ASD

The Evidence Base

Slenyto^® (paediatric prolonged-release  melatonin) for:

treatment of insomnia in children and adolescents aged 2-18 years with Autism Spectrum Disorder (ASD), and/or neurogenetic disorders with aberrant diurnal melatonin secretion and/or nocturnal awakenings, where sleep hygiene measures have been insufficient
treatment of insomnia in children and adolescents aged 6-17 years with attention-deficit hyperactivity disorder (ADHD) where sleep hygiene measures have been insufficient
significant improvements, over baseline, in total sleep time, sleep initiation (latency) and maintenance, child behaviours (externalising), caregivers’ quality of life and resolution of caregiver sleep disturbance

The Paediatric Investigational Plan (PIP) included a Phase III study demonstrating the product’s short, and long-term efficacy and safety.

The short-and long-term efficacy of Slenyto for insomnia in children with autism spectrum disorder (ASD) were investigated in a randomised, 13- week, placebo controlled trial¹ followed by a long-term (up to 2 years) open-label treatment phase and 2 weeks withdrawal on placebo.^2,3

Effects on child’s sleep.

The double-blind period included 125 children (aged 2–17.5 years ) with insomnia: 96.8% ASD, 3.2% Smith-Magenis Syndrome (SMS) and 28.8% ASD comorbid with ADHD.¹

At 13 weeks

628ae8798df1949bb0f11cbed1465ee0505de5fc

57.5

Mins increase in
total sleep time

d0552ca3e34599c19787c47994da23d057a6b1ba

39.6

Mins decrease in sleep
onset latency

48d8e053149f4a11af01487294c1eba673becfd7

77.9

Mins increase in longest
uninterrupted sleep episode

At 52 weeks

Mins increase in
total sleep time

Mins decrease in
sleep onset latency

Mins increase in longest
uninterrupted sleep episode

Longest uninterrupted sleep episode is especially important for caregivers and families.

After 13 weeks of treatment with Slenyto, children slept on average 57.5 minutes more per night and went to sleep on average 39.6 minutes earlier. Using the definition of clinical response as an increase in Total Sleep Time (TST) of ≥45 mins and/or reduction in Sleep Latency (SL) by ≥ 15 mins (versus baseline), 68.9% of participants responded to Slenyto by 13 weeks (versus 39.3% with placebo; p=0.001). Thus 2 of 3 children with ASD are expected to have a clinically meaningful response to a 2 or 5 mg dose.¹

This study chose to explore an important explanatory, often neglected, sleep outcome; duration of uninterrupted sleep (Longest Sleep Episode, LSE). This is especially important for caregivers and families since a child who sleeps for 5 hours but wakes twice every hour is more disruptive to parents than a child who sleeps for 5 hours but wakes 10 times in the first hour. By the end of the 13-week double-blind period, the mean LSE increased on average by 77.9 minutes in the Slenyto-treated group i.e. the LSE improved by over an hour.¹

At optimal dose of Slenyto (at 52 weeks), participants slept on average 62 minutes longer at  night (increased TST), fell asleep on average 49 minutes faster (decreased SL) and the longest continuous sleep episode (LSE) was on average 89 minutes longer compared to baseline. The latter is equivalent to one or two complete sleep cycles in young children.⁴

Effects on child daytime behaviour.

After 13 weeks treatment, 53.7% of Slenyto 2 mg/5 mg participants displayed a significant and clinically relevant improvement in externalising behaviours (hyperactivity/inattention and conduct scores - assessed by the Strength and Difficulties Questionnaire, SDQ) compared to 27.7% in the placebo-treated group (Odds ratio 3.0; p = 0.008). The 26% difference in percentage between the groups corresponds to an NNT of 3.8 in this domain.⁵

Caregiver outcomes

Effective management of sleep problems in children with autism with, or without, comorbid ADHD, can improve the overall health of the family²

*A change of 10% in WHO-5 score.
WHO-5 World Health Organisation Wellbeing Index-5

There was a significant improvement in caregiver’s quality of life as assessed by the WHO-5 after 13 weeks of double-blind treatment with treatment difference between the Slenyto-treated group and the placebo-treated group of 2.17 points (p=0.01) and Cohen’s d effect size of 0.52.⁵

By 52 weeks² 49% of caregivers of children who had been randomised to Slenyto and treated continuously attained:

complete remission of their own insomnia
a clinically relevant improvement in quality of life

It is pertinent to ask whether the improvement in parents’ quality  of life, subsequent to the improvement in child’s sleep, might provide  a “positive bias” on the parent-completed rating scales of patient behaviour or influence parenting and therefore behaviour of children. Yet, the change in caregiver quality of life seems strongly related to the improvements in daytime behavior rather than to the improvements  in child’s sleep.

