Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder

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The prevalence of insomnia in children and adolescents with autism spectrum disorder (ASD) is high compared with typically developing peers and estimated at 50% to 80%.1x1Cuomo, B.M., Vaz, S., Lee, E.A.L., Thompson, C., Rogerson, J.M., and Falkmer, T. Effectiveness of sleep-based interventions for children with autism spectrum disorder: a meta-synthesis. Pharmacotherapy. 2017;
37: 555–578
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Clinical guidelines recommend sleep hygiene and/or behavioral intervention as the first-line treatment, but if this fails, there are no medications approved by the Food and Drug Administration for the treatment of pediatric insomnia.11x11Badin, E., Haddad, C., and Shatkin, J.P. Insomnia: the sleeping giant of pediatric public health. Curr Psychiatry Rep. 2016;
18: 47
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Whereas the ongoing need of using melatonin in the treatment of sleep problems in children with ASD is recommended as part of good clinical practice,1x1Cuomo, B.M., Vaz, S., Lee, E.A.L., Thompson, C., Rogerson, J.M., and Falkmer, T. Effectiveness of sleep-based interventions for children with autism spectrum disorder: a meta-synthesis. Pharmacotherapy. 2017;
37: 555–578
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A randomized, double-blind (DB), placebo-controlled, parallel-group, multicenter (European Union and United States) study of PedPRM for 13 weeks (2 mg with an optional dose escalation to 5 mg after 3 weeks) in children (N = 25; age range 2–17.5 years) with ASD and SMS with or without ADHD comorbidity demonstrated that PedPRM was efficacious and safe compared with placebo for treatment of insomnia.14x14Gringras, P., Nir, T., Breddy, J., Frydman-Marom, A., and Findling, R.L. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2017;
56: 948–957.e944
Abstract | Full Text | Full Text PDF | PubMed | Scopus (42)
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Once all participants in the OL phase completed 39 weeks of follow-up (week 54), the 1-year data were summarized and published,16x16Maras, A., Schroder, C.M., Malow, B.A. et al. Long-term efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Child Adolesc Psychopharmacol. 2018;
28: 699–710
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Method

Participants

Participants included children and adolescents (2–17.5 years of age) with confirmed physician-diagnosed ASD according to DSM-IV/DSM-5 or ICD-10 criteria or SMS and a minimum of 3 months of impaired sleep, defined as ≤6 hours of continuous sleep and/or ≥0.5-hour sleep latency from light off 3 out of 5 nights per week for 2 weeks based on parent reports and patient medical history as described.14x14Gringras, P., Nir, T., Breddy, J., Frydman-Marom, A., and Findling, R.L. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2017;
56: 948–957.e944
Abstract | Full Text | Full Text PDF | PubMed | Scopus (42)
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Study Procedures

The study design is illustrated in Figure 1A. Parents of children who did not have a documented history of sleep hygiene and behavioral intervention at screening received education in behavioral sleep interventions provided through a standardized pamphlet14x14Gringras, P., Nir, T., Breddy, J., Frydman-Marom, A., and Findling, R.L. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2017;
56: 948–957.e944
Abstract | Full Text | Full Text PDF | PubMed | Scopus (42)
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Figure 1

Overall Study Design, Patient Disposition, and Dose Breakdown for Participants

Note: CSDI = Composite Sleep Disturbance Index; SND = sleep and nap diary; TST = total sleep time.

The starting dose was 2 mg PedPRM (or placebo equivalent) with optional dose escalation from 2 to 5 mg after 3 weeks of DB treatment (week 5 in the trial) and from 2 to 5 mg or from 5 to 10 mg/day after 13 weeks of OL treatment (week 28) if participants failed to improve TST and/or sleep latency by at least 60 minutes from baseline. Optional decrease in dose was allowed at all times during the study, based on investigator decision (Figure 1B).

