Traumatic Brain Injury Clinical Trial
Official title:
PLAY GAME: Post-concussion Syndrome Affecting Youth: GABAergic Effects of Melatonin. A Randomized Double-blind Placebo-controlled Trial of MELATONIN
PURPOSE: The long-term goal of this line of research is to develop rational, biologically
based evidence for the treatment of post-concussion syndrome (PCS) in children. The
objective of this application is to examine the effect of melatonin on the symptoms of PCS
and its neurobiology using integrated neurodiagnostic techniques in children.
OVERVIEW: PCS is a constellation of clinical symptoms including physical (i.e. headaches),
cognitive (i.e. memory), and behavioral disturbances. PCS is associated with significant
morbidity in the child and his/her family), and yet there are no evidence-based medical
treatments available. This suggests an urgent need to develop novel treatment options to
improve outcomes for children suffering from PCS. Melatonin has several relevant mechanisms
of action, and neuroprotective effects. Recent research suggests that the explanations for
persistent PCS symptoms may be due to alterations in neurotransmissions and neuronal
circuitry, particularly involving the dorsolateral prefrontal cortex (DLPFC). Investigators
have two specific aims:
1. To determine if treatment with melatonin improves PCS in children following mild
traumatic brain injury. Hypothesis: treatment of mTBI children with PCS with 3mg or
10mg of oral melatonin for 28 days will result in a decrease in PCS symptoms as
compared with placebo. Effects will be dose-dependent and may be independent of sleep
effects. Methods: A randomized double blind, placebo controlled trial (RCT); Outcome
measure is a PCS symptom questionnaire. A subsequent RCT will then be performed using
the optimal melatonin dose at a second centre.
2. To understand the neurophysiological mechanisms of paediatric PCS and assess any
resultant effects of treatment with melatonin. Methods: A case-controlled study within
the RCT, using functional MRI and Transcranial Magnetic Stimulation to investigate the
neurophysiological properties of paediatric mTBI before and after treatment; Treatment
groups from the RCT will be compared with two control groups: i) normal controls and
ii) asymptomatic mTBI children.
SIGNIFICANCE: This study has the potential to 1) provide a safe and effective treatment for
PCS and 2) will provide valuable information about the neurophysiological properties of the
brain associated with PCS following mTBI in children and how these change with symptom
resolution.
We hypothesize that the treatment of children with PCS following mTBI with 3mg or 10mg of
Melatonin for 28 days will result in a decrease in PCS symptoms as compared with placebo.
Primary research question:
Does the treatment of children with PCS symptoms following mTBI with 3mg sublingual
Melatonin or 10mg of sublingual Melatonin for 28 days result in a decrease in PCS (physical,
cognitive and behavioural) symptoms as compared with placebo?
Secondary research questions:
Is there a dose-response relationship? Is the treatment effect independent of the effect on
sleep?
Research Design:
This study will be conducted as a randomized, double blind, placebo-controlled superiority
trial. Three parallel treatment groups will be examined with a 1:1:1 allocation: 1)
sublingual placebo, 2) sublingual Melatonin 3mg, and 3) sublingual Melatonin 10mg. Groups
will be allocated using a randomization sequence that will be created in variable random
block sizes (multiples of 3: 3, 6, and 9) to aid in concealment of next allocation, using
random number generating software. The primary endpoint is the change on the Post-Concussion
Symptom Inventory Score for parent and adolescent. The design allows for dose dependent
response assessment.
Study Setting: Two academic children's hospitals in Canada Target Population: All children
aged 13 to 18 years presenting to the ED of ACH and CHEO with a mTBI who remain symptomatic
at 30 days post-injury.
Intervention:
Eligible patients will be randomized in equal proportions between three groups: placebo, 3mg
Melatonin and 10mg Melatonin. Medication is taken sublingually one hour before sleep time at
night for 28 days and will be continued even if there is symptom resolution.
Rationale for proposed dosages: Receptor-mediated effects occur at physiological doses
(e.g., in children with chronic insomnia effects are achieved at 0.05-0.15mg/kg). However,
to achieve non-Melatonin receptor mediated effects (e.g. GABAergic effects, direct free
radical scavenging and antioxidant effects) may require supra-physiological doses. 3mg
Melatonin is a standard dose used in clinical practice and lower doses do not achieve the
same analgesic and anxiolytic effects; however, 3mg may be insufficient to saturate
Melatonin receptors and could fall short of the supraphysiological doses we are aiming for
to achieve the non-receptor mediated effects. To do this, a higher dose of 10mg will be used
which is a logarithmical increase and is still in a clinically acceptable range.
Modifications: No serious side effects have been reported with Melatonin treatment at the
above doses. Higher doses (70mg/day) have been used in children with muscular dystrophy with
no adverse events. Occasionally excessive daytime sleepiness has been reported which should
be reported as an adverse event. This usually resolves in a few days. Treatment should
continue unless the sleepiness is problematic for more than 3 days in which case half a
tablet may be tried (after reporting this to the study team).
Adherence:
Administration of study pill will occur at home under the supervision of the parent. When
the study pill is dispensed, the research coordinator will review the importance of
following study guidelines, instructions about taking study pills including timing, storage,
and what to do in the event of a missed dose. Instructions about the purpose, use, and care
of the study pill will be included with the package. Families will be notified that there
will be a pill count at every study visit and the importance of calling the clinic if
experiencing problems possibly related to study product such as symptoms, or lost pills.
Methodologies to maximize follow-up and compliance include convenient follow-up times,
participant engagement strategies (e.g. newsletters, website) and experienced research
personnel.
Adherence assessments will include a daily diary, and abreview of the medication log, pill
count every week, and a review of reasons for non-compliance. Unused tablets will be counted
and recorded on the appropriate case report form.
Concomitant care: There are no restrictions on the use of other medications. All
participants will be advised to try to avoid analgesia overuse. Participants will be asked
to complete a diary of any medications, medical appointments and alternative therapies.
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