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Post-concussion SyndromePhase 2/3PLAYGAMENCT01874847

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

A Phase 2/3 study testing Melatonin and Sugar pill in people with Post-concussion Syndrome and Post-concussive Symptoms, run by University of Calgary at 1 site in Canada.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 8 to 19 yearsHealthy volunteers can take part
What is being tested?
Melatonin and Sugar pill
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
99 participants
Where
1 siteCanada
Study dates
Sep 2013to Sep 2019
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 8 to 19 years
  • All sexes
  • Healthy volunteers accepted
  • Child, Adult

Who may be able to join

  • Concussion/mild traumatic brain injury trauma with an increase in symptoms (increase in PCS symptoms compared with pre-injury status) at 30 days post injury
  • must be able to swallow pills

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

Canada1 site
  • Alberta Children's Hospital

    Calgary, Alberta, T3B6A8

Other trials in Canada

About this study

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:

Read more
  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.

Read the detailed description

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.

Being tested
Melatonin, Sugar pill
Keywords
melatonin, placebo, post-concussion syndrome, mild traumatic brain injury, concussion, treatment, outcome, children, functional magnetic resonance imaging, transcranial magnetic stimulation, sleep
Medical subject headings
Post-Concussion Syndrome, Brain Injuries, Traumatic, Brain Concussion

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MelatoninDietary supplement

    Melatonin 10mg or 3mg capsule, one will be given at night, for 28 days

  • Sugar pillDietary supplement

    Sugar pill will be given, one capsule, once at night, for 28 days

Study groups in NCT01874847
Study groupRoleWhat they receive
Melatonin 10mgExperimentalMelatonin 10mg capsule(high dose arm), oral, once at night, given for 28 days
Receives: Dietary Supplement: Melatonin
Sugar PillPlacebo comparatorSugar Pill, one capsule, once at night, 28 days
Receives: Dietary Supplement: Sugar pill
Melatonin 3mgExperimentalMelatonin 3mg capsule (low dose arm), once, at night, 28 days
Receives: Dietary Supplement: Melatonin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline, 4 weeks and 12 weeks

Secondary outcomes (1)
  1. Number of Patient's Adverse Events

    Measured: 1, 2, 3 and 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jun 2013 (estimated)
  2. Study startSep 2013
  3. Primary completionApr 2017
  4. Study completionSep 2019 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Placebo controlled
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
99 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01874847
Sponsor's protocol ID
TMT-127046
Acronym
PLAYGAME
Status last verified
Apr 2017
First submitted
6 Jun 2013
Last updated
18 Apr 2017
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No: No plan to share IPD

Publications

  • Kuczynski A, Crawford S, Bodell L, Dewey D, Barlow KM. Characteristics of post-traumatic headaches in children following mild traumatic brain injury and their response to treatment: a prospective cohort. Dev Med Child Neurol. 2013 Jul;55(7):636-41. doi: 10.1111/dmcn.12152. Epub 2013 Apr 5.

    PubMed 23560811
  • Barlow KM, Crawford S, Stevenson A, Sandhu SS, Belanger F, Dewey D. Epidemiology of postconcussion syndrome in pediatric mild traumatic brain injury. Pediatrics. 2010 Aug;126(2):e374-81. doi: 10.1542/peds.2009-0925. Epub 2010 Jul 26.

    PubMed 20660554
  • Barlow KM, Brooks BL, MacMaster FP, Kirton A, Seeger T, Esser M, Crawford S, Nettel-Aguirre A, Zemek R, Angelo M, Kirk V, Emery CA, Johnson D, Hill MD, Buchhalter J, Turley B, Richer L, Platt R, Hutchison J, Dewey D. A double-blind, placebo-controlled intervention trial of 3 and 10 mg sublingual melatonin for post-concussion syndrome in youths (PLAYGAME): study protocol for a randomized controlled trial. Trials. 2014 Jul 7;15:271. doi: 10.1186/1745-6215-15-271.

    PubMed 25001947
  • Iyer KK, Zalesky A, Cocchi L, Barlow KM. Neural Correlates of Sleep Recovery following Melatonin Treatment for Pediatric Concussion: A Randomized Controlled Trial. J Neurotrauma. 2020 Dec 15;37(24):2647-2655. doi: 10.1089/neu.2020.7200. Epub 2020 Sep 14.

    PubMed 32772826
  • Barlow KM, Brooks BL, Esser MJ, Kirton A, Mikrogianakis A, Zemek RL, MacMaster FP, Nettel-Aguirre A, Yeates KO, Kirk V, Hutchison JS, Crawford S, Turley B, Cameron C, Hill MD, Samuel T, Buchhalter J, Richer L, Platt R, Boyd R, Dewey D. Efficacy of Melatonin in Children With Postconcussive Symptoms: A Randomized Clinical Trial. Pediatrics. 2020 Apr;145(4):e20192812. doi: 10.1542/peds.2019-2812. Epub 2020 Mar 26.

    PubMed 32217739

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Melatonin and Sugar pill in people with Post-concussion Syndrome and Post-concussive Symptoms, run by University of Calgary at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 18 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change on the Post Concussion Symptom Inventory (PCSI)-(8 - 18 years) (time frame: Baseline, 4 weeks and 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01874847, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2017.

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