DHA and placebo are flavored with sweet orange flavoring and masking agents.

They are supplied in sealed white plastic bottles containing 100-200 capsules per bottle, depending on dose. Each bottle has the lot number stamped on it. The capsules will be stored in a dry, locked compartment at room temperature (60 to 75 F). Martek's Quality Assurance department completes regularly scheduled chemical and long-term stability analyses on each lot of capsules. If shipments will occur during warmer months, arrangements will be made for capsules to be shipped with ice packs or other temporary refrigeration. Capsules will be dispensed to subjects in separate bottles in quantities sufficient to last until their next appointment. Any unused capsules will be returned to the PI or research staff and sent to the pharmacy for destruction in compliance with Children's regulations.

Subjects will be randomized to 2 g of DHA or matched placebo for 12 weeks. In order to achieve this dose of DHA, subjects will receive 2 950 mg capsules twice a day. Subjects who cannot tolerate the divided dose of 2000 mg per day will be discontinued from the study.

Although much of our knowledge of the pathophysiology of concussion comes from animal models, it is believed that the mechanical trauma to the brain causes a sudden disruption in the ionic balances, leading to an increase in calcium and an increase in glucose metabolism as cells try to compensate for the potassium/calcium imbalance. This is followed by a period of decreased glucose metabolism which may last up to 4 weeks in humans, resulting in continued high levels of calcium which interfere with mitochondrial oxidative metabolism. This decrease in mitochondrial oxidative metabolism appears to be biphasic, with improvement seen at 2, followed by a decrease which bottoms out on day 5 and recovers around day 10. Other important aspects of the concussive trauma include free radical production, initiation of inflammatory responses, and altered neurotransmission.

DHA has several important functions in the brain with relatively few side effects, making it a good option for concussion treatment. DHA is helpful in modulating ion channels; higher levels of DHA are associated with higher levels of sodium pump activity, so it is possible that providing DHA post-injury may help the cells reduce the calcium balance more quickly or efficiently. DHA also has an apparent anti-inflammatory action. DHA interferes with the inflammatory arachidonic acid cascade by reducing the affinity of platelet thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor for its ligand. Additionally, higher levels of DHA in the cerebral cortex cause significantly higher levels of the anti-oxidant enzymes catalase, glutathione and glutathione peroxidase -- resulting in decreased cerebral levels of lipid peroxides. DHA reduces formation of the peroxynitrite free radical and reduces formation of pro-inflammatory cytokines by inhibiting transcription factor NF-κB and inducible nitric oxide synthetase. Finally, DHA is highly concentrated in synapses, indicating a role in synaptic signal transduction. DHA appears to address many different aspects of how we believe concussive injury affects the brain.

The primary outcomes of this feasibility trial are to determine the willingness of patients to be randomized, the expected rate of enrollment based on the clinic population, and protocol adherence of enrolled study participants. We anticipate the results from this study will provide data to inform a larger randomized trial of DHA for the treatment of pediatric sports concussion. Secondary outcomes are time to clearance to return to play (in days) and improvement in balance, as assessed by the Balance Error Scoring System (BESS) which is a component of the Sport Concussion Assessment Tool 3 (SCAT-3). Time to clearance to return to play was chosen as a clinically significant measurement for medical professionals in the sports medicine field. The investigators will determine clearance for return to full competitive game play (Stage 6 of graduated return to play protocol) according to Consensus Statement guidelines and following the law in Texas, House Bill 2038. Criteria for return to play include complete clinical recovery from the concussion including returning to baseline symptoms, exam and neurocognitive function and successful completion of a gradual return to play progression. The BESS was chosen because it is a relatively simple assessment that has been noted by the investigators to be a good predictor of neurological recovery.

In addition to time to return to play and the BESS, the SCAT-3 and Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) computerized neurocognitive testing programs will be used to evaluate recovery. The SCAT-3 is a standardized method of evaluating injured athletes for concussion and can be used in athletes aged from 10 years and older. The ImPACT program is a computerized exam that helps to quantify the degree of symptom, injury, or dysfunction that occurs after a sports related concussion. Although this test is utilized by many professionals, college, and high school sports programs throughout the country, it is unclear if its use contributes to a safer or more expedited return to activity.

Finally, information on side effects will be collected at every visit in order to track the rate and severity of side effects in this patient population.

We plan to enroll 40 subjects for this study, which consists of 20 subjects to be treated with DHA and 20 subjects to be treated with placebo. In order to achieve enrollment of 40 total subjects, we anticipate screening 80 subjects in order to consent 40. Because this is a pilot study, information on early withdrawals is important to us and no extra subjects will be consented due to this. We anticipate that it will take approximately 12 months to complete enrollment, with an additional 3 months for patient follow-up once the last patient has been enrolled. We anticipate that it will take approximately 6-9 months to complete data clean-up, analysis, and manuscript submission for total study duration of 2 years.

