Do Sleep and Circadian Rhythm Disturbances Impact the Cognitive and Behavioural Development of Children With Autism?

Study Overview
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Brief Summary
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The primary objective of this study is to undertake a longitudinal investigation of the impact of sleep and circadian rhythm disturbances on cognitive and behavioural trajectories in children with autism spectrum disorder (ASD) age 3-10 years old. This innovative study will use objective quantifiable measures of sleep and circadian rhythms in addition to subjective measures. The investigators aim to assess the hypotheses that, in pre-pubertal children with ASD, sleep disturbances are correlated with circadian rhythm disturbances; both sleep and circadian rhythm disturbances are negatively correlated with cognitive performance and positively correlated with behavioural disturbances; sleep and circadian rhythm disturbances, most notably abnormal melatonin secretion, impact the cognitive and behavioural development of children with ASD, depending on age (prospective longitudinal analyses).

Official Title
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Do Sleep and Circadian Rhythm Disturbances Impact the Cognitive and Behavioural Development of Children With Autism?

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Other: polysomnography


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age: from 3 to 8 years of age at inclusion, as per defined entry ages (longitudinal accelerated design) Diagnostic criteria of autism spectrum disorder (ASD) Autism Diagnostic Interview (ADI) - revised (R) score compatible with ASD diagnosis Autism Diagnostic Observation Schedule (ADOS) score compatible with ASD diagnosis Study information has been understood Study consent signed by both parents or legal representatives and by the child if the child is capable of expressing his consent Stable medication over the 2 months-period preceding inclusion and during evaluation periods (exception: (1) medication mentioned in the exclusion criteria, (2) a new medication instaurated between two evaluation periods is not in itself an exclusion criteria, but will be taken into account in data analysis) Compliance with study procedures Priori clinical medical examination Child affiliated with social security Concerning sleep disorders: the discovery of a primary sleep disorder (e.g.: sleep apnea syndrome, restless legs syndrome, periodic limb movements during sleep) as well as their treatment is not a criteria for terminating the study but will be taken into account in data analysis Exclusion criteria: Secondary autism: e.g. associated with Rett syndrome, fragile X syndrome, Down syndrome, Bourneville tuberous sclerosis, von Recklinghausen disorder, Cytomegalovirus (CMV) encephalitis, congenital rubeola, phenylketonuria. Current treatment with melatonin or melatonin agonists before study entry (before baseline assessment) Changes in medication over the 2 months-period preceding the study (exception: a new medication instaurated between two evaluation periods is not in itself an exclusion criteria, but will be taken into account in data analysis) Transmeridian travel (> 2 time zones) in the month preceding the study Participation in other research studies in the 3 months period preceding the study Treatment with betablockers, local or systemic non-steroidal anti-inflammatory (NSAI) agents, benzodiazepines, antidepressants Severe other intercurrent disorder. Severe allergies.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 8 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: ASD<br> | Other: polysomnography<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sleep latency at 1 year follow-up and 2 year follow-up compared to baseline | Sleep latency derived from actigraphy | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in sleep fragmentation index at 1 year follow-up and 2 year follow-up compared to baseline | Sleep fragmentation index derived from polysomnography (PSG) | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in nocturnal melatonin secretion at 1 year follow-up and 2 year follow-up compared to baseline | Nocturnal melatonin secretion (6-SMT measured in night urine from 8pm to 8am) | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in amplitude of the day-night melatonin secretion at 1 year follow-up and 2 year follow-up compared to baseline | Amplitude of the day-night melatonin secretion (6 sulfatoxy-melatonin (6-SMT) measured in 12h-night versus 12h-day urine) | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in non-verbal index (INV, derived from the Kaufmann-Assessment Battery fir Children II (K-ABC II)) at 1 year follow-up and 2 year follow-up compared to baseline |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in verbal intelligence quotient (IQ) at 1 year follow-up and 2 year follow-up compared to baseline | Change in verbal intelligence quotient (IQ) derived from the appropriate Wechsler scales for children (WPPSI or WISC) at 1 year follow-up and 2 year follow-up compared to baseline | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in Raven performance IQ at 1 year follow-up and 2 year follow-up compared to baseline | Raven performance IQ derived from Raven progressive matrices (CPM-BF) at 1 year follow-up and 2 year follow-up compared to baseline | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in Autism Diagnostic Observation Schedule (ADOS), module 1-3: part 'D' et 'E' (repetitive and abnormal behaviour) at 1 year follow-up and 2 year follow-up compared to baseline |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Change in aberrant Behaviour Checklist (ABCL) global score at 1 year follow-up and 2 year follow-up compared to baseline |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| presence of an intrinsic sleep disorders (e.g. obstructive or central sleep apnea syndrome, restless legs syndrome and periodic limb movements during sleep…) |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Total sleep time (TST) |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Time and percentage of TST spent in different sleep stages (slow wave sleep, rapid eye movement (REM) sleep) |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Sleep spindle density in light slow wave sleep |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Density of rapid eye movements in REM sleep |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Spectral analysis of the sleep electro-encephalogram (EEG) |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| 24h urinary 6-sulfatoxymelatonin levels (ng/ml) |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Inter-daily stability (IS) and intra-daily variability (IV) of circadian rhythms (actigraphy derived) | Level of ferritin in plasma | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Circadian phase of body temperature |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 
| Level of ferritin in plasma |  | Three annual assessments: baseline, 1 year follow-up, 2 year follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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autism, autism spectrum disorder, ASD, sleep, Circadian, Biological rhythms, melatonin, Cognition, Behavior, Longitudinal, Longitudinal accelerated design