Of note, caregivers’ quality of life had already improved significantly with the Slenyto-treated compared to the placebo-treated group  after 3 weeks treatment; by that time the hyperactivity/inattention scores also improved significantly in the Slenyto- compared to the placebo-treated groups.⁵

These findings could be interpreted as improvement of wellbeing of parents is mediated by improvement of daily behaviour in the child and not directly by sleep improvement in the child or parent. It is therefore most likely that the improvement in sleep in the subjects led to the improvement in behaviour and that this improvement is more valuable to the caregivers’ quality of life than the improvement in child sleep per se. These effects might benefit both the caregivers and the children, making caregivers more able to cope and potentially reducing stress in the parent–child relationship.⁵

Outcomes for children with ASD and comorbid ADHD

Results of the 13-week double-blind phase of the study indicated that Slenyto (2/5 mg) was efficacious compared with placebo for treatment of insomnia in children with ASD with/without ADHD and neurogenetic disorders with clinically meaningful improvements in total sleep time (TST), duration of uninterrupted sleep (longest sleep episode, LSE), and sleep latency (SL) and without causing earlier wake-up time.²
Diagnosis (ASD with/without ADHD or SMS) and co-medication (e.g., stimulants) did not affect Slenyto efficacy outcomes.²

Treatment compliance

In contrast to the usual difficulties with tablet and liquid formulations experienced by children with ASD, acceptability and compliance with Slenyto were excellent, without the need to crush or dissolve the mini-tablets (thus preserving the prolonged-release properties). Treatment compliance calculated by returned mini-tablets after 104 weeks of double-blind treatment was almost 100% throughout the study.⁴

Dose response to treatment

After 52 weeks of continuous treatment, 76% of patients achieved a clinically meaningful response (i.e. overall improvement ≥1 hour in TST,  SL or both over baseline). Of the 55 responders, 22% (16 patients) used 2mg/day, 36% (26 patients) used 5mg and 18% (13 patients) used 10mg. Seventeen subjects (24%) had partial, or no measurable, response compared with baseline even at the highest (10mg) dose. The average daily dose after 1 year of treatment in patients who satisfied this criterion was 5.3mg.²

Of note, in the double-blind phase, approximately 80% of patients in the placebo group were escalated to the 5mg (placebo) dose and, therefore, entered the open-label follow-up on a starting dose of 5mg. It is postulated that if these patients had started 2mg Slenyto treatment, a comparable number (up to 40%) would have stayed on the 2mg dose, as was seen in the Slenyto-assigned group.²

Adverse effects

The 1-year study of Slenyto reported that there were no serious treatment-related adverse effects. Adverse effects were few and generally mild, with fatigue emerging as the main treatment-emergent adverse event.²

After 2 years of continuous use of Slenyto, no child (31 participants aged 8 to 17 years) showed a delay in sexual maturation.³

Attrition of effect

A clinically described difficulty with some melatonin formulations has been the gradual loss of effect over time. Looking at the evolution of efficacy in patients receiving Slenyto without any dose escalation, it appears that they remained responsive throughout the study and no increase in dosage was necessary to avoid attrition of effects. Rather, the response further evolved gradually, and these improvements were maintained throughout the rest of the follow-up.²

Treatment of insomnia in children and adolescents aged 2-18 with neurogenetic disorders

Based on the results of a 6-year French compassionate use study which included children with insomnia and autism and/or a neurogenetic disorder, the indication for Slenyto was extended to include the treatment of insomnia in children and adolescents aged 2-18 with ASD and/or neurogenetic disorders with aberrant diurnal melatonin secretion and/or nocturnal awakenings, where sleep hygiene measures have been insufficient.⁶

Treatment of insomnia in children and adolescents aged 6-17 with ADHD where sleep hygiene measures have been insufficient

Melatonin treatment has been studied in a 4-week randomised, double-blind, placebo-controlled study conducted in 105 children between  6-12 years of age, with ADHD and chronic sleep onset insomnia who did not receive ADHD medications or behavioural intervention. This study employed immediate-release melatonin at a dose of 3 mg or 6 mg for 4 weeks. Melatonin treatment advanced circadian rhythms of sleep-wake and shortened sleep latency in children with ADHD and chronic sleep onset insomnia. Mean sleep latency decreased by 21.3 minutes in the melatonin group and increased by 3 minutes in the placebo group (p=0.001). Total time asleep increased by 19.8 minutes in the melatonin group and decreased by 13.6 minutes in the placebo group (p=0.001). Immediate release melatonin had no effect on problem behaviour, cognitive performance, or quality of life.⁷

Based on this efficacy data (and through the Well Established Use procedure) Slenyto was approved for the treatment of insomnia in children and adolescents aged 6-17 years with ADHD where sleep hygiene measures have been insufficient.