Subjects who are non-compliant with the protocol either by not keeping appointments or by not taking study pills as directed may be discontinued from the study. Subjects who do not tolerate the minimum dose of 2000 mg of DHA per day or who experience intolerable side effects will be discontinued. Subjects who choose to withdraw consent will be discontinued early.

Arms: arm 1: The placebo capsules are supplied as 950 mg capsules consisting of 475 mg corn oil and 475 mg soy oil. Both DHA and placebo are flavored with sweet orange flavoring and masking agents. Subjects will be instructed to take 2 capsules at breakfast and 2 capsules at dinner (with food). Subjects will take their first dose in the office to assure their ability to swallow the pills. Subjects will be dosed with the placebo for 12 weeks. arm 2: The DHASCO capsules are supplied as 950 mg capsules with an effective dose of 500 mg DHA per capsule. Both DHA and placebo are flavored with sweet orange flavoring and masking agents. Subjects will be instructed to take 2 capsules at breakfast and 2 capsules at dinner (with food). Subjects will take their first dose in the office to assure their ability to swallow the pills. Subjects will be dosed with the DHA for 12 weeks.
Interventions: intervention 1: Docosahexaenoic acid (DHA) intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects presenting with a new concussion within 4 days of their initial injury will be identified and screened for eligibility from the investigators' regularly scheduled clinic patients. Subjects who enroll will complete 5 scheduled visits, although additional visits may be clinically indicated for symptom evaluation and treatment. All assessments done for this study are routinely done as part of the standard clinic visits for concussion at the Sports Medicine Center. Subjects will be randomized to either DHA or placebo in a 1:1 ratio, and receive enough DHA or placebo capsules to reach the target dose of 2 g of DHA per day (or placebo) until the day of their next appointment. Subjects will be instructed to take 4 capsules (2 at breakfast and 2 at dinner) for 12 weeks. intervention 2: Subjects presenting with a new concussion within 4 days of their initial injury will be identified and screened for eligibility from the investigators' regularly scheduled clinic patients. Subjects who enroll will complete 5 scheduled visits, although additional visits may be clinically indicated for symptom evaluation and treatment. All assessments done for this study are routinely done as part of the standard clinic visits for concussion at the Sports Medicine Center. Subjects will be randomized to either DHA or placebo in a 1:1 ratio, and receive enough DHA or placebo capsules to reach the target dose of 2 g of DHA per day (or placebo) until the day of their next appointment. Subjects will be instructed to take 4 capsules (2 at breakfast and 2 at dinner) for 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Official title: Docosahexaenoic Acid (DHA) For The Treatment of Pediatric 
Concussion Related to Sports Injury 
 NCT number: NCT01903525 
IRB Protocol approval date: 8/3/2017 


Page 1 of 11 
 
 
 
Docosahexaenoic Acid (DHA) for the Treatment of Pediatric 
Concussion Related to Sports Injury 
 
 
 
 
Principal Investigator: Shane Miller, MD 
Co-Investigators: Robert Dimeff, MD


Page 2 of 11 
 
1. Introduction and Purpose: 
In  recent  years,  media attention has focused on  the  long-term  sequelae  of  repeated  concussive 
episodes in professional athletes. The growing understanding of the damage done by what was once 
considered a “ding” during a game or match, and the neurologic consequences of “playing through” or 
returning to play too soon has led to additional interest in and concern for pediatric athletes (18 or 
under) who experience sports-related concussions during game or practice play. 
 
Because it has only been in recent years that the full scope of damage done by repeated concussive 
episodes has come to light, very little research has been done on treatment of concussion in either adults 
or children.  Brain injuries in children can be especially problematic, as the brain may continue to develop 
until the child reaches the age of 24 or older, so concussion during this time of development may be 
particularly damaging. 
 
Docosahexaenoic acid (DHA) is an omega-3 fatty acid commonly found in both fish oils and algae. 
DHA is known to improve development of the eyes and brain in young children.  It is thought to be an 
effective anti-inflammatory and anti-oxidant, and since it occurs naturally and causes very few harmful 
side effects, it may be a useful compound in the treatment of pediatric concussion. 
 
This is a feasibility trial of DHA for the treatment of sports concussion in a pediatric population. Our 
primary aim is to determine acceptability of randomization for this compound as well as rate of enrollment 
given our clinical population.  Our secondary aim is to examine preliminary outcomes. We hypothesize 
that subjects who take 2 g of DHA daily for 3 months will see a shorter time to full recovery and return to 
play and a shorter time to resolve balance disturbance.   These are good, albeit unvalidated, clinical 
indicators of concussive recovery. 
 
