WARSAW, Poland — Prolonged-release melatonin improves sleep quality in children with autism spectrum disorder (ASD) and is associated not only with improved externalizing behaviors in kids, but also better quality of life for parents, results of a phase 3 trial and extended follow-up show.
Here at the European Psychiatric Association (EPA) 2019 Congress, investigators presented the results of two studies of pediatric prolonged-release melatonin (pedPRM; Slenyto, Neurim Pharmaceuticals).
Athanasios Maras, MD, PhD, Yulius Academy, Yulius Mental Health Organization, Barendrecht, The Netherlands, presented the initial phase 3 trial results that showed that pedPRM was associated with significantly improved sleep from baseline compared with placebo.
The drug was also associated with a threefold improvement in externalizing behavior scores among the children, as well as significant improvements in parental quality of life and satisfaction with their child’s sleep.
Presenting the open-label follow-up data, Carmen Schroder, MD, PhD, Department of Child and Adolescent Psychiatry, Strasbourg University Hospital, France, said children treated continuously with pedPRM had significantly longer sleep, fell asleep faster, and had longer uninterrupted sleep compared with baseline.
Schroder said that the two presentations demonstrated that “pediatric prolonged release melatonin is efficient not only short term but maintains its effect long term in children and adolescents with ASD and has positive effects on their caregivers.”
Maras began his presentation by pointing out that externalizing behaviors such as hyperactivity and aggression are significantly and negatively correlated with impaired sleep quality in children with ASD.
To examine the drug‘s safety and efficacy, investigators conducted a randomized phase 3 multicenter trial in children with ASD and other neurodevelopmental disorders and impaired sleep that compared the active drug with placebo.
All participants switched to melatonin for a 9-month open-label phase using three different doses of the drug.
Sleep impairment was defined as 6 or less hours of continuous sleep and/or sleep latency of a half-hour or more in 60 or more nights for more than 3 months, having failed to improve with basic sleep hygiene and behavioral interventions.
After 2-week run-in phase, 125 children from 24 sites in the US and European Union were randomly assigned in a 1:1 fashion to pedPRM 2 mg for 3 weeks followed by pedPRM 2 mg or 5 mg for 10 weeks, or an equivalent placebo.
Children from both the active and control groups were then switched to open-label follow-up, in which they were given pedPRM 2 mg or 5 mg for 18 weeks, followed by a further 78 weeks of the intervention at 2 mg, 5 mg, or 10 mg doses.
Finally, all participants entered a 2-week washout phase.
Reporting results from the initial 13-week treatment phase, Maras said children receiving pedPRM had significant improvements from baseline for total sleep time on the self-report Strength and Difficulties Questionnaire (SDQ) vs placebo.
The differences were significant at both the 3-week (P = .006) and 13-week (P = .034) assessments.
Moreover, children treated with pedPRM had significant improvements on the Child Externalizing Behavior scale of the SDQ over baseline compared with those given placebo at 13 weeks (P = .021), although not at 3 weeks.
This was reflected in a substantially higher proportion of children reporting a decrease in the SDQ externalizing scores of ≥1 unit among those given pedPRM vs those in the placebo group, at 53.7% vs 27.7% (odds ratio, 3.03; P = .008).
Impact on Parents
To assess the impact on parents, the researchers used the World Health Organization Well-Being Index (WHO-5).
This showed that the parents of children given pedPRM had significantly improved quality of life from baseline over those whose children received placebo, at both 3 weeks (P = .03) and 13 weeks (P = .01).
Parents of children treated with pedPRM also reported significantly greater satisfaction with their child’s sleep pattern on the Composite Sleep Disturbance Index (CSDI) compared with parents of children given placebo. This was seen at both 3 weeks (P = .004) and 13 weeks (P = .005).
In a poster presentation, Schroder reported the results of the 9-month, open-label follow-up, saying that the improvements in sleep quality seen in the double-blind, placebo-controlled phase were continued.
She said that the 41 children treated with pedPRM continuously for 52 weeks slept an average of 62.08 minutes longer than at baseline (P = .007).
They also fell asleep an average of 48.6 minutes faster than they did at the start of the study (P < .001) and had a longer mean duration of interrupted sleep, at 89.1 minutes longer than at baseline (P = .001).
Schroder reported that the children had significantly improved sleep quality (P < .001) over baseline, and the number of nighttime awakenings fell by more than 50% (P = .001).
In addition, when looking at the 79 children from the initial pedPRM and placebo groups who completed the open-label phase, the team found that parental outcomes improved significantly.
Specifically, parents reported improvements in satisfaction with their child’s sleep on the CSDI (P < .001), better quality of life on the WHO-5 (P = .001), and improvements on the Pittsburgh Sleep Quality Index (P < .001).
Schroder also said that pedPRM was generally safe, with the most common treated-related adverse events being fatigue (5.3%) and mood swings (3.2%).
Discussing the different doses used in the open-label phase, Maras said the children fell into three groups in terms of the amount of pedPRM they need to have an effect.
“We have about one third of the children reacting sufficiently 2 mg, which was the lowest dose on this study, so this was enough for a group of children,” he said.
“The biggest group, about 50%, needed to get about 5 mg per day melatonin, and there is also a smaller group, about 20%–22%, that needed even 10 mg per day to get sufficient treatment effects,” Maras noted.
Long-Term Effects Unknown
Commenting on the findings for Medscape Medical News, Haviva Veler, MD, director of the Pediatric Sleep and Breathing Disorders Center at New York-Presbyterian Hospital and Weill Cornell Medicine, New York City, said that the study is “timely and well done.”
“As a sleep physician taking care of children with autism, I am glad this study was done and shows what we knew for a while, that use of melatonin improves insomnia associated with autism,” said Veler, who was not involved with the current studies.
However, Veler noted a potential cause for concern over using the drug long-term.
“We know melatonin is a potent sleep inducer, but less active in sleep maintenance. When following internal levels of melatonin, we see increased levels toward bedtime and a few hours after falling asleep, with a slow decrease at the latter part of sleep and a drastic fall toward morning awakening,” she said.
“Maintaining higher levels of melatonin throughout the night, which is not physiological, has unknown effects that needs to be evaluated. In addition, even though melatonin is considered to be safe to use, it has unknown side effects, and these were not assessed in the study presented,” Veler added.
She also noted that the use of questionnaires to assess the effect of melatonin on sleep and well-being is subject to recall bias.
“The use of a placebo group reduces the likelihood of this bias,” she said, “but there were no objective tests on these children to assess the improved daytime function.”
Nevertheless, Veler said that she “will definitely recommend use of long-acting melatonin in this challenging group of patients.” However, she added, she will wait “to hear more from this group about any side effects they found using long-acting melatonin.”
The studies were funded by Neurim Pharmaceuticals. Maras reports speaker fees from InfectoPharm, Lilly, and Neurim; educational grants from Lilly; research grants from Janssen-Cilag, EU FP7, and Dutch ZonMw; consultancy fees from Janssen-Cilag and Shire. Veler has disclosed no relevant financial relationships.
European Psychiatric Association (EPA) 2019 Congress: Abstract OC-0030 – presented April 7, 2019; Poster EPA19-0180 – presented April 9, 2019.