The first participants were registered and randomised on 11 December 2007 and 28 January 2008, respectively, and the last registered and randomised on 7 May 2010 and 4 June 2010. All children had intellectual/learning disability and included those with epilepsies, autistic spectrum disorders, and a range of genetic and chromosomal disorders. The CONSORT diagram shows the screening, randomisation, and follow-up of the patients . Baseline characteristics were similar between the groups (table 1).
Screening, randomisation, and follow-up of children with neurodevelopmental disorders and sleep disorders allocated to melatonin or placebo
Table 1 Baseline characteristics of children with neurodevelopmental disorders in study of effect of melatonin on sleep problems
The proportion of randomised participants who completed follow-up was high at 94% (66/70) for melatonin and 92% (70/76) for placebo. Proportions included within the primary outcome analysis were 73% (51/70) for melatonin and 78% (59/76) for placebo, largely because of the longitudinal data required (minimum of five nights’ complete sleep diary). We conducted a range of sensitivity analyses with regards to the missing data. These sensitivity analyses, which included reducing the number of nights’ sleep required to contribute to the analysis and imputing worse/best recorded sleep parameters to complete the sleep diaries, showed the robustness of conclusions.
Table 2 shows that participants randomised to placebo titrated more rapidly up to the maximum dose capsules. Twelve weeks after randomisation only 19 (38%) participants receiving active melatonin had escalated to the maximum dose (12 mg) compared with 49 (83%) receiving placebo. Nine children (18%) in the active group remained taking the lowest dose (0.5 mg) compared with one child (2%) in the placebo group.
Table 2 Dose escalation for participants included in primary outcome analysis of effect of melatonin on sleep problems in children with neurodevelopmental disorders
Table 3 provides results for primary and secondary sleep outcomes. Melatonin increased total sleep time as measured with sleep diaries (P=0.04), the primary outcome, but the confidence interval excluded the 60 minute value determined to be the minimum clinically relevant. The increase in total sleep time was reduced as measured by actigraphy (P=0.36). A range of prespecified sensitivity analyses showed the robustness of conclusions to missing data.
Table 3 Primary and secondary sleep outcomes in study of effect of melatonin on sleep problems in children with neurodevelopmental disorders. Figures are means (SD)
Melatonin reduced sleep onset latency when measured by both sleep diaries (P<0.001) and actigraphy (P<0.001). The size of the improvement was larger when measured by actigraphy (37.5 v 45.3 minutes). Sleep efficiency did not improve with melatonin (P=0.09).
Table 4 summarises the questionnaire outcomes. The composite sleep disturbance index (CSDI) showed a significant reduction favouring melatonin, indicating that parents thought the frequency and duration of sleep problems had reduced after treatment with melatonin. The Epworth sleepiness scale showed a clinically small but statistically significant improvement of 1.6 points on the 24 point scale for melatonin compared with placebo.
Table 4 Outcomes of questionnaires used to determine effect of melatonin on sleep problems in children with neurodevelopmental disorders. Figures are mean (SD) scores
The results of the other measures tended to favour melatonin but were not significant (table 5).
Table 5 Global measure of parents’ perception of child’s sleep quality in study of effect of melatonin on sleep problems in children with neurodevelopmental disorders. Figures are means (SD)
After randomisation, 67% (47/70) and 79% (60/76) of participants on melatonin and placebo, respectively, provided saliva samples for the calculation of dim light melatonin onset, of which 15 and 12, respectively, were of insufficient volume for analysis and the time of onset could not be ascertained for 25 (melatonin) and seven (placebo) participants. This difference between the two groups was not detected before randomisation. Where onset could not be calculated the reasons were possible contamination (23 melatonin and three placebo); high baseline concentrations (two melatonin), and low volume (four placebo). The limited data prevent meaningful analysis of the impact of this phenomenon on treatment response.
Table 6 shows the number of participants experiencing any treatment emergent sign or symptom (TESS). No formal statistical tests were undertaken, and the results for each group seemed similar. Seven serious adverse events were reported, of which two (one in the placebo group and one in the melatonin group) were considered related to the study drug in a blinded assessment.
Table 6 Treatment emergent signs and symptoms (TESS) in study of effect of melatonin on sleep problems in children with neurodevelopmental disorders
Sixteen children (eight in each group) had a diagnosis of epilepsy before randomisation. Thirteen of these 16 children experienced seizures in the period between randomisation and the end of the study; none showed any deterioration in seizure control or emergence of a new seizure type during this period. No child developed seizures or a new diagnosis of epilepsy.
Tables 7 and 8 show the results of exploratory analyses
. The treatment effect was not modified by the presence of autism (P=0.85) or by the type of initial sleep disorder as reported by care givers for total sleep time (P=0.56) or sleep onset latency (autism P=0.56, sleep disorder P=0.43). Inclusion of age or weight in the models did not improve the fit. The magnitude of sleep onset latency as determined by baseline sleep diaries, however, modified the treatment effect for sleep onset latency such that melatonin had a greater effect in those with a greater problem of getting to sleep (P=0.009); this was not evident for total sleep time (P=0.19).
Table 7 Frequency and duration of night time awakenings and wake up time in study of effect of melatonin on sleep problems in children with neurodevelopmental disorders
Table 8 Exploratory regression models in study of effect of melatonin on sleep problems in children with neurodevelopmental disorders. Figures are estimates (95% confidence intervals)
No differences were observed between groups for change in average duration or frequency of night time awakenings.
Children woke 16.7 minutes earlier than at baseline after 12 weeks of treatment with melatonin, compared with children in the placebo group who woke an average of 10.9 minutes later than at baseline (table 7). The comparison between groups was significant (P<0.001), with children in the melatonin group waking on average 29.9 minutes earlier than children in the placebo group after adjustment for baseline (95% confidence interval 13.6 to 46.3).