 
 
2. Background: 
Current estimates suggest that 300,000 to 3.8 million recreation- and sports-related concussions occur 
each year in the U.S., and that 8.9% of all high school athletic injuries are concussions. Other reports 
indicate that concussion accounts for 3-5% of injuries in all high school sports, but self-report data 
suggests a significantly higher incidence of unreported concussion. Additionally, girls have a higher 
reported rate of concussion than boys in similar sports.  The athletes at highest risk of concussion are 
boys participating in high school football and girls participating in soccer and basketball. Approximately 
50% of high school and college football players report experiencing concussion-like symptoms each 
season. Other high contact sports, such as ice hockey and rugby, also place athletes at risk, but 
participation in these sports is often limited to club sports, so data are limited. Due to a paucity of data 
in younger athlete populations, no estimates of concussion rate are available. 
 
Research into this population is complicated by numerous issues, including  a parent and athlete 
perception that it was “just a little bump to the head;” growing competitiveness among younger athletes 
and athletic organizations; and the under-reporting of injury or symptoms that result from this lack of 
understanding of the serious nature of concussion, compounded with a desire not to be taken out of 
play due to the competitive environment. Our understanding of concussion is still somewhat limited, but 
most sports medicine doctors currently agree that even a minor hit to the head may be a serious 
concussion, and that rating how serious a concussion is cannot truly be done until well after the injury 
has occurred.  Consequently, the evaluation and management of all concussions must proceed with a 
very conservative approach. 
 
Omega-6 and omega-3 fatty acids are both required for normal human development.  However, it is 
thought that the omega-3 fatty acids are more beneficial, and in fact there is mounting evidence that 
omega-3  supplementation,  particularly  the  omega-3  fatty  acid  docosahexaenoic  acid  (DHA),  may


Page 3 of 11 
 
benefit the heart, triglyceride levels, retinal health, and emotional health.  The precise mechanism of 
action is not known, but there is also evidence that DHA may also have an anti-inflammatory process, 
as patients with rheumatoid arthritis who took DHA reported shorter durations of morning stiffness and 
lower levels of NSAID use than patients who did not take it.  Omega-6 fatty acids are associated with 
increased production of inflammatory processes, a necessary and adaptive response to injury in the 
human body.  However, due to the greater consumption of omega-6 than omega-3 in the western diet, 
it is also thought that this increased consumption of omega-6 may be contributing to increased rates of 
cancer, allergies, and other immune dysfunction disorders.   Omega-3 supplementation may have a 
perceived anti-inflammatory effect not because of actual anti-inflammatory processes, but by competing 
for receptors for the omega-6 fatty acids, thus slowing down the inflammatory processes. 
 
Omega-3 fatty acids, and specifically DHA, are also an essential component of neuronal structures in 
the brain and are thought to be an essential part of memory and cognition processes.  2006 Dietary 
Reference Intakes for Omega-3 fatty acids are for 1.1g/day (female adolescents) and 1.6 g/day (male 
adolescents).  These  values  are  based  on  similar  adult  values  and  are  minimum  recommended 
amounts, and are specified for alpha linoleic acid, with the recommendation that 10% of these fatty 
acids be DHA and EPA.  Because DHA is necessary for proper function of the brain, and its potential 
for reducing inflammation and increasing memory, we propose a study to examine the effects of DHA 
supplementation in adolescents after a concussive sports injury. 
 
The neuroprotective effects of fish oil have been studied and documented in experimental models, 
however the effects of DHA after TBI have not been studied.  To date, there have been no clinical trials 
investigating the effects of DHA and/or EPA dietary supplementation on the treatment or prevention of 
TBI.   A recent  report shows  that  DHA supplementation for  30  days can  reduce axonal  injury in 
brainstem white matter tracts in a rodent head acceleration injury model (Bailes and Mills, 2010). 
 
Several studies have demonstrated the safety of high doses of DHA in children. For example, Sorgi, 
Hallowell, Hutchins, and Sears (2007) studied the effects of an open-label pilot study with high dose 
EPA/DHA  concentrates  on  plasma  phospholipids  and  behavior  in  children  ages  8-16  years  with 
attention deficit hyperactivity disorder. Study participants were administered a dose of EPA/DHA 
concentrate per  day based on the ratio of  arachidonic  acid  (AA)  to EPA  in  the  isolated  plasma 
phospholipids at 4 weeks. All subjects were initially supplemented with 16.2 g of long-chain omega-3 fatty 
acids (10.8 g EPA and 5.4 g DHA) per day. After four weeks, if the AA:EPA ratio was below 1.0, the 
dosage was decreased to 5.4 g EPA and 2.7 g DHA per day. If the AA:EPA ratio was between 1.0 and 
1.5 the dosage was decreased to 8.1 g EPA and 4 g DHA per day. The assigned dosage was continued 
for eight weeks (the duration of the study). Findings suggested that high-dose EPA/DHA supplementation 
may improve behavior in children with ADHD. No adverse effects on bleeding were reported. One 
participant reported loose stools when taking the initial dose of 10.8 g EPA and 5.43 g DHA. This was 
reportedly corrected with a decreased dose. 
 
