The use of melatonin in children with neuro-developmental disorders and impaired sleep; a randomised, double-blind, placebo-controlled, parallel study

ISRCTN	ISRCTN05534585
DOI	https://doi.org/10.1186/ISRCTN05534585
EudraCT/CTIS number	2006-004025-28
Secondary identifying numbers	HTA 05/14/02

Submission date: 23/01/2007
Registration date: 26/01/2007
Last edited: 12/07/2016

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

Background and study aims
The management of sleep problems in children with learning difficulties is often less than ideal because the drugs used have unwanted side-effects or behaviour management is very difficult to arrange. Melatonin is a drug which may improve sleep in these children and it seems to have far fewer side-effects than the other drugs used. The aim of this study is to find out how effective and safe melatonin is at improving night-time sleep in children with developmental or learning difficulties.

Who can participate?
Children aged 3 to 15 with developmental or learning difficulties and sleep problems

What does the study involve?
Participants are randomly allocated to receive either melatonin or an inactive treatment (called a 'placebo' or 'dummy'). The study looks at two main outcomes. These are total night-time sleep and the time taken to fall asleep. The study also measures how many times the children wake up during the night. These outcomes are measured using nightly sleep diaries, a simple device worn at the wrist (like a watch), and questionnaires. Some questionnaires are also used to assess quality of life in the children and their families.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
Alder Hey Children's NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
May 2007 to November 2010

Who is funding the study?
Health Technology Assessment Programme (UK)

Who is the main contact?
Dr Richard Appleton
Richard.Appleton@alderhey.nhs.uk

Contact information

Dr Richard Appleton
Scientific

The Roald Dahl EEG Department
Paediatric Neurosciences Foundation
Alder Hey Children's NHS Foundation Trust
Eaton Road
Liverpool
L12 2AP
United Kingdom

Phone	+44 (0)151 252 5851
Email	Richard.Appleton@alderhey.nhs.uk

Study information

Study design	Randomised double-blind placebo-controlled parallel study
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet
Scientific title	The use of MElatonin in children with Neuro-developmental Disorders and impaired Sleep; a randomised, double-blind, placebo-controlled, parallel study
Study acronym	MENDS
Study hypothesis	Current information as of 08/06/10: Compared with placebo, melatonin treatment will increase total sleep duration. Initial information at time of registration: Compared with placebo, melatonin treatment will reduce sleep latency and increase total sleep duration. More details can be found at: http://www.nets.nihr.ac.uk/projects/hta/051402 Protocol can be found at: http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0015/51162/PRO-05-14-02.pdf
Ethics approval(s)	North West MREC, 26/05/2007, ref: 07/MRE08/43
Condition	Neuro-developmental disorders
Intervention	4 week run in period with sleep hygiene intervention, followed by treatment with either melatonin or placebo. At the end of 4 weeks (T0), assuming the child continues to fulfil the entry criteria and further consent is provided, the child will be randomised into the study. Each child will be followed up for 12 weeks from date of randomisation, by a combination of home visits, telephone contact and clinic attendance. The active compound (melatonin) and placebo (matching in package and appearance) will be administered at the time that is appropriate to the childs usual bedtime; wherever possible, this time will remain the same throughout the study. The starting dose will be 0.5 mg and will increase every 7 days through 2 mg and 6 mg up to a maximum of 12 mg, depending upon the patients response to the preceding dose.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Melatonin
Primary outcome measure	Current information as of 08/06/2010: Total night-time sleep Initial information at time of registration: 1. Total night-time sleep 2. Time to sleep onset (sleep latency)
Secondary outcome measures	Current information as of 08/06/2010: 1. Total night time sleep calculated using actigraphy data 2. Sleep efficiency calculated by (number of minutes spent sleeping in bed/total number of minutes spent in bed) x 100 3. Composite sleep disturbance index scores 4. Daily global measure of parental perception of childs sleep quality 5. Behavioural problems assessed using Aberrant Behaviour Checklist (ABC) 6. Quality of Life of the parent assessed using the Family Impact Module of the PedsQL™ 7. Level of daytime sleepiness in caregivers assessed using Epworth Sleepiness Scale 8. Number and severity of seizures evaluated using seizure diaries throughout trial follow-up 9. Adverse effects of melatonin treatment assessed weekly between weeks T0W to T12W using TESS (Treatment Emergent Signs and Symptoms) 10. Salivary melatonin concentrations 11. Associations between genetic variants and abnormal melatonin production 12. Sleep onset latency (the time taken to fall asleep) calculated using actigraphy 13. Sleep onset latency (the time taken to fall asleep) calculated using sleep diaries Amended as of 28/04/2008: 1. Total night time sleep calculated using actigraphy data 2. Sleep efficiency calculated by (number of minutes spent sleeping in bed/total number of minutes spent in bed) x 100 3. Composite sleep disturbance index scores 4. Daily global measure of parental perception of childs sleep quality 5. Behavioural problems assessed using Aberrant Behaviour Checklist (ABC) 6. Attention and vigilance assessed in care-givers using the car game from the DENEM project 7. Attention and vigilance assessed in children using the Go/No go game from the MARS battery 8. Quality of Life of the parent assessed using the Family Impact Module of the PedsQL™ 9. Level of daytime sleepiness in caregivers assessed using Epworth Sleepiness Scale 10. Number and severity of seizures evaluated using seizure diaries throughout trial follow-up 11. Adverse effects of melatonin treatment assessed weekly between weeks T0W to T12W using TESS (Treatment Emergent Signs and Symptoms) 12. Salivary melatonin concentrations 13. Associations between genetic variants and abnormal melatonin production Initial information at time of registration: 1. Number and severity of seizures evaluated using seizure diaries throughout trial follow-up 2. Level of concentration and severity of learning difficulties and behaviour problems assessed using the Aberrant Behaviour Checklist (ABC) 3. Motor skills and memory assessed using electronic tests (DENEM project and MARS battery items) completed by care-givers and children 4. Quality of life of care-giver assessed using the Kidscreen-10 index and child assessed using the Family Impact Module of PedsQL™ 5. Adverse effects of melatonin treatment assessed weekly between weeks T0 to T12W using TESS (Treatment Emergent Signs and Symptoms) 6. Salivary melatonin concentrations
Overall study start date	01/05/2007
Overall study end date	30/11/2010

