Assessment of the Pharmacokinetics of Circadin® in Children With Neurodevelopmental Disorders and Sleep Disturbances

Study Overview
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Brief Summary
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There is increasing evidence that chronic sleep disorders in children with autism spectrum disorder (ASD), Angelman Syndrome (AS) and Smith-Magenis syndrome (SMS) are associated with disturbed melatonin secretion and melatonin administration has been shown to be effective in these populations. For children who have difficulties swallowing a tablet, Neurim has developed an age-appropriate Melatonin formulation in the form of mini-tablets which have the same dissolution profile as the Circadin® tablets product, thus should produce the same melatonin concentration-time profile with the same effects. This study concerns the pharmacokinetic study. The purpose of this study is to : Establish the 24 hour baseline profile of endogenous saliva melatonin concentrations and urine 6-SMT excretion in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances. Establish the concentration-time profile of saliva melatonin concentrations and 24 hour 6-SMT urine excretion after 2 and 10 mg Circadin® mini-tablets single dose administration in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances. Evaluate the adverse event profile after a single dose of 2 or 10 mg Circadin® mini-tablets in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances.

Official Title
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Open Label, Single Ascending Dose, Cross-over Study to Assess the Pharmacokinetics of Circadin® (Prolonged-Release Melatonin) Mini Tablets in Children With Neurodevelopmental Disorders and Sleep Disturbances

Conditions
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Sleep Problems

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be 2 to 17 years old Subject has a documented history of autistic spectrum disorder (ASD; as confirmed according to, DSM-IV-TR 299.00, 299.10 and 299.80 or ICD 10: F 84.0, F84.2, F84.3, F84.5, F84.9 ) or one of the following neurogenetic diseases according to ICD 10: Smith-Magenis syndrome, Angelman syndrome or Tuberous Sclerosis (Bourneville's disease) Subject has current sleep problems; defined as difficulty initiating or maintaining sleep, or non restorative sleep, for at least 1 month (DSM-IV 307.42). Subject is able to comply with taking the study drug and collaborate freely with the study procedures; Written informed consent from parents having parental responsibility or from the legal guardian(s). In the case of a child is aged 12 years or older the written informed consent of the child is needed in addition to that of parents having responsibility/legal guardian; Subject is able to understand instructions in Dutch. Exclusion Criteria: Subject has history of difficulty with swallowing and/or easy choking; Subject has current symptoms suggestive of obstructive sleep apnea syndrome or any breathing related sleep disorders or periodic limb movements; Subject has known clinically significant disturbance(s) in hepatic and/or renal function; Subject has non-stable epileptic attacks within 3 months prior to screening, in case of a history of epilepsy; Subject who currently has asthmatic symptoms; Subject has untreated medical/psychological condition that may be the etiology of sleep disturbances; Subject is unable to refrain from the use of disallowed concomitant medication ordietary supplements (see paragraph 3.4) from 1 week prior to study occasions; Subject is unable to refrain from caffeine-containing products for 24 hours before each occasion; Subject has a known allergy to melatonin; Female subject who is pregnant at time of screening; Subject has unstable use of allowed medication within 2 months prior to the screening; Subject has clinically relevant periodontal disease and/or oral injuries as judged by the investigator; Subject is unable to refrain from eating bananas and chocolate during the entire day before saliva collection; Subject is unable to refrain from drinks containing artificial colorants, caffeine (including but not limited to coffee, tea, cola), or alcohol during the day of the collection; Subject is unable to refrain from aspirin or drugs that contain ibuprofen on the collection day; Participation in an investigational drug study within 90 days prior to the first dose and/or participation in more than 4 clinical trials in the last year. -

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Circadin 10 mg<br>Second arm higher dose | Drug: Circadin 10 mg<br>* Second arm higher dose<br>|
| Active Comparator: Circadin 2 mg<br>First arm lower dose | Drug: Circadin 2 mg<br>* First arm lower dose<br>* Other names: non;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| baseline profile of endogenous saliva melatonin concentrations and urine 6-SMT excretion | To establish the 24 hour baseline profile of endogenous saliva melatonin concentrations and urine 6-SMT excretion in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances. | up to 1 year | 
| concentration-time profile of saliva melatonin concentrations and 24 hour 6-SMT urine excretion after 2 and 10 mg Circadin® mini-tablets single dose administration | To establish the concentration-time profile of saliva melatonin concentrations and 24 hour 6-SMT urine excretion after 2 and 10 mg Circadin® mini-tablets single dose administration in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances. | up to 1 year | 
| adverse event profile after a single dose of 2 or 10 mg Circadin® mini-tablets | To evaluate the adverse event profile after a single dose of 2 or 10 mg Circadin® mini-tablets in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances. | up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep problems, autism spectrum disorder, prolonged-release melatonin, Circadin, endogenous saliva melatonin, Smith-Magenis syndrome, Angelman syndrome, Tuberous Sclerosis