In a study of the safety of a high-dose of DHA in cystic fibrosis patients, Lloyd-Still et al. (2006) 
randomized twenty subjects, ages 8 to 20 years old, to receive 50mg/kg/day of DHA (1 to 4.2 g of DHA 
per subject per day) or placebo for eight weeks. This high dose of DHA was shown to be well-tolerated 
and safe with no adverse effects. 
 
A study targeting the effect of DHA on deterioration of nutritional status in children with acute 
lymphoblastic leukemia, in which enrollment is currently ongoing, provides a dose of 100 mg/kg/day DHA, 
which translates to approximately 5-6 g per day,  to children ages 4 to 15 years for a period of three 
months (NCT01051154).


Page 4 of 11 
 
Furthermore, high doses of DHA are currently being used in adults for sports-related injuries. For 
example, The Center for the Study of Retired NFL Athletes at the University of North Carolina at Chapel 
Hill is studying memory and cognition in retired NFL athletes with cognitive impairment. The athletes 
receive either DHA (2 g per day) or placebo for nine months whilst undergoing intermittent 
neuropsychological testing. At Virginia Tech, participating adult males currently follow a protocol of 2 
grams per day of DHA vs. placebo for a total of 6 weeks during a resistance training and exercise program  
in a study  of  inflammation,  soreness and  strength.  And  finally,  the  Texas  A&M football program 
is conducting a study of inflammation, power and cardiovascular risk in their participating players who are 
randomized to 2 grams per day of DHA or placebo. The study runs from summer training through the end 
of fall camp. 
Regarding dosage, a DRI has not yet been established for DHA. An Acceptable Macronutrient 
Distribution Range (AMDR) that has been set. The AMDR is the current mean intake in the United 
States, which for EPA and DHA is approximately 100mg/day, which is much lower than research is 
recommending. While side effects such as blood thinning may be seen at very high dosages, doses as 
high as 11.5 mg/kg DHA are recommended to treat asthma symptoms in children, which translates to 
approximately 575-750 mg/day DHA for an average high school male. Our suggested dose in this protocol 
is only slightly higher. In adults, recommended doses for preventing blood clots is as high as 6 g fish oil 
per day, which is approximately 6000 mg DHA per day, more than twice our protocol dose. 
(http://www.nlm.nih.gov/medlineplus/druginfo/natural/993.html). Additionally, the studies we have 
discussed above show that research has demonstrated - and continues to utilize - high doses of DHA in 
children and adults safely with minimal or no side effects. 
 
 
 
3. Concise Summary of Project: 
This is a double-blind, randomized, placebo-controlled feasibility trial of DHA for the treatment of pediatric 
concussion related to sports-injury. The definition used for concussion is from the Consensus Statement 
on Concussion in Sport: the 3rd International Conference on Concussion in Sport (Br J Sports Med 
2009;43:Suppl 1 i76-i84 doi:10.1136/bjsm.2009.058248) and will meet the following criteria: 
 
a) Direct blow to the head, face, neck or a blow elsewhere on the body with 
an “impulsive” force transmitted to the head. 
b) Rapid onset of short-lived impairment of neurologic function in one or more of the 
following clinical domains that resolves spontaneously: 
1. symptoms: somatic (eg, headache), cognitive (eg, feeling like in a fog) and/or 
emotional symptoms (eg, lability). 
2. physical signs (eg, loss of consciousness, amnesia). 
3. behavioural changes (eg, irritability). 
4. cognitive impairment (eg, slowed reaction times). 
5. sleep disturbance (eg, drowsiness). 
c) No abnormality on standard structural neuroimaging studies, if such neuroimaging 
studies are completed for a clinically-indicated reason. Note: neuroimaging is not a 
part of this study protocol. Study participants will not undergo neuroimaging as part 
of this study. 
 
Subjects will be randomized in a 1:1 fashion. DHA is an omega-3 fatty acid that occurs naturally in fish 
oil and algae.   There are many dietary supplements containing DHA available in the marketplace. 
Martek Biosciences provides an algae-based DHA compound which minimizes the side effects of 
“fishiness” in both flavor and “fish burps.” The DHA produced by Martek Biosciences is also used for 
many infant formula companies in the US. DHA and identical placebo will be provided by Martek 
Biosciences.


Page 5 of 11 
 
The DHASCO capsules are supplied as 950 mg capsules with an effective dose of 500 mg DHA per 
capsule. The placebo capsules are supplied as 950 mg capsules consisting of 475 mg corn oil and 475 
mg soy oil. Both DHA and placebo are flavored with sweet orange flavoring and masking agents. 
 
