The starting dose of active (or placebo) was 2 mg once daily, 30-60 minutes before habitual bedtime and with or after food. After 3 weeks of double-blind treatment, sleep variables were reassessed. If the patient did not improve from baseline by at least 1 hour, as measured by a shortening of SL and/or increase in total sleep time (TST), the dose was escalated to 5 mg. Patients continued double blind on 2 or 5 mg of active or placebo for the remaining 10 weeks, with an efficacy assessment by the end of the 13-week double-blind treatment period.6
See Figure 3.

Image adapted from: Slentyo (2022) Why Slenyto? Available at: https://www.slenyto.com/slenyto-clinical-evidence (accessed: 05 July 2022).
- The change from baseline in duration of wake after sleep onset
- Number of awakenings, and longest (uninterrupted) sleep episode (LSE)
- Change from baseline in Composite Sleep Disturbance Index (CSDI) score and subscores
- Number of dropouts during the 13-week double-blind treatment period
Whilst the number of participants with an SMS diagnosis were too small to extrapolate the benefits to the population as a whole, these findings do demonstrate improvements in externalising behaviours which might be particularly beneficial in SMS patients.6
Importantly, and unlike IR melatonin, Slenyto did not result in earlier waking. In an earlier study of IR melatonin, a proportion of children fell asleep more quickly (i.e., SL was reduced) but also started to wake earlier (phase shifting).5 Slenyto improved both sleep initiation and sleep maintenance since it has been developed to mimic the endogenous profile and releases melatonin throughout the night.6 See Figure 4

Figure 4a. Pharmacokinetics of Immediate-Release versus Prolonged-Release Melatonin9

Figure 4b. Endogenous Production of Melatonin9
*Data derived from studies in adults
Using improvement (i.e., decrease) in externalising behaviours score by 1 unit or more as a criterion of clinical response, the percentage of responders after 13 weeks of double-blind treatment in the Slenyto group was 53.7% compared to 27.7% in the placebo-treated group (Odds ratio 3.0; p = 0.008), providing evidence for the clinical meaningfulness of the treatment effect.1,7 The 26% difference in percentage between the groups corresponds to an NNT of 3.8. For the total SDQ score after 13 weeks of double-blind treatment, there was a trend to benefit in favour of Slenyto (p=0.077).

Schroder, C.M et al. 2019 'Pediatric Prolonged-Release Melatonin for Sleep In Children with Autism Spectrum Disorder: Impact on Child Behaviour and Caregiver's Qua-lity of Life', Journal of Autism and Developmental Disorders. 49(8), 3218-30
See Figure 6.

Schroder, C.M et al. 2019 'Pediatric Prolonged-Release Melatonin for Sleep In Children with Autism Spectrum Disorder: Impact on Child Behaviour and Caregiver's Qua-lity of Life', Journal of Autism and Developmental Disorders. 49(8), 3218-30
Of note, caregivers’ quality of life had already improved significantly with the Slenyto-treated compared to the placebo-treated groups after 3 weeks; by that time the hyperactivity/inattention scores also improved significantly in the Slenyto compared to the placebo-treated groups. Furthermore, caregivers’ own sleep did not improve significantly with a Slenyto-treated child compared to a placebo-treated child and improved further only months later in the open-label study.7
No unexpected safety issues were reported. Adverse effects were few and mild, with only headaches and daytime somnolence increased in the treatment group relative to placebo group. There was no increase in, or new onset of, seizures. In contrast to the usual difficulties with tablet formulations experienced by children with ASD, compliance was excellent.8

Flynn Pharma Ltd (2022) ‘Slenyto ® Treatment Goals and Therapy Optimisation – A Guide for Healthcare Professionals’ (2022). Available at: https://flynnforum.com/education_training/slenyto-treatment-goals-and-therapy-optimisation-a-guide-for-healthcare-professionals/ (accessed: 05 July 2022).
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2. Williams, S.R. et. al. 2012. ‘Smith-Magenis Syndrome Results in Disruption of CLOCK Gene Transcription and Reveals an Inegral Role for RAI1 in the Maintenance of Circadian Rhythmicity’, The American Journal of Human Genetics. Volume 90, Issue 6, 941-949
3. De Leersnyder, H. 2006. ‘Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment’, TRENDS in Endocrinology and Metabolism. Volume 17, Issue 7, 291-298
4. Chen, Li. et. al. 2015. ‘Smith-Magenis syndrome and its circadian influence on development, behaviour, and obesity – own experience’, Developmental Period Medicine. Volume 19, Issue 2, 149-56
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8. Schroder, C.M et al. 2019 'Pediatric Prolonged-Release Melatonin for Sleep In Children with Autism Spectrum Disorder: Impact on Child Behaviour and Caregiver's Quality of Life', Journal of Autism and Developmental Disorders. 49(8), 3218-30
9. Zisapel, N. 2018. ‘New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation’, British Journal of Pharmacology. 175(16), 3190-3199
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11. National Sleep Foundation. https://www.thensf.org/how-many-hours-of-sleep-do-you-really-need/ (Accessed May 2022)