Sleep variables, reported by parent/caregiver, were assessed using a validated sleep and nap diary (SND) that has been used in previous trials including a previous pediatric immediate-release melatonin trial.17x17Gringras, P., Gamble, C., Jones, A.P. et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ. 2012;
345: e6664
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Child sleep was assessed at each visit throughout the 2-year study using the Composite Sleep Disturbance Index (CSDI), which scores the frequency and duration of the participant’s sleep habits over the previous month (six habits: settling at bedtime, sleep induction, waking up during the night, resettling, early wake time, and co-sleeping with caregivers; scored 0–2; total score range 0–12).19x19Quine, L. Sleep problems in children with mental handicap. J Ment Defic Res. 1991;
35: 269–290
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Safety was monitored throughout the study, using standard clinical trials methods and definitions (treatment-emergent signs and symptoms [TESS],23x23Nilsson, M.E. and Koke, S.C. Defining treatment-emergent adverse events with the medical dictionary for regulatory activities (MedDRA). Drug Inf J. 2001;
35: 1289–1299
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Child development was assessed in children ≥8 years of age using Tanner pubertal staging done by a physician, body mass index (BMI) percentiles (obesity), and z-scores. The Tanner scores consist of three scores for boys and three for girls, describing genitals, testicles, and pubic hair in boys and breasts, pubic hair, and menarche in girls. Results in our population were compared with the general Dutch population to assess pubertal development.23x23Nilsson, M.E. and Koke, S.C. Defining treatment-emergent adverse events with the medical dictionary for regulatory activities (MedDRA). Drug Inf J. 2001;
35: 1289–1299
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Statistical Methods

Changes from baseline were analyzed using paired t tests for all observed cases (significance level < .05). Safety analyses were performed on all randomly assigned participants who took at least one dose of study medication.

Results

Study Population

Of 119 randomly assigned and treated participants, 95 completed the DB phase (week 15) (51 of the PedPRM-treated and 44 of the placebo-treated groups, mean [SD] age 9 [4.2] years, range 2–17 years, 74.7% male participants). Completers entered the OL phase with PedPRM; 74 completed the treatment (week 106), and 73 completed the run-out phase (70 had ASD [95.9%] and 3 [4.1%] had SMS) (Figure 1B). In the DB phase, significantly more participants discontinued in the placebo group than PedPRM-treated group; the most common reasons for discontinuation were withdrawal of parent consent mainly because of personal reasons (n = 6) and adverse events (n = 6).

Treatment adherence was close to 100% throughout the study. Principal investigators reported that children were able to swallow the mini-tablets without crushing, thus confirming acceptability and suitability of 3-mm-diameter mini-tablets for preschoolers ≥2 years of age.24x24Thomson, S.A., Tuleu, C., Wong, I.C., Keady, S., Pitt, K.G., and Sutcliffe, A.G. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics. 2009;
123 ()
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Efficacy

The change from baseline in CSDI score after 13 weeks of treatment significantly correlated with the changes in TST recorded in the SND (Spearman’s rank correlation −0.375; p < .001) regardless of whether receiving the active drug or placebo (Supplemental Figure S1, available online).14x14Gringras, P., Nir, T., Breddy, J., Frydman-Marom, A., and Findling, R.L. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2017;
56: 948–957.e944
Abstract | Full Text | Full Text PDF | PubMed | Scopus (42)
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Table 1Changes From Baseline in Child Sleep and Caregiver Variables at Week 106 in Pediatric Prolonged-Release Melatonin (PedPRM) and Placebo Groups
Variable PedPRM (n = 38) Placebo (n = 35)
Mean Change From Baseline (95% CI) Mean Change From Baseline (95% CI)
CSDI (scale of 0–12) −3.18 (−4.49, −1.86) −3.59 (−4.86, −2.31)
p < .001 < .001
CSDI caregiver satisfaction (scale of 1–5) 1.79 (1.35, 2.24) 1.82 (1.40, 2.25)
p < .001 < .001
WHO-5 3.44 (1.51, 5.36) 1.52 (−0.55, 3.58)
p .001 .145
PSQI (scale of 0–21) −1.26 (−2.46, −0.07) −1.88 (−3.28, −0.48)
p .039 .010


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Figure 2

Effects of Pediatric Prolonged-Release Melatonin (PedPRM) Treatment on Child and Caregiver Parameters

Note: Effects of PedPRM (2, 5, or 10 mg/day) for 28 weeks,15x15Schroder, C.M., Malow, B.A., Maras, A. et al. Pediatric prolonged-release melatonin for sleep in children with autism spectrum disorder: impact on child behavior and caregiver’s quality of life. J Autism Dev Disord. 2019;
49: 3218–3230
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54 weeks,15x15Schroder, C.M., Malow, B.A., Maras, A. et al. Pediatric prolonged-release melatonin for sleep in children with autism spectrum disorder: impact on child behavior and caregiver’s quality of life. J Autism Dev Disord. 2019;
49: 3218–3230
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and 106 weeks and placebo withdrawal (2 weeks) on (A) CSDI child sleep disturbance, (B) CSDI caregiver satisfaction, and (C) WHO-5 caregiver quality of life. Data from 106 weeks and 2 weeks withdrawal are mean (SE) change from baseline in the combined PedPRM and placebo population. CSDI = Composite Sleep Disturbance Index; PSQI = Pittsburgh Sleep Quality Index; WHO-5 = 5-item World Health Organization Well-Being Index.