Eligibility

Participant type(s)	Patient
Age group	Child
Lower age limit	3 Years
Upper age limit	15 Years
Sex	Both
Target number of participants	114
Participant inclusion criteria	Current information as of 08/06/2010: 1. Children aged 3 years to 15 years 8 months at screening All other inclusion criteria remain the unchanged. Amended as of 29/04/2008: 1. Children aged 5 years to 15 years 8 months at screening 2. Diagnosis of a neuro-developmental disorder that has been made by a community paediatrician, paediatric neurologist or paediatric neurodisability consultant, categorised as: 2.1. Developmental delay alone 2.2. Developmental delay and epilepsy* 2.3. Developmental delay and autistic spectrum disorder* (ASD) 2.4. Developmental delay with other (other is defined as the child having a specific genetic/chromosomal disorder), or 2.5. Any combination of the above 3. Adaptive Behaviour Assessment System (ABAS) questionnaire score with a percentile rank below 7 4. Minimum 5 months history of impaired sleep at screening as defined by: 4.1. Not falling asleep within one hour of 'lights off' or 'snuggling down to sleep' at age-appropriate times for the child*, and/or: 4.2. Less than 6 hours of continuous sleep in three nights out of five 5. Children whose parents are likely to be able to use the actigraph and complete sleep diaries 6. Children who are able to comply with taking the study drug 7. English speaking 8. Children whose parents have completed sleep diaries for an average of 5 out of 7 nights at T0W. In coding the presence of epilepsy and ASD diagnoses, we will require sight of documentation from relevant services that demonstrate appropriate diagnostic assessments and investigations have been used ** This will be the child's usual bedtime (recorded in the sleep diary) based upon the familys normal routine Initial information at time of registration: 1. Children aged 5 years to 15 years 11 months / < 16 years 2. Diagnosis of a neuro-developmental disorder that has been made by a community paediatrician, paediatric neurologist or paediatric neurodisability consultant, categorised as: 2.1. developmental delay alone 2.2. developmental delay and epilepsy* 2.3. developmental delay and Autistic Spectrum Disorder* (ASD) 2.4. developmental delay with other (other is defined as the child having a specific genetic/chromosomal disorder) 3. Vineland assessment score of at least 2 SD below the age standardised reference population mean 4. No plans to commence the following medication: 4.1. Any benzodiazapines 4.2. alimemazine tartrate 4.3. amisulpride (Solian) 4.4. chlorpromazine (Largactil) 4.5. haloperidol (Haldol) 4.6. olanzapine (Zyprexa) 4.7. risperidone (Risperdal) 4.8. sertindole (Serdolect) 4.9. sulpiride (Sulpidil, Sulpor) 4.10. thioridazine (Melleril) 4.11. trifluoperazine (Stelazine) 5. Diagnosis of impaired sleep as defined by: 5.1. not falling asleep within one hour of 'lights off' or 'snuggling down to sleep' at age-appropriate times for the child*, and/or: 5.2. less than 6 hours of continuous sleep in three nights out of five In coding the presence of epilepsy and ASD diagnoses, we will require sight of documentation from relevant services, that demonstrate appropriate diagnostic assessments and investigations have been used ** This will be the childs usual bedtime based upon the family's normal routine
