Post concussion syndrome in youth:

the GABA- effects of melatonin

Play Game Trial

Rationale: There are no evidence-based pharmacological treatment trials for PCS in children. In preliminary work, we found that children with prolonged PCS and headaches had a significant response to sublingual melatonin treatment (168,162,163).

Melatonin’s therapeutic potentials in mTBI include:

1) as a free radical scavenger and broad-spectrum antioxidant (92,117-119,126) and  2) symptomatically via the GABAergic system and opiate receptors (106,136,137,149,150) .

An absence of overt clinical symptoms does not always coincide with brain metabolic recovery following mTBI (14). A key rationale to this trial is that we are proposing a treatment that both may improve clinical symptoms but will also objectively monitor neurophysiological alterations in neuronal circuitry and cortical inhibition over time. Thus this will be the first study to systematically assess a pharmacotherapy in mTBI children and will concurrently provide biological markers for monitoring neuronal recovery.
 
Aim 1: To determine if treatment with melatonin improves PCS following mTBI.
Hypothesis 1: We hypothesize that the treatment of children with PCS following mTBI with low dose or high dose of sublingual melatonin for 28 days will result in a decrease in PCS symptoms as compared with placebo.

Research Questions

Does the treatment of children with PCS symptoms following mTBI with sublingual melatonin for 28 days result in a decrease in PCS (physical, cognitive and behavioural) symptoms as compared with placebo?
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 trial.
Three treatment groups will be examined: 1) sublingual placebo, 2) sublingual melatonin low, and 3) sublingual melatonin high. The design allows for dose dependent response assessment. This is a single centre study recruiting patients over 3 years.

Methods:
Target Population: All children aged 8 to 18 years presenting to with a mTBI who remain symptomatic at 30 days post-injury and consent to the study will be eligible.

Inclusion criteria:
1.Concussion as defined by the American Academy of Neurology: trauma-induced alteration in mental status that may or may not involve loss of consciousness (LOC) and
2.Symptomatic (increase in PCS symptoms compared with pre-injury status) at 30 days post injury.

 Exclusion criteria
1.Previous significant medical history, or previous concussion within 3 months
2.Participant in a natural history study of concussion
3.Lactose intolerance, as the placebo contains lactose
4.Use of drugs that are likely to affect TMS, fMRI and/or sleep
5.Inability to complete questionnaires/evaluation e.g. non-English language


Ethics ID: REB13-0372 Title: Play Game: Post -concussion syndrome Affecting Youth: GABAergic effects of Melatonin
Version 2.1 Date: May 15, 2014

Rationale

Study Design

Randomization and protection against bias:

Groups will be allocated using a randomization sequence that will be created in variable random block sizes (multiples of 3: 3, 6, 9, 12) to aid in concealment of next allocation, using random number generating software. An epidemiologist who is not connected with the trial will keep the resultant master list. The research pharmacist will receive the list and keep it concealed except under directions from the Data Safety Monitoring Committee. The active drugs and placebo will be packaged identically. The pharmacy will prepare sequential patient packets containing study treatments in sealed, opaque numbered bags.

In order to assess the accuracy of the blinding, the physician, RA, parent and child will be asked at the end of treatment and day 90 to indicate which drug they believe the patient received. To ensure no switching of bags, once a patient has been given the study number, the holder of the list will log patient initials, coupled with the study number.


Medication is taken one hour before sleep time at night. Treatment will be continued for 28 days even if there is symptom resolution.


Sample Size
The main objective and hypothesis is based on the difference between the placebo and the low dose melatonin groups. The outcome of interest is the change in the PCSI-P score (day 30 minus day 59) and calls for a test of means between groups using Analysis of Variance (ANOVA). We find that in practice a 10-point PCSI change is clinically significant. Using a significance level alpha of 0.05, expecting a power of 80%, assuming a within group standard deviation of 14.7 and using as an effect size a difference between groups of 10, a sample size of 30 per group is required. Allowing for a 10% attrition rate, 33 participants per group are required

Post Concussion Symptom Inventory – Youth and Parent (PCSI-P). This standardized questionnaire of symptoms provides an overall rating of PCS. It has four specific domains: physical, cognitive, emotional and fatigue and a high level of internal consistency reliability, alpha=0.92 (175,176). Parent and youth PCSI scores correlate (2,175). Low symptom rates are found in normative samples (177). The version for youth will also be recorded (PCSI-Y). Change in PCSI scores allows us to account for baseline variability and gender (178). The PCSI-P will be repeated approximately 21, 30, 44 and 59 and 90 days post-injury.

Secondary Outcomes (Appendix 1):
1.PCSI-Y (parent): completed around 21, 30, 44, 59 and 90 days post-injury.
2.Child Health questionnaire (CHQ): Parent and child rating of functional impairment will be obtained using the 50-item Child Health Questionnaire, parent CHQ-PF50 and child, CHQ-CH87 (179,180). The reliability and validity is established in TBI (181-184).

