Melatonin for Pediatric Traumatic Brain Injury

(SMARTKids Trial)

Overseen By Andrea Rano, BS

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Oregon Health and Science University

Disqualifiers: Dialysis, Pregnancy, Prisoners, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether melatonin can aid children in recovering from traumatic brain injuries by reducing sleep disturbances. Participants will receive either melatonin or a placebo (a pill with no active medicine) and will also receive sleep education. The study aims to determine if melatonin is feasible and acceptable and if it improves sleep after hospital discharge. Children treated for traumatic brain injury at Oregon Health & Science University may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that melatonin is likely to be safe for children with traumatic brain injury?

Research has shown that melatonin is a safe and well-tolerated treatment for children with sleep problems following a traumatic brain injury (TBI). One study found that melatonin is generally safe for short-term use, with most individuals not experiencing major side effects. Another study demonstrated its effectiveness in addressing sleep issues in children with mild TBI and confirmed its safety for them. Additionally, melatonin may protect brain cells, potentially aiding recovery after a brain injury. Overall, evidence suggests that melatonin is a safe option for helping children with sleep problems during TBI recovery. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Melatonin is unique because it is a naturally occurring hormone known for regulating sleep, now being explored for its potential to aid recovery in pediatric traumatic brain injury (TBI). Unlike standard treatments for TBI, which primarily focus on managing symptoms like headaches and cognitive issues through medications such as pain relievers and anti-seizure drugs, melatonin might help protect the brain from further injury and reduce inflammation. Researchers are excited about this treatment because melatonin’s antioxidant properties could offer a novel approach to healing the brain more effectively and safely, with minimal side effects compared to conventional drugs.

What evidence suggests that melatonin might be an effective treatment for sleep disturbances in pediatric traumatic brain injury?

This trial will compare melatonin with a placebo to assess its effectiveness in children with traumatic brain injuries (TBI). Studies have shown that melatonin improves sleep problems in these children. Research indicates that melatonin not only enhances sleep quality but also helps children sleep longer and more soundly. It possesses important brain-protecting qualities, aiding recovery after a TBI. Melatonin has also been found to alleviate TBI-related insomnia, leading to better behavior and brain health. Overall, melatonin appears promising for reducing sleep issues following a TBI. ^{1 2 3 4 6}

Who Is on the Research Team?

Cydni N Williams, MD, MCR

Principal Investigator

Oregon Health and Science University

Are You a Good Fit for This Trial?

This trial is for children aged 6 to <19 years with traumatic brain injury, who are expected to survive their hospital stay at Oregon Health & Science University Hospitals. They must be able to take medications orally within 72 hours of admission and live with a parent or guardian. Excluded are pregnant individuals, prisoners, those without stable communication means, if there's safety concerns about the intervention by the clinical team, suspected abuse cases, patients on dialysis or ECMO, or significant liver injury.

Inclusion Criteria

I can take medicine by mouth within 3 days of being admitted.

Deemed likely to survive hospitalization by clinical care team

Child participant resides with parent or legal guardian

Exclusion Criteria

Significant liver injury defined as >2x normal levels for AST or ALT

Prisoners

Extracorporeal support (e.g. ECMO)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive melatonin or placebo during hospitalization and continue for 30 days post-discharge

4 weeks

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with outcomes assessed at hospital discharge and 1-month post-discharge

1 month

2 visits (in-person or virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Melatonin
• Placebo

Trial Overview The study tests whether melatonin can help kids recover better from traumatic brain injuries by improving sleep after they leave the hospital. It compares melatonin treatment started in the hospital and continued at home against a placebo (a dummy pill). The effectiveness will be measured using sleep scales and activity monitors one month post-discharge.

How Is the Trial Designed?

Group I: Melatonin Experimental Treatment 1 Intervention

(melatonin doses of 3mg or 5mg based on patient size given nightly 1 hour prior to bedtime every night for 30 days)

Group II: Placebo Placebo Group 1 Intervention

Placebo

Melatonin is already approved in European Union, United States for the following indications:

Approved in European Union as Circadin for:

• Insomnia in adults aged 55 and over
• Sleep disorders in children with autism spectrum disorder

Approved in European Union as Slenyto for:

• Insomnia in children and adolescents aged 2-18 with autism spectrum disorder

Approved in United States as Melatonin for:

• Sleep disorders in children with autism spectrum disorder
• Insomnia in adults

Who Is Running the Clinical Trial?

Oregon Health and Science University

Lead Sponsor

Trials

1,024

Recruited

7,420,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Melatonin can help adults with delayed sleep phase disorder fall asleep earlier, but its use in children is concerning because it is not officially approved for them and lacks formal safety testing.