They are supplied in sealed white plastic bottles containing 100-200 capsules per bottle, depending 
on dose. Each bottle has the lot number stamped on it. The capsules will be stored in a dry, locked 
compartment at room temperature (60 to 75 F). Martek’s Quality Assurance department completes 
regularly scheduled chemical and long-term stability analyses on each lot of capsules.  If shipments will 
occur during warmer months, arrangements will be made for capsules to be shipped with ice packs or 
other temporary refrigeration.  Capsules will be dispensed to subjects in separate bottles in quantities 
sufficient to last until their next appointment.   Any unused capsules will be returned to the PI or 
research staff and sent to the pharmacy for destruction in compliance with Children’s regulations. 
 
Subjects will be randomized to 2 g of DHA or matched placebo for 12 weeks.  In order to achieve this 
dose of DHA, subjects will receive 2 950 mg capsules twice a day.  Subjects who cannot tolerate the 
divided dose of 2000 mg per day will be discontinued from the study. 
 
Although much of our knowledge of the pathophysiology of concussion comes from animal models, it is 
believed that the mechanical trauma to the brain causes a sudden disruption in the ionic balances, leading 
to an increase in calcium and an increase in glucose metabolism as cells try to compensate for the 
potassium/calcium imbalance.  This is followed by a period of decreased glucose metabolism which may 
last up to 4 weeks in humans, resulting in continued high levels of calcium which interfere with 
mitochondrial oxidative metabolism.  This decrease in mitochondrial oxidative metabolism appears to 
be biphasic, with improvement seen at 2, followed by a decrease which bottoms out on day 5 and recovers 
around day 10. Other important aspects of the concussive trauma include free radical production, initiation 
of inflammatory responses, and altered neurotransmission. 
 
DHA has several important functions in the brain with relatively few side effects, making it a good option 
for  concussion  treatment.  DHA  is  helpful  in  modulating  ion  channels;  higher  levels  of  DHA  are 
associated with higher levels of sodium pump activity, so it is possible that providing DHA post-injury may 
help the cells reduce the calcium balance more quickly or efficiently.  DHA also has an apparent anti-
inflammatory action. DHA interferes with the inflammatory arachidonic acid cascade by reducing the 
affinity of platelet TxA2/PGH2  receptor for its ligand. Additionally, higher levels of DHA in the 
cerebral cortex cause significantly higher levels of the anti-oxidant enzymes catalase, glutathione and 
glutathione peroxidase -- resulting in decreased cerebral levels of lipid peroxides. DHA reduces formation 
of the peroxynitrite free radical and reduces formation of pro-inflammatory cytokines by inhibiting 
transcription factor NF−κB   and inducible nitric oxide synthetase. Finally, DHA is highly concentrated in 
synapses, indicating a role in synaptic signal transduction. DHA appears to address many different 
aspects of how we believe concussive injury affects the brain. 
 
The primary outcomes of this feasibility trial are to determine the willingness of patients to be randomized, 
the expected rate of enrollment based on the clinic population, and protocol adherence of enrolled study 
participants. We anticipate the results from this study will provide data to inform a larger randomized trial 
of DHA for the treatment of pediatric sports concussion. Secondary outcomes are  time to clearance to 
return to play (in days) and improvement in balance, as assessed by the Balance Error Scoring System 
(BESS) which is a component of the Sport Concussion Assessment Tool 3 (SCAT-3). Time to clearance 
to return to play was chosen as a clinically significant measurement for medical professionals in the sports 
medicine field. The investigators will determine clearance for return to full competitive  game  play  (Stage  
6  of  graduated  return  to  play  protocol)  according  to  Consensus Statement guidelines and following 
the law in Texas, House Bill 2038. Criteria for return to play include complete clinical recovery from the 
concussion including returning to baseline symptoms, exam and


Page 6 of 11 
 
neurocognitive function and successful completion of a gradual return to play progression. The BESS 
was chosen because it is a relatively simple assessment that has been noted by the investigators to be 
a good predictor of neurological recovery. 
 
In addition to time to return to play and the BESS, the SCAT-3 and Immediate Post Concussion 
Assessment and Cognitive Testing (ImPACT) computerized neurocognitive testing programs will be used 
to evaluate recovery.   The SCAT-3 is a standardized method of evaluating injured athletes for 
concussion and can be used in athletes aged from 10 years and older. The ImPACT program is a 
computerized exam that helps to quantify the degree of symptom, injury, or dysfunction that occurs 
after a sports related concussion.  Although this test is utilized by many professionals, college, and high 
school sports programs throughout the country, it is unclear if its use contributes to a safer or more 
expedited return to activity. 
 
Finally, information on side effects will be collected at every visit in order to track the rate and severity 
of side effects in this patient population. 
 
We plan to enroll 40 subjects for this study, which consists of 20 subjects to be treated with DHA and 
20 subjects to be treated with placebo.   In order to achieve enrollment of  40 total subjects, we 
anticipate screening 80 subjects in order to consent 40.  Because this is a pilot study, information on 
early withdrawals is important to us and no extra subjects will be consented due to this.  We anticipate 
that it will take approximately 12 months to complete enrollment, with an additional 3 months for patient 
follow-up once the last patient has been enrolled.   We anticipate that it will take approximately 6-9 
months to complete data clean-up, analysis, and manuscript submission for total study duration of 2 
years. 
 
