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

The purpose of this study is to establish the efficacy and safety of Circadin in children with neurodevelopmental disorders and to determine the dose, this randomized, placebo-controlled study is planned to evaluate the efficacy of a double-blind, 13 week treatment period with Circadin 2/5mg in improving maintenance of sleep, sleep latency and additional parameters in children with neurodevelopmental disabilities. The efficacy and safety of Circadin 2/5 mg will continue to be assessed during an open-label extension period of 13 weeks.

This is a randomized placebo-controlled study in children diagnosed with autism spectrum disorders (ASDs) and neurodevelopmental disabilities caused by neurogenetic diseases.

Children who are found to be eligible for the study will follow a 4-week, basic sleep hygiene and behavioral intervention wash-out period, and will continue in a 2-week single-blind (SB) placebo run-in period. Then, they will be randomized in a 1:1 ratio to receive either Circadin® 2 mg or placebo for 3 weeks in a double-blind treatment period.

After 3 weeks of treatment, on the last day of Week 5 ±3 days (Visit 3), sleep variables will be assessed to determine if dose modification (an increase to 5 mg) is required. Children will then continue on 2 or 5 mg of Circadin® or placebo for an additional double-blind period of 10 weeks. This double-blind period will be followed by an open-label period of 13 weeks. At the end of the 13-week open-label period on the last day of Week 28 ±3 days (Visit 5), sleep variables will be assessed to determine if a potential additional dose modification (i.e., an increase either to 5 mg for patients who are still on 2 mg or an increase to 10 mg for patients who are on 5 mg) is necessary (If a dose increase is decided upon, the dose increase should be from 2 mg to 5 mg, or 5 mg to 10 mg). Children will continue at 2, 5, or 10 mg Circadin® in an open-label period for another 78 weeks of follow-up, which will include continuous safety monitoring and 2 efficacy assessment time points at Weeks 41 and 54. The study will end with a 2-week SB placebo run-out period.

Each patient will participate in the study until the end of the second open-label safety follow-up period, and 2 week run-out period. The study duration will be 112 weeks, including the 4-week wash-out period with sleep hygiene and behavioral intervention.

Eligibility Criteria:
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 (International Classification of Diseases) or DSM-5/4 (Diagnostic and Statistical Manual of Mental Disorders) 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 inhibitors \[SSRIs\]), 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 \[this does not include patients who participated in the Phase I Pharmacokinetics (PK) study who can be already included in the study\]
10. Children with known renal or hepatic insufficiency