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, 28 (10), 699-710
[Online ahead of print]

Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder

Affiliations

Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder

Athanasios Maras et al. J Child Adolesc Psychopharmacol.

Abstract

Objective: A recent double-blind randomized placebo-controlled study demonstrated 3-month efficacy and safety of a novel pediatric-appropriate prolonged-release melatonin (PedPRM) for insomnia in children and adolescents with autism spectrum disorder (ASD) and neurogenetic disorders (NGD) with/without attention-deficit/hyperactivity disorder comorbidity. Long-term efficacy and safety of PedPRM treatment was studied.

Methods: A prospective, open-label efficacy and safety follow-up of nightly 2, 5, or 10 mg PedPRM in subjects who completed the 13-week double-blind trial (51 PedPRM; 44 placebo). Measures included caregiver-reported Sleep and Nap Diary, Composite Sleep Disturbance Index (CSDI), caregiver's Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, and quality of life (WHO-5 Well-Being Index).

Results: Ninety-five subjects (74.7% males; mean [standard deviation] age, 9 [4.24]; range, 2-17.5 years) received PedPRM (2/5 mg) according to the double-blind phase dose, for 39 weeks with optional dose adjustment (2, 5, or 10 mg/day) after the first 13 weeks. After 52 weeks of continuous treatment (PedPRM-randomized group) subjects slept (mean [SE]) 62.08 (21.5) minutes longer (p = 0.007); fell asleep 48.6 (10.2) minutes faster (p < 0.001); had 89.1 (25.5) minutes longer uninterrupted sleep episodes (p = 0.001); 0.41 (0.12) less nightly awakenings (>50% decrease; p = 0.001); and better sleep quality (p < 0.001) compared with baseline. The placebo-randomized group also improved with PedPRM. Altogether, by the end of 39-week follow-up, regardless of randomization assignment, 55/72 (76%) of completers achieved overall improvement of ≥1 hour in total sleep time (TST), sleep latency or both, over baseline, with no evidence of decreased efficacy. In parallel, CSDI child sleep disturbance and caregivers' satisfaction of their child's sleep patterns (p < 0.001 for both), PSQI global (p < 0.001), and WHO-5 (p = 0.001) improved in statistically significant and clinically relevant manner (n = 72) compared with baseline. PedPRM was generally safe; most frequent treatment-related adverse events were fatigue (5.3%) and mood swings (3.2% of patients).

Conclusion: PedPRM, an easily swallowed formulation shown to be efficacious versus placebo, is an efficacious and safe option for long-term treatment (up to 52 weeks reported here) of children with ASD and NGD who suffer from insomnia and subsequently improves caregivers' quality of life.

Keywords: autism; insomnia; long-term; melatonin; pediatric; sleep disorders.

Conflict of interest statement

A.M., B.A.M., and C.M.S. were investigators; P.G. was the chief investigator and paid consultant; R.L.F. was the chief investigator and receives or has received research support, acted as a consultant, and/or served on a speaker's bureau for Aevi, Akili, Alcobra, Amerex, American Academy of Child and Adolescent Psychiatry, American Psychiatric Press, Bracket, Epharma Solutions, Forest, Genentech, Guilford Press, Ironshore, Johns Hopkins University Press, KemPharm, Lundbeck, Merck, NIH, Neurim, Nuvelution, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press, Purdue, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Syneurx, Teva, Tris, TouchPoint, Validus, and WebMD, J.B. was the statistician of the study; all were paid by Neurim Pharmaceuticals and declare no interests. S.S. and T.N. are employees and N.Z. is the founder and Chief Scientific Officer of Neurim Pharmaceuticals.

Figures

<b>FIG. 1.</b>
FIG. 1.
Overall study patient disposition (CONSORT diagram) (A) and dose breakdown for patients with SNDs (B). The study comprised 9-month, open-label PedPRM treatment on 2 or 5 mg doses with optional dose adjustment after 13 weeks of the open-label phase. PedPRM, pediatric prolonged-release melatonin; SND, Sleep and Nap Diary.
<b>FIG. 2.</b>
FIG. 2.
Effects of continuous PedPRM treatment (52 weeks) on child sleep. SND-reported change from baseline (end of the single-blind placebo run-in phase) in mean (SE) TST (minutes), SL (minutes), duration of uninterrupted sleep (LSE, minutes), NOA, quality of sleep, and CSDI in the PedPRM-assigned group during the 52 weeks of continuous treatment (n = 41). For completion of the picture, data from the 13-week, double-blind phase for this group (Gringras et al. 2017) are also depicted and marked with yellow outline. # represents significant differences over placebo in the double-blind phase (MMRM analysis; Gringras et al. 2017). CSDI, Composite Sleep Disturbance Index; LSE, longest sleep episode; NOA, number of awakenings; PedPRM, pediatric prolonged-release melatonin; SL, sleep latency; SND, Sleep and Nap Diary; TST, total sleep time.
<b>FIG. 3.</b>
FIG. 3.
Sustained response to 2 mg PedPRM treatment over the follow-up phase (39 weeks). Change from baseline in mean (SE) SND-reported TST (minutes), SL (minutes), duration of uninterrupted sleep (minutes), and NOA during the 39-week, open-label follow-up in patients treated with 2 mg PedPRM throughout the observation period (n = 16). PedPRM, pediatric prolonged-release melatonin; SND, Sleep and Nap Diary.
<b>FIG. 4.</b>
FIG. 4.
Effects of continuous PedPRM treatment (52 weeks) of the children on their caregivers. Change from baseline in the combined patient groups in mean (SE) caregivers' sleep quality (PSQI), quality of life (WHO-5), ESS, and CSDI-recorded parents' satisfaction of the child's sleep during the 39-week follow-up (n = 78). CSDI, Composite Sleep Disturbance Index; ESS, Epworth Sleepiness Scale; PedPRM, pediatric prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index.

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