A Phase 2/3 interventional study of Melatonin and Sugar pill in Post-concussion Syndrome, Post-concussive Symptoms and Traumatic Brain Injury, sponsored by University of Calgary. Status unknown at 1 site in Canada. Open to participants aged 8 Years to 19 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2017-04-18.
Sponsored by University of Calgary · Phase 2/3, Interventional, and Treatment
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:
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.
136 studies on the registry are indexed under Post-Concussion Syndrome; 34 are open to participants now.
This study's enrollment of 99 is above the median of 52 across 112 interventional studies indexed under Post-Concussion Syndrome.
Browse Post-Concussion Syndrome studies →University of Calgary is the lead sponsor of 699 studies on the registry; 192 are open to participants now.
Of its 10 completed or terminated interventional studies of FDA-regulated products, 2 (20%) have results posted.
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Exclusion Criteria:
Melatonin 10mg capsule(high dose arm), oral, once at night, given for 28 days
Dietary Supplement: Melatonin
Sugar Pill, one capsule, once at night, 28 days
Dietary Supplement: Sugar pill
Melatonin 3mg capsule (low dose arm), once, at night, 28 days
Dietary Supplement: Melatonin
Melatonin 10mg or 3mg capsule, one will be given at night, for 28 days
Sugar pill will be given, one capsule, once at night, for 28 days
Change on the Post Concussion Symptom Inventory (PCSI)-(8 - 18 years)
The PCSI is a standardized questionnaire of 26 symptoms provides an overall rating of Post concussion symptoms. It has four specific domains: physical (including headaches), cognitive, emotional (including mood) and fatigue and high level of internal consistency, alpha=0.92. Parent and youth PCSI scores correlate. Low symptom rates are found in normative samples. The version for youth will also be recorded (PCSI-Y). Change in PCSI scores allows us to account for baseline variability and gender.
Time frame: Baseline, 4 weeks and 12 weeks
Number of Patient's Adverse Events
Time frame: 1, 2, 3 and 4 weeks
Change on the Child Health Questionnaire (CHQ)
Parent and child rating of functional impairment will be obtained using the 50-item Child Health Questionnaire, parent CHQ-Parent Form (PF)50 and child, CHQ-Child Form (CF)87. The reliability and validity is established in TBI and PCS.
Time frame: Baseline, 4 and 12 weeks
Change on the Behavior Assessment System for Children (BASC)-2 -Parent
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) (
Time frame: Baseline, 4 and 12 weeks
Change on the Post Concussion Symptom Inventory (PCSI)- Parent questionnaire
The PCSI is a standardized questionnaire of 26 symptoms provides an overall rating of Post concussion symptoms. It has four specific domains: physical (including headaches), cognitive, emotional (including mood) and fatigue and high level of internal consistency, alpha=0.92. Parent and youth PCSI scores correlate. Low symptom rates are found in normative samples. The version for youth will also be recorded (PCSI-Y). Change in PCSI scores allows us to account for baseline variability and gender.
Time frame: Baseline, 2 , 4 and 12 weeks
Plan to share: No — No plan to share IPD
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Studies of the drug tested here: Melatonin