PLAY GAME trial: Post Concussion in Youth

Randomized, placebo-controlled trial of Melatonin

Dr. Karen M. BarlowAssociate Professor of Pediatric Neurology

Director of the Alberta Children’s Hospital TBI Research Program

Melatonin Mechanisms of action

• lipophilic and crosses BBB easily

• receptor-mediated (physiological levels)– MT1 and MT2– retinoid orphan nuclear hormone receptors

• cell differentiation and immune response

• non-receptor mediated (physiological and supraphysiological)– broad spectrum, direct free radical scavenger and

antioxidant

Melatonin:Mechanisms of action

• Neuroprotective• GABAergic effects• Modulates neuroinflammation

• Pain• Anxiety• Sleep

Melatonin in TBI models• decreases brain edema, BBB permeability and ICP - inhibition of

oxidative stress (Kabadi 2010; Dehghan 2013) • Increased antioxidant enzymes, and in particular lowering lipid

peroxidation (Kerman 2005; Beni 2004, Ozdemir 2005)

• decreases oxidative stress, inactivation of transcriptional factors (cytokine signaling) (Tsai 2011)

• prevented tau hyperphosphorylation (Gutierrez-Cuesta 2007)

• MEL and dexamethasone reduction in lesion size less apoptosis (Campolo 2013);

• MEL and MIN – no effect (Kelso, 2011)

• Melatonin has been registered in 203 trials with clinicaltrials.gov

• 75 trials ongoing– HIE– Stroke– IUGR– Acute MI– Oncology

Safe

No significant complications Does not suppress endogenous production

Dose?– Speculative – 3mg saturates receptors– Non-receptor mediated require higher levels– Neonatal studies 10mg/kg/dose over 2 hours

with repeated dosing over 72 hours.

Neonatal brain injury

• Open label term neonates with sepsis• decreased mortality

• RCT in HIE term neonates– decreased mortality

• Two RCTs in preterm – decreased mortality (total 230 patients)

Ongoing trials:• PREMELIP trial

– neuroprotective effects (white matter) in very preterm

• Phase II trial – RCT – post-natal melatonin in preterm infants and brain injury

Melatonin in paediatric TBI

• 18 children with mTBI, headaches and sleep disorder

• Time since injury was > 10.6 months post-injury

• Treatment response was assessed every 4 weeks. • Treatment response: significant decrease in

headaches of >50% was considered a response. • 7 children 3-5mg MEL; 11 children 6-10mg MEL

• Response to melatonin 81% – All treatments 64%

PLAY GAME trial: PCS in Youth and the GABAergic effects of

Melatonin

• Randomized double blind placebo controlled trial– Dose dependent response assessment – parallel group design

• Placebo• 3mg melatonin• 10mg melatonin

• Use adjunctive techniques (integrating fMRI, DTI and TMS) to elucidate alterations in neuronal function and circuitry (including Cortical Excitation)

Protocol30-40 days post TBI

Symptomatic

Placebo

3mg Melatonin

10mg Melatonin

Asymptomatic

Normal

AssessmentsPre-treatment(4-6 weeks post-TBI)

• PCSI• CHQ, BASC,

BRIEF• Cognitive• Actigraphy• MRI

• fMRI, DTI, MRS (H and GABA)

• TMS• cortical

excitability

28 days treatment

• Mid-treatment

• PCSI• Actigraph

y

Target Population• All children aged 8 to 18 years symptomatic at 30

days post-injury• Inclusion criteria:

– Symptomatic (increase in PCS symptoms compared with pre-injury status) at 30 days post injury.

• Exclusion criteria– Previous significant medical history, or previous

concussion within 3 months– Use of drugs that are likely to affect TMS, fMRI

and/or sleep– Contraindications to MRI or TMS

Trial Progress– Trial documentation, registration and committees

established– Health Canada/Ethical approval August 2013– 5p study November 2013– Recruitment started December 2013

– Bi-monthly Trial Steering Committee meetings– DSMB met April 2013

– Slow recruitment• 13 participants to date

» No withdrawals or adverse events

• HCT-Amendment to double potential participants– Age range increased 8 – 18 years– If Previous concussion > 3 months prior

Acknowledgementswww.playgametrial.ca

• Deborah Dewey – Co-PI• Brenda Turley – Trial

coordinator

• Brian Brooks – Neuropsychology• Adam Kirton – TMS• Val Kirk – Sleep dysfunction• Frank MacMaster – fMRI/MRS• Michael Esser – Translational models• Alberto Nettel-Aguirre – Biostatistics • Susan Crawford – Biostatistics• Jeff Buchhalter – Medical advisor• Angelo Mikrogianakis – ED medicine• David Johnson – Clinical trials• Roger Zemek – Ottawa site

Collaborators• Lisette Lockyer• Carolyn Emery (independent

advisor)DSMB• Jamie Hutcheson• Robert Platt• Lawrence Richer

Post-grad Students• Trevor Seegor • Angela Villavincencio-Requis