PLAY GAME: Post-concussion Syndrome in Youth - Assessing the GABAergic Effects of Melatonin (PLAYGAME)

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.