Subjects who are non-compliant with the protocol either by not keeping appointments or by not taking 
study pills as directed may be discontinued from the study.  Subjects who do not tolerate the minimum 
dose of 2000 mg of DHA per day or who experience intolerable side effects will be discontinued. Subjects 
who choose to withdraw consent will be discontinued early. 
 
 
 
4. Study Procedures: 
Subjects presenting with a new concussion within 4 days of their initial injury will be identified and 
screened for eligibility from the investigators’ regularly scheduled clinic patients. Once a patient has been 
identified, the PI or research personnel will approach the family for consent.  Patients who choose not to 
participate will continue to receive clinically indicated care. 
 
Subjects  who  enroll  will  complete  5  scheduled  visits,  although  additional  visits  may  be  clinically 
indicated for symptom evaluation and treatment. All assessments done for this study are routinely done 
as part of the standard clinic visits for concussion at the Sports Medicine Center. 
 
At Visit 1, the patient will sign the consent form and complete the SCAT-3, ImPACT, and concussion 
assessment questionnaire.  The ImPACT computerized test has standardized scores for subjects in the 
age  range for  the population and is  used clinically to  assess  neurocognitive  deficits  after  sports 
concussion.   The concussion assessment consists of  medical history, symptom assessment, and 
sports and school activity components. Subjects will be randomized to either DHA or placebo in a 1:1 
ratio, and receive enough DHA or placebo capsules to reach the target dose of 2 g of DHA per day (or 
placebo) until the day of their next appointment. Subjects will be instructed to take 2 capsules at breakfast 
and 2 capsules at dinner (with food). Subjects will take their first dose in the office to assure their ability 
to swallow the pills.  Subjects will be instructed to bring their pill bottle with any remaining pills with 
them to their next research visit. This visit will last approximately 90 minutes.


Page 7 of 11 
 
Visit 2 will occur 7 days after enrollment (+/- 2 days).  Subjects will complete the SCAT-3 and ImPACT 
at this visit. Subjects will also be asked if they are experiencing any side effects.   At this visit, the 
research personnel will count how many capsules remain in the bottle, and enough additional capsules 
will be dispensed to last a week, until the next scheduled visit. This visit will last approximately 90 minutes. 
 
Visit 3 will occur at 2 weeks after enrollment (+/- 2 days).  Subjects will again undergo the SCAT-3 and 
ImPACT, and be asked about side effects. The research personnel will count the capsules returned and 
the patient will receive enough capsules for another 2 weeks, until their next appointment. This visit will 
last approximately 90 minutes. 
 
Visit 4 will occur at 4 weeks after enrollment (+/- 2 days). Subjects will complete the SCAT-3 and ImPACT 
at this visit, and be asked if they are experiencing any side effects.  The research personnel will count 
the capsules returned and the patient will receive enough capsules for another 8 weeks, until their next 
appointment. This visit will last approximately 90 minutes. 
 
Visit 5/Exit, the final visit, will occur at 12 weeks (+/- 2 days).  Subjects will complete the SCAT-3, and 
ImPACT test. Research personnel will count the capsules returned, and any unused capsules will be 
stored until the expiration date or end of the study, whichever comes first, then all returned stock will be 
turned over to the pharmacy for destruction. If subjects choose to withdraw early or are terminated for 
lack  of  protocol  compliance,  they  will  be  asked  to  return  for  this  final  visit.  This  visit  will  last 
approximately 90 minutes. 
 
In addition to the office visits listed above, the patient will be contacted by phone at week 8 to see how 
the patient is doing, assess study capsule supply, and answer any questions the patient or family currently 
have.  This phone contact will last approximately 5-10 minutes. 
 
Patient participation in this research will last approximately 12 weeks.   If patients require additional 
clinically indicated visits, data from any assessments done during these visits will be collected. Subjects 
are not responsible for research costs (DHA or placebo capsules), but will be responsible for the portions 
of their visits that are clinically indicated (Visit 1 ImPACT testing, all SCAT-3, BESS, and concussion 
assessments, and visit 5 ImPACT testing if clinically indicated). Subjects (or their insurance companies) 
will be charged for visits that are clinically indicated (i.e., Visits 1-4) but will not be charged for the DHA 
or placebo capsules, or Visit 5 unless that visit is clinically indicated by the patient’s course of recovery. 
 
In addition, subjects who are released to play prior to Visit 4 (4 weeks post-enrollment) will not be 
asked to return for additional weekly visits, but instead will be asked to complete a symptom questionnaire 
and answer questions about side effects online via MyChart in lieu of these visits. Once patients have 
returned to their baseline and are returned to play, there is no need for additional visits for well subjects. 
As a safety precaution, subjects will fill out symptom questionnaires and a side effects scale so that if a 
patient does worsen, additional clinical follow-up may be scheduled. This does not place the patient at 
additional risk, and encourages protocol compliance as subjects will not be required to miss additional 
school or other activities for appointments that are not clinically necessary.  Subjects will receive follow-
up phone calls to remind them to complete these forms online. Subjects will still be asked to return for 
visit 5, but will not be charged for this visit if it is not clinically indicated.