After the 2-weeks run-out on placebo (week 108), the treatment effects decreased but remained significantly better compared with baseline (Figure 2). Similarly, mean (SE) change from baseline in caregiver PSQI for the combined PedPRM and placebo groups (n = 74) at week 106 improved −1.55 (0.448) (p = .001) showing maintenance of beneficial effect from values seen a year before (week 54).16x16Maras, A., Schroder, C.M., Malow, B.A. et al. Long-term efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Child Adolesc Psychopharmacol. 2018;
28: 699–710
Crossref | Scopus (17)
| Google ScholarSee all References

Safety

Mean time of PedPRM treatment in the entire study was 517.8 days (range 3–666 days) in the PedPRM group and 545.5 days (range 80–659 days) in the placebo group. By week 106, 23% (17/74) of participants used 2 mg/day, 42% (31/74) used 5 mg/day, and 35% (26/74) used 10 mg/day PedPRM (mean daily dose 6.06 mg/day). No particular traits in optimal dose used, such as age, comedication, diagnosis, or symptom severity, were noticed.

During the DB phase, one participant in the PedPRM group had a dose reduction from 5 mg to 2 mg owing to an unacceptable increase in daytime fatigue, and two participants in the placebo group had unscheduled dose decreases owing to unacceptable behavioral changes. In the 91-week OL phase, six participants had unscheduled dose decreases owing to unacceptable increases in daytime fatigue; in four of six participants, the increases in daytime fatigue occurred shortly after dose escalation and resolved by decreasing the dose to that used before the dose escalation. One patient had a dose decrease because of another reason, and one patient had a dose decrease because the treatment effect was reduced at the highest (10 mg) dose.

Treatment-Emergent Adverse Events

No deaths were reported during any phase of the study. The most commonly reported severe treatment-emergent adverse events (TEAEs) in both randomization groups were agitation, fatigue, and mood swings (Table S1, available online). In the placebo group, one participant temporarily discontinued owing to two serious adverse events (pneumonia and viral respiratory tract infection) and one nonserious adverse event (tachypnea).

Overall, TEAEs were reported by 51 (85.0%) participants in the PedPRM group and 50 (76.9%) participants in the placebo-treated group during the DB period and by 80 (84.2%) participants (PedPRM and placebo groups) during the 91-week OL phase (Table S2, available online). Most of these TEAEs were similar between groups and known symptoms in children with ASD (eg, agitation, mood swings) or generally in children (eg, upper respiratory tract infection, cough, dyspnea, vomiting). In the DB period, somnolence was significantly more common in the PedPRM-treated group than placebo-treated group (p = .044), and headaches were more common in the PedPRM-treated group than placebo-treated group but not significantly (p = .29). In the PedPRM group, one participant discontinued use owing to nonserious adverse events (fatigue, agitation, and stereotypies). During the OL phase, 24 participants reported 31 somnolence events for a rate of 0.19 events per participant for 1 year of treatment (Table S2, available online). This rate of 0.19 translates into less than 1 event per participant per 5 years of treatment. Six participants had unscheduled dose decreases owing to unacceptable increases in daytime fatigue. Most of these events occurred shortly after dose escalation, with resolution by decreasing the dose to that used before the dose escalation.

Treatment-Related Adverse Events

The rate of adverse events considered by the clinician to be treatment-related adverse events per participant per 1 year PedPRM treatment decreased from 1.87 in the DB phase to 0.078 in the OL phase (Table S3 available online). The most commonly reported treatment-related adverse events in the OL period were somnolence, fatigue, and mood swings (Table S3, available online).

No noticeable changes were found in vital signs at any time point during the study. There were no differences from baseline in the physical examination except for BMI and pubertal state (detailed under “Child Growth Parameters”), which were within normal ranges for their age.

