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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Placebo-controlled Study to Investigate the Efficacy and Safety of Circadin® to Alleviate Sleep Disturbances in Children With Neurodevelopmental Disabilities

Conditions
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Sleep Disorders

Intervention / Treatment
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* Drug: Circadin 2/5/10 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for study entry, all patients must satisfy all of the following criteria at screening: Must be children 2 to 17.5 years of age at Visit 2 who comply with taking the study drug Must have written informed consent provided by a legal guardian and assent (if needed) 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. 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.) 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) 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: Have had treatment with any form of melatonin within 2 weeks prior to Visit 1 Have a known allergy to melatonin or lactose Have a known moderate to severe sleep apnea Have an untreated medical/ineffectively treated/psychological condition that may be the etiology of sleep disturbances Did not respond to previous Circadin® therapy based on past medical history records in the last 2 years Are taking or have been taking prohibited medication within 2 weeks prior to Visit 1 (Section 7.1) 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.) Pregnant females 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) Children with known renal or hepatic insufficiency

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Circadin 2/5/10 mg<br> | Drug: Circadin 2/5/10 mg<br>* Active arm<br>|
| Placebo Comparator: Placebo<br>Placebo arm | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Total Sleep Time Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary Questionnaire After the 13 Week, Double-blind Treatment Period. | Total Sleep Time - To compare the treatment effect of Circadin® 2/5 mg minitablets to that of placebo on total sleep time (TST) as assessed by the Sleep and Nap Diary after 13 weeks of double-blind treatment | 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep Latency Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment. | questionnaire - To compare the treatment effect of Circadin® 2/5 mg minitablets to that of placebo on sleep latency as derived from a Sleep and Nap Diary after 13 weeks of double-blind treatment | 13 weeks | 
| The Duration of Wake After Sleep Onset Period Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment. | Questionnaire | up to 1.5 years | 
| The Number of Awakenings During the Night Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment. | Questionnaire | up to 1.5 years | 
| The Duration of the Longest Sleep Period Will be Measured for the Circadin 2/5 mg and Placebo by a Sleep and Nap Diary After 13 Weeks of Double-blind Treatment. | Questionnaire | up to 1.5 Years | 
| The Children's Social Functioning at Home, in School, and Community Settings Will be Measured for the Circadin 2/5 mg and Placebo by the Children Global Assessment Scale (CGAS) Questionnaire After 13 Weeks of Double-blind Treatment. | Questionnaire | up to 1.5 years | 
| The Children's Behavior at Home, in School, and Community Will be Measured for the Circadin 2/5 mg and Placebo by the Strength of Difficulties Questionnaire (SDQ) Questionnaire Filled Out by the Parents After 13 Weeks of Double-blind Treatment. | Questionnaire | up to 1.5 years | 
| The Number of Dropouts Between Circadin 2/5 mg to That of Placebo Will be Compared During the 13 Weeks of Double-blind Treatment. |  | up to 1.5 years | 
| Sleep Parameters (Rest/Activity Cycles) Will be Measured for the Circadin 2/5 mg and Placebo as Measured by Actigraphy After 13 Weeks of Double-blind Treatment. | The Actigraph will be worn on the wrist at night and collect the Sleep parameters | up to 1.5 years | 
| Safety and Tolerability Throughout the Study Will be Measured for the Circadin 2/5 mg and Placebo Throughout the Study Using AE Eliciting Method Treatment Emergent Signs and Symptoms (TESS) | Questionnaire | up to 2.5 years | 
| The Following Vital Signs Will be Measured: Blood Pressure, Pulse, Breathing and Body Temperature. They Will be Compared Between the Circadin and Placebo Groups. |  | up to 2.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep disturbance, Circadian, Prolong release melatonin, Autism Spectrum Disorder, Smith-Magenis Syndrome, Angelman Syndrome, tuberous sclerosis