Getting SMART for Pediatric Epilepsy (Sleep, Melatonin, and Research Trial, SMART)
Phase: PHASE2
Conditions: Epilepsy in Children
Sponsor: National Taiwan University Hospital

 
 
 
 
Getting SMART for Pediatric Epilepsy 
NCT05439876 
Study Protocol and Statistical Analysis Plan 
2025/06/18

Sleep disturbances are more prevalent in children with epilepsy whose sleep can 
be disrupted by seizures occurring during the night and/or during the day. Melatonin is 
a naturally occurring hormone produced in the pineal which regulates sleep-wake 
cycles and facilitates quality sleep. Therefore, the purpose of this study is to evaluate 
the effect of melatonin for improving sleep and seizure control in children and 
adolescents with epilepsy. 
This single-center, randomized, placebo-controlled crossover study was conducted 
at the pediatric neurologic clinic of National Taiwan University Hospital (NTUH), a 
tertiary care center in northern Taiwan. The study protocol was approved by the NTUH 
institutional review board. Written informed consent was obtained from parents, and 
assent was obtained from participants where appropriate. The study followed the 
Consolidated Standards of Reporting Trials (CONSORT) guidelines. Eligible 
participants were children aged 1 to 18 years with a confirmed diagnosis of epilepsy 
and with sleep problems. Exclusion criteria included: (1) children who are bedridden 
with limited mobility; (2) children with liver or kidney dysfunction; (3) children on 
hypnotics, antidepressants, or anxiolytics within 4 weeks before the baseline clinic visit; 
(4) adolescent girls who are pregnant or breastfeeding; and (5) adolescent girls who 
have sexual activities but cannot take effective contraceptive measures during the trial. 
Participants first underwent a 2-week prescreening period, during which they 
received behavioral and educational interventions targeting sleep health. They were 
instructed to follow a consistent sleep schedule and adhere to proper sleep hygiene 
practices. The prescreening period served as an opportunity to identify children whose 
sleep problems could be effectively managed with non-pharmacological behavioral 
interventions, ensuring that only those requiring additional treatment were randomized. 
Following prescreening, participants were randomized to receive either oral melatonin 
(2 mg/d for children younger than 6 years or 4 mg/d for those 6 years and older) or 

placebo once daily after dinner, 1 to 2 hours before bedtime for 4 weeks. Following a 
2-week washout period, participants crossed over to the alternate treatment. The study 
medication was administered as an adjunct to participants’ existing epilepsy treatments, 
which maintained unchanged throughout the study. Study assessments were conducted 
at the beginning and end of each treatment period. These included actigraphy sleep 
recordings, seizure assessments, completion of study questionnaires, documentation of 
adverse events, collection of blood and urine samples, and adherence monitoring 
through pill counts. 
Analyses followed a modified intention-to-treat approach, excluding participants 
who withdrew before treatment allocation. Baseline participant characteristics were 
compared between treatment groups using independent-sample t-tests for continuous 
variables and chi-squared tests or Fisher’s exact tests for categorical variables. Given 
the crossover design, generalized estimating equations (GEE) with an unstructured 
working correlation matrix and robust standard error estimates were used to assess 
treatment effects and carryover effects on study outcomes adjusted for age and sex as 
covariates. Sensitivity analyses were conducted using paired-sample t-tests to compare 
within-subject differences in outcomes before and after treatment between the 
melatonin and placebo conditions. Statistical analyses were conducted using Statistical 
Program for Social Sciences Version 22.0 (SPSS™, IBM Inc., Armonk, NY, USA). All 
tests were two-sided at α = .05.