Page 8 of 11 
 
5. Criteria for Inclusion of Subjects: 
1.  Male or females age 14-18 inclusive 
2.  Diagnosed with concussion due to sports-related injury. Concussion is defined as: 
a)  Direct blow to the head, face, neck or a blow elsewhere on the body with an “impulsive” 
force transmitted to the head. 
b)  Rapid onset of short-lived impairment of neurologic function in one or more of the following 
clinical domains that resolves spontaneously: 
i.  Symptoms:  somatic  (eg,  headache),  cognitive  (eg,  feeling  like  in  a  fog  and/or 
emotional symptoms (eg, lability). 
ii.  Physical signs (eg, loss of consciousness, amnesia). 
iii.   Behavioral changes (eg, irritability). 
iv.   Cognitive impairment (eg, slowed reaction times). 
v.    Sleep disturbance (eg, drowsiness). 
c)  No abnormality on standard structural neuroimaging studies, if such neuroimaging studies 
are completed for a clinically-indicated reason. Note: neuroimaging is not a part of this 
study protocol. Study participants will not undergo neuroimaging as part of this study. 
3.  Concussion within 4 days of enrollment 
4.  Presenting for treatment to the Sports Medicine Center at Children's Medical Center 
 
 
 
6. Criteria for Exclusion of Subjects: 
1.  Subjects not actively participating in an organized sport at time of enrollment 
2.  Subjects who received a concussion from an event other than playing a sport (motor vehicle 
accident, fall, etc.) 
3.  Subjects who participate in or received a concussion during participation in motorized sports 
(i.e., motorcross, dirt biking, jet skiing, etc.) 
4.  Subjects with radiographic evidence of traumatic brain injury (i.e., skull fracture, intracranial 
hemorrhage, cerebral contusion, etc). 
5.  Subjects with a prior diagnosed concussion in the previous 6 months. 
6.  Pregnant women. 
7.  Subjects sensitive to aspirin 
8.  Subjects diagnosed with high blood pressure and currently being treated with blood pressure 
medications 
9.  Subjects allergic to soy bean oil or corn oil. 
10. Subjects currently taking fish oil or DHA supplements. 
 
 
 
7. Sources of Research Material: 
Data collected for this research will come from the SCAT-3, concussion assessment questionnaire, 
ImPACT testing results, and the medical record. All of the assessments used for this research are 
routinely collected during regular clinic visits for pediatric concussion subjects. As such, there is no 
additional burden on patients or families for time to complete assessments. Data will be prospectively 
collected, after consent and enrollment, from both patient medical records and directly from patients. 
 
 
 
8. Recruitment Methods and Consenting Process: 
Patients will be recruited from the population presenting to the Sports Medicine Center located at 
Children’s Medical Center. Patients will be recruited from all clinical locations including Dallas, Legacy, 
and Southlake. All eligible patients will be patients of the investigators, as they are the primary physicians 
at the Sports Medicine Center.


Page 9 of 11 
 
Each morning, the patient schedule will be reviewed by research personnel and any new potential 
concussion patients identified.  A HIPAA waiver will be obtained for the purposes of screening so that 
researchers may pre-screen based on any history provided (i.e., mechanism of injury, MRI/CT results, 
allergies on file, date of injury if available) and age. 
 
Once identified, patients will be seen for their regular appointment. If a diagnosis of concussion is 
made, either the investigator or the research coordinator will approach the family in the exam or 
consultation room to ascertain if there is interest in the research study. The informed consent form will be  
fully  explained  to  both  the  parent  and  the  child,  and  if,  after  reading  the  consent  form  and 
considering the study, the family wishes to participate, both parental consent and child assent will be 
obtained. Non-English speaking subjects may be consented using the Spanish short form and an 
interpreter. 
 
All information gathered during the screening process will be either destroyed upon screen failure or the 
patient’s choice not to participate, or stored in the patient’s research file.  Paper files are stored in a 
locked filing cabinet in a locked, restricted access room. Electronic files will be stored inRedCap, which 
is a secure data capturing web-based application. The login is password protected and the study can 
only be accessed by approved study members. . In order to ensure the privacy of patients during 
consent,  the  researchers  will  speak  to  the  families  in  either  a  private  exam  room  or  a  private 
consultation room. 
 