There are significant safety concerns regarding melatonin's effects on children's reproductive, cardiovascular, immune, and metabolic systems, as well as potential drug interactions, which have not been adequately studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential safety issues in the use of the hormone melatonin in paediatrics. Kennaway, DJ.[2015]

Children with persistent symptoms after a mild traumatic brain injury (mTBI) reported significantly more sleep-related problems compared to those who had recovered and healthy controls, indicating a potential link between ongoing symptoms and sleep disturbances.

Despite the increased sleep-related problems in symptomatic children, there were no significant differences in sleep activity patterns or melatonin production between the groups, suggesting that the biology of sleep disturbances post-mTBI may not be directly related to these factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep Parameters and Overnight Urinary Melatonin Production in Children With Persistent Post-concussion Symptoms. Barlow, KM., Girgulis, KA., Goldstein, G., et al.[2021]

In a 12-week trial involving 146 children with neurodevelopmental disorders, melatonin significantly reduced the time it took for children to fall asleep by an average of 37.5 minutes, while also increasing total sleep time by about 22.4 minutes according to parent-reported diaries.

While melatonin improved sleep onset, it resulted in earlier waking times and did not lead to significant improvements in child behavior or family functioning, indicating that while it is safe and tolerable, its overall impact on sleep quality may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. Gringras, P., Gamble, C., Jones, AP., et al.[2022]

Melatonin treatment (3 mg) significantly reduced sleep-related problems in youth with persistent post-concussion symptoms (PPCS) after mild traumatic brain injury (mTBI), showing a notable improvement compared to placebo.

Short-term melatonin use was well-tolerated and also associated with a decrease in depressive symptoms, indicating potential benefits beyond just sleep improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Melatonin for Sleep Disturbance in Children with Persistent Post-Concussion Symptoms: Secondary Analysis of a Randomized Controlled Trial. Barlow, KM., Kirk, V., Brooks, B., et al.[2022]

A study involving 99 youths aged 13 to 18 with post-concussion syndrome will test the efficacy of sublingual melatonin (3 mg and 10 mg) over 28 days, aiming to reduce symptoms associated with mild traumatic brain injury.

Melatonin is considered a safe treatment option with potential neuroprotective effects, and this trial will assess its impact on not only symptom relief but also neurobehavioral function and quality of life in affected children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Barlow, KM., Brooks, BL., MacMaster, FP., et al.[2021]

A systematic review of literature on melatonin for treating sleep issues in children after acquired brain injury found only seven relevant studies, indicating a lack of high-quality evidence in this area.

While the existing evidence suggests that melatonin may be effective for sleep impairment following pediatric ABI, inconsistencies in dosage and study quality highlight the need for more rigorous research to establish clear treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of melatonin for sleep impairment post paediatric acquired brain injury: evidence from a systematic review. Keegan, LJ., Reed-Berendt, R., Neilly, E., et al.[2018]

A systematic review of three randomized clinical trials involving 35 children with neurodevelopmental disabilities found that melatonin significantly reduced the time it took for children to fall asleep compared to a placebo.

However, melatonin did not show significant effects on total sleep time or the number of awakenings during the night, indicating that while it may help with sleep onset, its overall impact on sleep quality remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment. Phillips, L., Appleton, RE.[2019]

A follow-up study of 44 children with neurodevelopmental disabilities showed that long-term melatonin therapy was well-tolerated, with no adverse reactions or development of tolerance reported over a period of up to 3.8 years.

Caregivers noted significant improvements in sleep quality, which correlated with better health, behavior, and learning outcomes, suggesting that melatonin can be an effective treatment for children with treatment-resistant circadian rhythm sleep disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. Carr, R., Wasdell, MB., Hamilton, D., et al.[2013]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29901413/

Melatonin as a Treatment after Traumatic Brain Injury In conclusion, there is evidence that melatonin treatment after TBI significantly improves both behavioral outcomes and pathological outcomes; ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10123665/

Traumatic Brain Injury, Sleep, and Melatonin—Intrinsic ... However, melatonin has been shown to be effective at treating children with TBI-associated insomnia [145] and was also independently shown ...

3. publications.aap.org publications.aap.org/pediatrics/article/145/4/e20192812/36981/Efficacy-of-Melatonin-in-Children-With

Efficacy of Melatonin in Children With Postconcussive ... Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0003999322016562

The Utility of Melatonin for the Treatment of Sleep ... Significant improvements in subjective sleep quality, objective sleep efficiency, and total sleep time were found with melatonin. Reductions in self-reported ...

5. journals.sagepub.com journals.sagepub.com/doi/full/10.1089/neu.2020.7154

Efficacy of Melatonin for Sleep Disturbance in Children with ... Melatonin improved sleep disturbance in children and adolescents with persistent post-concussion symptoms following mild TBI. SRPs decreased gradually during ...

6. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/1745-6215-15-271

A double-blind, placebo-controlled intervention trial of 3 and ... The aim of this study is to determine if treatment with melatonin improves post-concussion syndrome in youths following mild traumatic brain injury.