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

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

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.

Study Overview

• Status: Completed
• Conditions: Sleep Problems
• Intervention / Treatment: Drug: Circadin 10 mg; Drug: Circadin 2 mg

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333
    • Centre For Human Drug Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Circadin 10 mg; Second arm higher dose	Drug: Circadin 10 mg; Second arm higher dose
Active Comparator: Circadin 2 mg; First arm lower dose	Drug: Circadin 2 mg; First arm lower dose; Other Names: non

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Neurim Pharmaceuticals Ltd.

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: July 16, 2013
• First Submitted That Met QC Criteria: July 16, 2013
• First Posted (Estimate): July 19, 2013

Study Record Updates

• Last Update Posted (Estimate): April 4, 2014
• Last Update Submitted That Met QC Criteria: April 3, 2014
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Sleep problems, autism spectrum disorder, prolonged-release melatonin, Circadin, endogenous saliva melatonin; Smith-Magenis syndrome, Angelman syndrome, Tuberous Sclerosis
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Wake Disorders; Dyssomnias; Parasomnias; Neurodevelopmental Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: CHDR1219