Although patients may be approached to participate by the treating physician, it will be made clear to both 
the patient and the family that participation is voluntary and that the decision not to participate does 
not impact their level of care at the Sports Medicine Center or Children’s Medical Center. There is no 
monetary incentive for participation in this study, and the assessments are the same as the routinely used  
assessments  for  this  clinic.  None  of  the  investigators  has  a  financial  interest  in  Martek Biosciences, 
nor is Martek Biosciences providing any monetary funding for this research. 
 
As mentioned previously, children will be required to provide written assent before participating in this 
research.  The inclusion criteria for this study includes only children older than 10.  Children who are 18 
at the time of their appointment may provide informed consent for themselves. 
 
 
 
9. Potential Risks: 
Burping or fishy after-taste have been infrequently reported. In clinical studies with DHASCO, these 
mild gastrointestinal side effects may be reduced by taking capsules with food. Other mild gastrointestinal 
symptoms such as diarrhea have been reported infrequently, but the incidence of these AEs is not 
different from that observed in subjects receiving placebo. DHA supplementation may result in modest 
elevations of LDL-C and non-HDL-C in some individuals. However, the increased level of LDL-C was 
associated with a shift of lipoprotein particle size toward larger, less atherogenic subfractions. In 
summary, adverse event monitoring revealed an excellent safety and tolerability profile for DHASCO. 
 
There are no known serious side effects from taking DHA.  However, based on the experiences of 379 
men and women, both children and adults, the following side effects occurred at a greater rate than in 
placebo and in greater than 2% of participants: burping (17.7%), headache (8.97%), bad taste in the 
mouth (7.65%), back pain (3.43%), abdominal distension (2.11%), and weight increase (2.11%). 
 
Patients taking placebo may also experience side effects.  These side effects occurred more frequently 
than DHA and in greater than 2% of participants, and are based on the experiences of 200 men and 
women, both children and adults, who took placebo during clinical trials of DHA: diarrhea (10%), flatulence 
(excessive gas; 8.5%), common cold (7%), upper respiratory infection (6%), upset stomach


Page 10 of 11 
 
(4%), nausea (3.5%), rash (3.5%), increased blood triglycerides (3%), frequent bowel movements 
(2.5%), cough (2.5%), stomach flu (2%), influenza (2%), and contact dermatitis (2%). 
 
 
 
10. Subject Safety and Data Monitoring: 
All patients will receive standard clinical treatment for concussion. Participation in this study does not 
preclude additional treatment for  concussion as  indicated,  including, but  not  limited to,  additional 
medications for headache, referrals for neurological or neuropsychological consultations, or other 
medications or consultations as deemed clinically appropriate. Patients with no diagnostic imaging studies 
for the current concussion who are later referred for imaging and found to have radiographical evidence 
of acute traumatic brain injury may continue on the study, but will also be referred for appropriate care as 
necessary based on imaging (i.e., referrals to neurology, neurosurgery, etc, as clinically indicated). 
 
The PI will monitor the safety of this protocol by reviewing adverse events. The patient or patient 
guardian(s) may request removal from the study, and this request will be honored. 
 
In addition, a data safety monitoring board consisting of Dr. Pam Okada, a pediatric emergency 
medicine physician at Children’s Medical Center, and a second Children’s Medical Center physician 
appointed by Drs. Okada and Miller. The Board will meet to review protocol compliance and safety data 
at the 50% and 100% enrollment points. An additional meeting will be triggered by any patient 
experiencing a severe adverse event. Statistics and reports will be prepared by a staff statistician. 
 
 
 
11. Procedures to Maintain Confidentiality: 
Any information obtained in connection with this research that can potentially identify a subject will remain 
confidential and be disclosed only with the permission of the subject or his/her parents or guardians.;. 
Data forms will be kept in locked file cabinets. Subject data will be entered into a password-secured 
database that can be accessed only by the investigators. Data will be deidentified at the time of data 
analysis, and In order to maintain confidentiality, each subject will be given a unique identification number. 
Keys linking subject names with identification numbers will be kept in a locked file within the Sports 
Medicine Center at TSRH. Information will be disclosed in a de-identified manner to the following study 
members: pharmacy staff and data analysis personnel. Collected information will be used exclusively in 
the context of this study. 
 
 
 
12. Potential Benefits: 
Patients who receive DHA may experience a faster recovery from concussion and a quicker return to 
play time, or they may experience no benefit.   This study may inform future treatment studies for 
pediatric concussion, which could benefit future pediatric concussion patients. 
 
 
 
13. Biostatistics: 
This will be a pilot study with 20 patients in each arm. The data will be used to estimate between- and 
within-patient components of variation and preliminary effect sizes in order to design a definitive study. 
Descriptive statistics including mean, median, range, and standard deviation will be calculated for 
global variables. Comparative data analysis will include t-tests and for continuous variables, with Chi- 
Square analysis conducted for nominal data where appropriate. P-values less than 0.05 will be 
considered statistically significant. The primary outcome of time to clearance to return to play and the 
secondary outcome of BESS scores will be analyzed using t-test for continuous variables.


Page 11 of 11 
 
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