assessment of the pharmacokinetics of circadin® in children with neurodevelopmental disorders and sleep disturbances

Conditions: Sleep Problems

Summary: 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.


Eligibility criteria:
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. -

Keywords: sleep problems, autism spectrum disorder, prolonged-release melatonin, circadin, endogenous saliva melatonin smith-magenis syndrome, angelman syndrome, tuberous sclerosis