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

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Sleep wake disturbances compound recovery in over half of pediatric traumatic brain injury survivors, leading to impaired quality of life, and few effective interventions exist to treat this important morbidity. Therefore, this study will conduct a randomized controlled trial evaluating a melatonin intervention started during hospitalization and continued after discharge compared to placebo. The trial will investigate if this intervention is feasible, acceptable, and effective at reducing sleep wake disturbances as measured on the Sleep Disturbances Scale for Children 1-month after hospital discharge. Participants will be randomly assigned to receive the intervention (melatonin) or to the control group (placebo) with a goal of equal numbers of participants in each group and all will receive sleep education. Participants will be followed closely after consent and outcomes will be assessed at hospital discharge, and 1-month. Outcomes will focus on feasibility (ability to recruit patients into the trial) and acceptability (patient safety and satisfaction), but will also assess the effectiveness of the intervention to reduce sleep disturbances after discharge. The investigators will assess sleep using questionnaires and actigraphy (watch-like activity monitors). Exploratory outcomes will include global health outcomes.

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 melatonin safe for children with traumatic brain injury?

Melatonin is generally well-tolerated in children, with studies showing no serious adverse effects when used for sleep disturbances in youth with post-concussion symptoms and in children with neurodevelopmental disorders. However, long-term safety in children has not been formally tested, and there are concerns about its effects on reproductive and other systems. ^{1 2 3 4 5}

How does the drug melatonin differ from other treatments for pediatric traumatic brain injury?

Melatonin is unique because it is a natural hormone that helps regulate sleep and has potential neuroprotective effects, which may be beneficial for children with traumatic brain injury. Unlike other treatments, it is used to improve sleep disturbances and may also reduce depressive symptoms in these patients. ^{2 3 4 6 7}

What data supports the effectiveness of the drug melatonin for treating pediatric traumatic brain injury?

Research shows that melatonin can help improve sleep disturbances in children with post-concussion symptoms after a mild traumatic brain injury. In a study, children taking melatonin experienced better sleep duration and efficiency compared to those taking a placebo, and it also helped reduce depressive symptoms. ^{2 3 4 6 8}

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 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 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 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 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]

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 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]

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]

Citations

1. United States 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Effectiveness of melatonin for sleep impairment post paediatric acquired brain injury: evidence from a systematic review. [2018]

3. England 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. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Sleep Parameters and Overnight Urinary Melatonin Production in Children With Persistent Post-concussion Symptoms. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. [2022]

7. Australia pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment. [2019]