DHA For The Treatment of Pediatric Concussion Related to Sports Injury
Condition: Concussion; Mild Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Brain Concussion; Wounds and Injuries; Athletic Injuries
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Docosahexaenoic acid (DHA); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment