The Paediatric Investigational Plan (PIP) included a Phase III study demonstrating the product’s short, and long-term efficacy and safety.
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
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
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 0.525.
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
Diagnosis (ASD with/ without ADHD or SMS) and co-medication (e.g., stimulants) did not affect Slenyto efficacy outcomes.2
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
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
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
References:
2. Maras et al., 2018
3. Malow et al., 2021
4. Schroder et al., 2021
5. Schroder et al., 2019
6. Flynn Pharma Data on File
7. van der Heijden et al. 2007