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