Participant exclusion criteria	Current information as of 08/06/2010: 2. Children who have been taking the following medication for less than 2 months: 2.1. Any benzodiazepines 2.2. Amisulpride (Solian) 2.3. Chlorpromazine (Largactil) 2.4. Haloperidol (Haldol) 2.5. Olanzapine (Zyprexa) 2.6. Risperidone (Risperdal) 2.7. Sertindole (Serdolect) 2.8. Sulpiride (Sulpidil, Sulpor) 2.9. Thioridazine (Melleril) 2.10. Trifluoperazine (Stelazine) 4. Current use of sedative or hypnotic drugs, including Choral hydrate, Triclofos, and alimemazine tartrate (Vallergan) (minimum of 14 days washout required) All other exclusion criteria remain unchanged. Amended as of 29/04/2008: 1. Children treated with melatonin within 5 months prior to screening 2. Any plans to commence the following medication: 2.1. Any benzodiazepines 2.2. Alimemazine tartrate (Vallergan) 2.3. Amisulpride (Solian) 2.4. Chlorpromazine (Largactil) 2.5. Haloperidol (Haldol) 2.6. Olanzapine (Zyprexa) 2.7. Risperidone (Risperdal) 2.8. Sertindole (Serdolect) 2.9. Sulpiride (Sulpidil, Sulpor) 2.10. Thioridazine (Melleril) 2.11. Trifluoperazine (Stelazine) 3. Current use of beta blockers (minimum of 7 days washout required) 4. Current use of sedative or hypnotic drugs, including Choral hydrate and Triclofos (minimum of 14 days washout required) 5. Children with a known allergy to melatonin 6. Regular consumption of alcohol (greater than 3 times per week) 7. Children for whom there are suggestive symptoms of Obstructive Sleep Apnoea Syndrome (OSAS) (such as combinations of snoring, gasping, excessive sweating or stopping breathing during sleep), physical signs supportive of OSAS (such as very large tonsils/very small chin), or results of investigations suggesting OSAS (such as overnight pulse oximetry or polysomnography) for which the child should be referred to appropriate respiratory or ENT colleagues for specific assessment and treatment 8. Girls or young women who are pregnant at the time of screening (T-4W) 9. Currently participating in a conflicting clinical study or participation in a clinical study involving a medicinal product within the last 3 months Previous exclusion criteria: 1. Children treated with melatonin within 6 months prior to screening 2. Children whose parents are unlikely to be able to use the actiwatch or complete sleep diaries, or both 3. Children where there may be a problem with major non-concordance with medication 4. Girls or young women who are pregnant at the time of screening (4 weeks prior to randomisation) 5. Currently participating in a conflicting clinical study or participation in a clinical study involving a medicinal product within the last 30 days
Recruitment start date	01/05/2007
Recruitment end date	30/11/2010

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Alder Hey Children's NHS Foundation Trust

Liverpool
L12 2AP
United Kingdom

Sponsor information

Alder Hey Children's NHS Foundation Trust (UK)
Hospital/treatment centre

c/o Dr Matthew Peak
Director of Research
Alder Hey Children's NHS Foundation Trust
Eaton Road
Liverpool
L12 2AP
England
United Kingdom

Email	Matthew.Peak@alderhey.nhs.uk
"ROR"	https://ror.org/00p18zw56

Funders

Funder type

Government

Health Technology Assessment Programme
Government organisation / National government

Alternative name(s): NIHR Health Technology Assessment Programme, HTA
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/11/2012		Yes	No
Results article	results	05/11/2012		Yes	No

Editorial Notes

17/03/2011: the target number of participants was changed from 172 to 114.
11/05/2009: the overall trial end date was changed from 31/05/2009 to 30/11/2010.