Clinical trial NCT05654415: Melatonin vs Sleep Deprivation for Nap EEG
Official title: Efficacy of Melatony Versus Sleep Deprivation for EEG Recordings in Sleep: a Randomized Crossed-over Study in Pediatric Patients With Epilepsy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Epilepsy
Keywords: Oral melatonin
Sleep deprivation
Nap EEG recordings
Time to fall asleep
Lead sponsor: IRCCS National Neurological Institute "C. Mondino" Foundation
Sponsor class: OTHER
First posted: 2022-12-16
Enrollment: 30
Sex: ALL
Minimum age (years): 4
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The patients will be subjected to two EEG recordings: in one they will receive the melatonin solution (5 mg), in the 'other they will undergo only partial sleep deprivation (about 50% of physiological sleep).
Primary purpose: TREATMENT

Brief summary: In the pediatric population, electroencephalographic (EEG) recordings are frequently performed in sleep, as it reduces the amount of artifacts and might activate epileptiform discharges. To date, no agreed-upon guidelines are available for hypno-induction for EEG recordings . Among the strategies used, the most commonly used are sleep deprivation, either total or partial, and the use of melatonin, alone or in combination. The investigators proposed a study aiming at evaluating the efficacy of a melatonin-based solution for sleep induction during EEG video recording VS sleep deprivation.

In a randomized, crossover study, 30 pediatric patients (aged 4-10 years) will be subjected to two EEG recordings: in one they will receive the melatonin solution (5 mg), in the other they undergo only partial sleep deprivation (about 50% of physiological sleep). The primary endpoint of the study is represented by the time to fall asleep, secondary objectives are represented by frequency of epileptiform discharges, presence/absence of epileptic seizures, In addition, the levels of 6-sulfatoxymelatonina, the primary metabolite of melatonin in saliva and urine, will be determined with a validated LC-MS method.

Detailed description: Background: Electroencephalographic recording is essential in children with suspected or diagnosed epilepsy. Due to difficulties in obtaining a reliable EEG, in pediatric patients electroencephalographic recordings are often performed during sleep in order to reduce the number of artefacts connected to movements and to activate epileptic discharges. To date, there are no shared guidelines about hypno-induction. Most of hypnotic drugs such as benzodiazepines and barbiturates are known to alter EEG registration, by changing background activity or epileptiform activities. Clinicians often aim to induce sleep by total or partial sleep deprivation. A recent survey assessing strategies used by various centers in Italy highlights that there is a great heterogeneous approach to obtain hypno-induction. Among sleep-inductive interventions, the use of melatonin is the most common alone or in combination with sleep-deprivation. Melatonin is a hormone (N-acetylmethoxytryptamine), produced by the pineal gland, whose secretion is regulated by the suprachiasmatic nucleus of the hypothalamus and which is able to regulate circadian rhythms. An open-lable study evaluated the role of melatonin on the EEG recordings (artefacts, anomalies) and its efficacy in inducing sleep in 50 children with epilepsy or with neurodevelopmental disorders. This study demonstrates that melatonin is not more effective than sleep deprivation in hypno-induction, without modifying the EEG pattern. Furthermore, melatonin is equally efficient as partial sleep deprivation in inducing sleep and does not affect the occurrence of epileptic discharges in the EEG recording. Another recent study combined sleep deprivation and melatonin revealing the greater effectiveness of the combination of the two methods against the use of them individually. However, this study was not randomized. Moreover, there is no clear consensus about when and in which doses melatonin should be administrated in children: doses vary between different studies ranging from 2 to 20 mg.

From these observations it is clear, therefore, that the role of melatonin is strategic in hypno-induction and no cases of toxicity or adverse effects in the short and long term deriving from the use of melatonin are known in the literature. The aim of this randomized study is to determine non-inferiority of melatonin 5 mg against sleep deprivation in inducing sleep in a cohort of children and adolescents with epilepsy and to determine if melatonin could affect the frequency of epileptic discharges or clinically detectable epileptic seizures during nap EEG recordings. Furthermore, the investigators try to indicate an adequate dose for melatonin for hypno-induction. Moreover, the levels of 6-sulfatoxymelatonina, the primary metabolite of melatonin in saliva and urine, will be determined with a validated LC-MS method to detect a possible correlation between sleep induction and melatonin metabolism.

Each enrolled patient will be subjected to two nap EEG recordings receiving in one the melatonin-based solution under study at a dosage of 5 mg, in the other they will be subjected to sleep deprivation (defined as 50% of physiological sleep). The electroencephalographic recordings with video and polygraphy in siesta at the same time, will be performed at a time distance of 1-3 months.

The study is open label and therefore no masking method is used. In order to minimize the bias deriving from the open label situation, the calculation of the time to fall asleep is based on objective EEG parameters (disappearance of the background rhythm of the alpha band on the posterior regions and appearance of the physiological hypnic figures, characteristics of the N1 phase of non-REM sleep), as well as the calculation of the frequency of epileptic anomalies which occurs through the use of special instrumentation (so-called "tip counter tool", an automatic tool for detecting epileptiform anomalies on the electroencephalographic trace ).

In addition, the levels of 6-sulfatoxymelatonina, the primary metabolite of melatonin in saliva and urine, will be determined with a validated LC-MS method.

Duration of the study: 52 weeks Duration of enrollment: 36 weeks

Eligibility criteria: Inclusion Criteria:

* pediatric patients with epilepsy aged between 4 and 10 years with normal psychomotor development and IQ\> 70;
* stable seizure frequency in the 3 months preceding the enrollment ;
* stable anti-seizure medications in the 3 months preceding the enrollment;
* written informed consent from the legal representative.

Exclusion Criteria:

* subjects diagnosed with obstructive sleep apnea or other sleep disorders;
* history of neurodevelopmental disorders;
* concomitant use of hypnotics, stimulants, systemic corticosteroids or other immunosuppressants;
* concomitant daily use of melatonin;
* any conditions which, in the investigator's judgment, would compromise the achievement of the study objectives;
* refusal to sign the informed consent from the legal representative.

Primary outcomes:
measure: Time elapsed (in seconds) from the starting of the EEG and beginning of sleep stages at EEG recording with melatonin
timeFrame: From 0 seconds to 1.5 hours
measure: Time elapsed (in seconds) from the starting of the EEG and beginning of sleep stages at EEG recording with deprivation
timeFrame: From 0 seconds to 1.5 hours
Secondary outcomes:
measure: Frequency of epileptic anomalies
timeFrame: From 0 seconds to 1.5 hours
measure: Clinically detectable seizures
timeFrame: From 0 seconds to 1.5 hours
measure: Levels of 6-sulfatoxymelatonina
timeFrame: 120 minutes after oral melatonin solution
Other outcomes:
Locations:
city: Pavia
country: Italy
facility: Child and Adolescent Epileptology Center
Study officials:
affiliation: Child and Adolescent Epileptology Center
name: Valentina De Giorgis, MD
role: PRINCIPAL_INVESTIGATOR
References:
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