Efficacy and Safety of Circadin® in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities

Inclusion Criteria:

To be eligible for study entry, all patients must satisfy all of the following criteria at screening:

1. Must be children 2 to 17.5 years of age at Visit 2 who comply with taking the study drug
2. Must have written informed consent provided by a legal guardian and assent (if needed)
3. Must have a documented history of ASD according to or consistent with the ICD-10 or DSM-5/4 criteria, or neurodevelopmental disabilities caused by neurogenetic diseases (i.e., Smith-Magenis syndrome, Angelman syndrome, Bourneville's disease [tuberous sclerosis]) as confirmed by case note review showing that diagnosis was reached through assessment by a community pediatrician or pediatric neurologist or other health care professionals experienced in the diagnosis who took into account early developmental history and school records.
4. Must have current sleep problems including: a minimum of 3 months of impaired sleep defined as ≤6 hours of continuous sleep AND/OR ≥0.5 hour sleep latency from light off in 3 out of 5 nights based on parent reports and patient medical history. (The maintenance and latency problems do not necessarily have to be in the same 3 nights of the week.)
5. May be on a stable dose of non-excluded medication for 3 months, including anti- epileptics, anti-depressants (selective serotonin reuptake inhibitor [SSRIs]), stimulants, all mood changing drugs and β-blockers. (Only morning administration of β-blockers is allowed since β-blockers at night have the potential to reduce endogenous melatonin levels and might cause disturbed sleep)
6. The sleep disturbance is not due to the direct physiological effects of any concomitant medications such as SSRIs, stimulants, etc.

After completing 4 weeks of sleep hygiene training (for those who need it) and 2 weeks of placebo run-in, patients will be eligible to continue the study if they comply with the following:

• Continue to fulfill sleep problem criteria (see Inclusion Criterion 4) based on the completed Sleep and Nap Diary entered into the electronic case report form
• Parents demonstrate compliance in Sleep and Nap Diary completion (5 out of 7 nights). Compliance means that in at least 5 out of 7 nights per week (total of 2 weeks before each scheduled visit) the parents complete the diary pages with all mandatory questions
• Continue to fulfil all other eligibility criteria

Exclusion Criteria:

Children who meet any of the following criteria will be excluded from participating in the study:

1. Have had treatment with any form of melatonin within 2 weeks prior to Visit 1
2. Have a known allergy to melatonin or lactose
3. Have a known moderate to severe sleep apnea
4. Have an untreated medical/ineffectively treated/psychological condition that may be the etiology of sleep disturbances
5. Did not respond to previous Circadin® therapy based on past medical history records in the last 2 years
6. Are taking or have been taking prohibited medication within 2 weeks prior to Visit 1 (Section 7.1)
7. Are females of child-bearing potential that are not using contraceptives and/or breastfeeding and that are sexually active (Abstinence is an acceptable method of contraception.)
8. Pregnant females
9. Are currently participating in a clinical trial or have participated in a clinical trial involving medicinal product within the last 3 months prior to the study (this does not include patients who participated in the Phase I PK study who can be already included in the study)
10. Children with known renal or hepatic insufficiency