3.Behavior Assessment System for Children-2 (BASC-2) is a standardized parent report measure of child behavior consisting of 150 items. It provides an indication of internalizing and externalizing behaviour (e.g., anxiety, depression). Items are rated using true-false, or a 4-point ordinal scale. The internal consistency for the composite subscales range from .87 to .96 and test-retest reliability is high, ranging from .81 to .96 (10–20 minutes) (185,186).
4.The Behavior Rating Inventory of Executive Function (BRIEF) The BRIEF (Gioia, Isquith, Guy, & Kenworthy, 2000) is an 86-item standardized questionnaire that allows for ratings of problems with daily executive abilities (ratings range from “never” to “always”). It is applicable for 5-18 years of age, takes 10-15 minutes, and has normative values (age and gender adjusted) based on 1419 children and adolescents. There are eight clinical scales (inhibit, shift, emotional control, initiate,working memory, plan/organize, organization of materials, and monitor), two summary indices (behavioural regulation and meta-cognition), a total or summary executive score (global executive composite), and two validity indices (negativity and inconsistency). The BRIEF has strong internal consistency (alpha=.82-.98), adequate retest reliability (r=.76-.88), strong correlations with other behavioural and objective measures, and has demonstrated validity in children and adolescents who have sustained traumatic brain injuries (Donders J, DenBraber D, Vos L, 2010).
5.The TOMM (Tombaugh, 1996) is a forced-choice visual recognition memory test designed to detect poor compliance with testing. Several studies have demonstrated the validity of the TOMM in pediatric patients.

Randomization

Randomization

Outcome measures

Statistical Analysis

Baseline demographic and clinical variables will be examined for group differences using ANOVA for continuous variables and chi square tests for categorical variables. Subsequent analyses will involve controlling for possible confounding factors. All
analyses will be done on an intent-to-treat basis (last observation carried forward). Group differences in the change in PCSI-P scores will be analyzed using ANOVA, with placebo,low melatonin and higher melatonin as groups. Estimates and corresponding 95% confidence intervals for the a-priori set pair wise comparisons of interest will be provided. Time to symptom resolution (as defined by a PCSI-P score equal or less than pre-injury) will be examined using the Cox proportional hazards model.


Adverse events will be tabulated. Complete documentation will be kept on “non-completers”, including their reasons for noncompletion. Differences between randomized groups for early termination will be descriptively reported. A secondary efficacy analysis will be done on “completers” per protocol only, excluding protocol violations.


Analyses of secondary outcomes will examine group differences with a series of ANOVAs examining changes in scores for: 1) change in PCSI-Y, 2) CHQ (parent and child), 3) BASC-2 (parent) 4) sleep parameters 5) cognition (CNS Vital Signs battery: attention, executive functioning, and reaction time, processing speed). Hierarchical
multiple regression modeling will be used to predict symptom improvement, by entering sleep parameters (Step 1), and treatment group (Step 2) in order to determine how predictive treatment is above and beyond any effects of melatonin on sleep. Bonferroni correction will be used for post hoc analysis.


Frequency of Analysis: The primary analysis will be performed annually given the usual ethical (i.e., providing treatment that is less effective) and efficiency (i.e., waste of resources) considerations (195) under the direction of the Data Safety Monitoring Committee by an independent biostatistician. Subgroup analysis will be based on the following dichotomies: personal or family history of migraine, loss of consciousness, and previous history of concussion.

Post Concussion Symptom Inventory – Youth and Parent (PCSI-P). This standardized questionnaire of symptoms provides an overall rating of PCS. It has four specific domains: physical, cognitive, emotional and fatigue and a high level of internal consistency reliability, alpha=0.92 (175,176). Parent and youth PCSI scores correlate (2,175). Low symptom rates are found in normative samples (177). The version for youth will also be recorded (PCSI-Y). Change in PCSI scores allows us to account for baseline variability and gender (178). The PCSI-P will be repeated approximately 21, 30, 44 and 59 and 90 days post-injury.

Secondary Outcomes (Appendix 1):
1.PCSI-Y (parent): completed around 21, 30, 44, 59 and 90 days post-injury.
2.Child Health questionnaire (CHQ): Parent and child rating of functional impairment will be obtained using the 50-item Child Health Questionnaire, parent CHQ-PF50 and child, CHQ-CH87 (179,180). The reliability and validity is established in TBI (181-184).

3.Behavior Assessment System for Children-2 (BASC-2) is a standardized parent report measure of child behavior consisting of 150 items. It provides an indication of internalizing and externalizing behaviour (e.g., anxiety, depression). Items are rated using true-false, or a 4-point ordinal scale. The internal consistency for the composite subscales range from .87 to .96 and test-retest reliability is high, ranging from .81 to .96 (10–20 minutes) (185,186).
4.The Behavior Rating Inventory of Executive Function (BRIEF) The BRIEF (Gioia, Isquith, Guy, & Kenworthy, 2000) is an 86-item standardized questionnaire that allows for ratings of problems with daily executive abilities (ratings range from “never” to “always”). It is applicable for 5-18 years of age, takes 10-15 minutes, and has normative values (age and gender adjusted) based on 1419 children and adolescents. There are eight clinical scales (inhibit, shift, emotional control, initiate,working memory, plan/organize, organization of materials, and monitor), two summary indices (behavioural regulation and meta-cognition), a total or summary executive score (global executive composite), and two validity indices (negativity and inconsistency). The BRIEF has strong internal consistency (alpha=.82-.98), adequate retest reliability (r=.76-.88), strong correlations with other behavioural and objective measures, and has demonstrated validity in children and adolescents who have sustained traumatic brain injuries (Donders J, DenBraber D, Vos L, 2010).
5.The TOMM (Tombaugh, 1996) is a forced-choice visual recognition memory test designed to detect poor compliance with testing. Several studies have demonstrated the validity of the TOMM in pediatric patients.

Outcome measures

The full trial protocol is published at http://www.trialsjournal.com/content/15/1/271