A history of seizures was present in 16 participants (12.8%). Four participants in the PedPRM group and three in the placebo group had received a diagnosis of epilepsy before the study. Two of these participants experienced absences seizures during the OL phase: one participant experienced two nonserious seizures of 1-minute duration each, and the other experienced one 1-minute mild seizure. Two participants experienced new-onset seizures: one experienced a nonserious absence seizure under placebo (DB), and the other experienced two generalized tonic-clonic seizures of 1-minute duration recorded at week 54 and week 106 (OL) as nonserious adverse events, moderate in severity, and unlikely to be related to study treatment.

Treatment-Emergent Signs and Symptoms

TESS events were based on the TESS questionnaire; all events were intermittent. In the 13-week DB period, moderate/severe somnolence was more commonly reported with PedPRM treatment (26 participants) than placebo treatment (12 participants; p = .005) and occurred most commonly within a short time after dose escalation. Headaches (mostly mild/moderate) were also more commonly reported with PedPRM treatment (23 participants) than placebo treatment (9 participants; p = .015). There were no other notable differences between the treatment groups for TESS. During the 91-week OL period, moderate/severe somnolence was reported by 33 participants (26 from the PedPRM group and 7 from the placebo group). None of the TESS symptoms became more prevalent at week 108 (placebo run-out) compared with the PedPRM treatment weeks indicating no signs of withdrawal symptoms following discontinuation.

Child Growth Parameters

There were no significant differences between PedPRM and placebo groups for weight, height, or BMI in the DB phase. The mean (SE) difference in BMI between PedPRM and placebo groups after the 13-week DB treatment was −0.21 (0.151) (p = .16). BMI z-score had increased by 0.008 ± 0.3087 in the PedPRM group compared with 0.065 ± 0.4279 in the placebo group with mean treatment difference (PedPRM-placebo) of −0.055 (95% CI −0.198, 0.088) (p = .445), indicating no significant difference between the treatment groups.

The mean (SE) change from baseline in BMI after the 91-week OL phase for the whole group was 1.67 (0.278) (95% CI 1.12, 2.23) (p < .001). The mean (SE) change from baseline in BMI z-score for the whole group after the 91-week OL phase was 0.47 (0.085) (95% CI 0.30, 0.64) (p < .001). At week 106, the mean BMI z-score, which takes into account the age and sex of the child, was approximately 1.163 for the PedPRM group, 1.072 for the placebo group, and 1.1 (range −2.39 to 3.55) for the total group, which is considered within the normal range.25x25Must A, Anderson SE. Body mass index in children and adolescents: considerations for population-based applications. Int J Obes (Lond). 2006;30:590-594.
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Tanner Assessment of Pubertal Development

More participants in the placebo group were preadolescent compared with the PedPRM group (Tanner assessments) reflecting a slightly lower age at study entry (mean age 8.4 years versus 9.0 years) (Table 2). After 2 years, 31 participants ≥8 years of age provided data, and 13 were reluctant to do so. The SD scores at week 106 for the PedPRM and placebo groups were within the normal range for their age (Table 2 and Figure 3). At week 15, change from baseline for SD scores of pubic hair, breast, and genitalia development were similar between the PedPRM and placebo-treated groups.14x14Gringras, P., Nir, T., Breddy, J., Frydman-Marom, A., and Findling, R.L. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2017;
56: 948–957.e944
Abstract | Full Text | Full Text PDF | PubMed | Scopus (42)
| Google ScholarSee all References

Table 2Pubertal Development and Change From Baseline in Mean Standard Deviation Scores at Week 106 in Children ≥8 Years of Age Treated With Pediatric Prolonged-Release Melatonin (PedPRM)
PedPRM Group Placebo Group
SDS Mean (SD) Range Mean (SD) Range
Pubic hair growth 0.881 (1.11), n = 19 −0.43 to 3.04 1.323 (0.998), n = 12 −0.43 to 2.63
Breast development 0.709 (1.16), n = 7 −0.12 to 3.14 NA NA
Genitalia development 0.692 (0.96), n = 12 −0.55 to 2.12 1.205 (0.8), n = 12 −0.55 to 2.11


