Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01903525 |
| Other study ID # |
STU 042012-055 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
September 2013 |
| Est. completion date |
August 2017 |
Study information
| Verified date |
December 2020 |
| Source |
University of Texas Southwestern Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