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Table 2Pubertal Development and Change From Baseline in Mean Standard Deviation Scores at Week 106 in Children ≥8 Years of Age Treated With Pediatric Prolonged-Release Melatonin (PedPRM)
Change From Baseline Mean (SD) Range (95%CI) p Mean (SD) Range (95%CI) p
Pubic hair growth 1.09 (1.24), n = 16 0.0 to 3.40 (0.49, 1.69) < .0001 1.55 (1.11), n = 11 0.0 to 2.85 (0.85, 2.35) < .001
Breast development 1.78 (1.70), n = 5 0.0 to 3.54 (0.21, 3.36) < .001 NA NA NA NA
Genitalia development 0.74 (1.09), n = 11 0.0 to 2.99 (0.05, 1.43) < .001 1.30 (1.00), n = 11 0.0 to 2.48 (0.67, 1.94) < .001


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Figure 3

Effects of Continuous Pediatric Prolonged-Release Melatonin (PedPRM) Treatment on Pubertal Development

Note: Effects of continuous PedPRM treatment (104 weeks PedPRM, 91 weeks placebo) on (A) male and female participant pubic hair growth by age (n = 31), (B) female participant breast development by age (n = 7), and (C) male participant genitalia development by age (n = 24). The individual standard deviation scores (SDS) at baseline (week 2, blue) and end of PedPRM treatment (week 106, red) are depicted. Normal ranges are marked on the right-hand y-axis.39x39van Buuren S. Puberty Plot Web Application Puberty Plot S-plus package. TNO Quality of Life. Copyright 2009 TNO.
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Discussion

This study strongly supports the longer-term effectiveness and safety of PedPRM for insomnia in children with ASD. The CSDI provides evidence on several aspects of child sleep disturbances: settling at bed time, sleep induction, waking up during the night, resettling, early wake time, and co-sleeping with caregivers. Changes in CSDI were significantly correlated with TST. The improvement in sleep CSDI was maintained throughout the 2 years under the optimal dose (2, 5, or 10 mg nightly) and so were the benefits to caregivers.

The pharmacological activity of PedPRM weans off after stopping the active treatment. With PedPRM, similar to prolonged-release melatonin in participants with insomnia ≥55 years of age,26x26Lemoine, P., Nir, T., Laudon, M., and Zisapel, N. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007;
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Treatment compliance and acceptance in children with ASD, many of whom have swallowing difficulties and are sensitive to smell, was excellent without the need to crush or dissolve the mini-tablets (which would negate the prolonged-release properties) supporting the use of the tasteless and odorless mini-tablets in this population.

There were no notable effects of long-term PedPRM on vital signs or measures of child growth, and no unexpected safety issues were reported. Adverse effects were few and generally mild, with fatigue and somnolence emerging as the main treatment-related TEAEs. Somnolence was usually reported only once by a participant at some time during the treatment period, most commonly within a short time after dose escalation, and was much less common in the OL phase (Table S2, available online). Fatigue was usually reported shortly after dose escalation and resolved by decreasing the dose to that used before the dose escalation. Treatment-related somnolence and fatigue most probably reflected the pharmacological effect of residual daytime melatonin secondary to the excessive dose. It is possible that some of these participants were poor metabolizers of CYP1A2 enzyme and developed daytime somnolence or fatigue owing to melatonin accumulation.28x28Rossignol, D.A. and Frye, R.E. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol. 2011;
53: 783–792
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Children and adolescents with ASD can have more frequent or more severe mood changes than typically developing teenagers,29x29Arnold, L.E., Aman, M.G., Cook, A.M. et al. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry. 2006;
45: 1196–1205
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In the DB period, there were no seizures on PedPRM treatment, and there was one new-onset absence seizure on placebo. During the 91-week OL period, one participant experienced two absence seizures, and one participant had a new-onset absence seizure, all considered by the clinicians unlikely to be related to study treatment. There has been only one short report in the literature30x30Sheldon, S.H. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet. 1998;
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It has been suggested that melatonin is involved in the modulation of human sexual maturation,32x32Silman, R.E., Leone, R.M., Hooper, R.J., and Preece, M.A. Melatonin, the pineal gland and human puberty. Nature. 1979;
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A limitation in this study was the OL design. With respect to growth and pubertal development, we relied on published statistics, which may vary by location and genetic origin. Another limitation was missing data from 13 participants who declined to be assessed. Nevertheless, the fact that the placebo randomized group had 3 months less exposure and did not show more rapid growth or pubertal development than the PedPRM group supports that there were no major effects on child development and sexual maturation.

In conclusion, melatonin treatment should be considered only when sleep hygiene (including minimizing blue light in the evening) and behavioral interventions have been tried and were not successful. The long-term safety and unique efficacy profiles indicate that PedPRM provides significant benefits for insomnia in children and adolescents with ASD.

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