E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
children with neuro-developmental disorders and impaired sleep |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064062 |
E.1.2 | Term | Neurodevelopmental disorder |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040984 |
E.1.2 | Term | Sleep disorder |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of this trial is to confirm (or refute) that immediate release melatonin is beneficial when compared to placebo in improving total duration of night-time sleep and in reducing sleep latency (the time taken to fall asleep) in children with neuro-developmental problems.
At randomisation, each patient will be allocated their own ‘individual patient package’ containing either melatonin or placebo. Each child will be given the first dose and kept on that dose for a minimum of seven days. For the next three weeks and at each one-week interval during this time, the child’s sleep disorder will be reviewed (using subjective and objective) and the medication either left unchanged or increased to the next dose increment. There are a maximum of 3 dose increments after the starting dose of 0.5 mg, through 2, 6 and up to a maximum of 12 mg. Each child will remain on whichever dose is felt to have been the most effective.
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E.2.2 | Secondary objectives of the trial |
Total night time sleep calculated using actigraphy data Sleep efficiency calculated from the actigraphy Composite sleep disturbance index scores Daily global measure of parental perception of child’s sleep quality Behavioural problems assessed using Aberrant Behaviour Checklist Quality of Life of the care-giver assessed using the Family Impact Module of the PedsQL Level of daytime sleepiness of caregiver assessed using the Epworth Sleepiness Scale Number and severity of seizures evaluated using seizure diaries throughout trial follow-up Adverse effects of melatonin treatment assessed weekly between weeks T0W to T12W using ‘TESS’ (Treatment Emergent Signs and Symptoms) Salivary melatonin concentrations Associations between genetic variants and abnormal melatonin production
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
“Processes in Recruitment to Randomised Controlled Trials (RCT’s) of medicines for children (RECRUIT)”. RECRUIT was approved in its own right by the North West MREC at its meeting on 2 March 2007 (REF 07/MRE08/6). RECRUIT will be examining communication processes in the recruitment of participants to MENDS with the aim of identifying strategies for subsequent trials of medicines for children to improve trial recruitment and conduct. RECRUIT will involve: a) Routine audio-recording of MENDS discussions (consultations) between families and practitioners (trial recruiters). b) Follow-up interviews with up to 8 families (parents and children where aged 7 or over) who agree to participate in MENDS. c) Follow-up interviews with up to 8 families (parents and children where aged 7 or over) who decline participation in MENDS. d) Follow-up interviews with up to 8 trial recruiters involved in approaching families to take part in MENDS. If permission for audio-recording is declined by a family the recruitment consultation will not be recorded. If permission is given the recruiter will activate an audio-recorder. At the end of the MENDS recruitment consultation the recruiter will discuss RECRUIT with the family and seek their permission to pass their details to one of the RAs employed on RECRUIT, who will then make contact with families and obtain written informed consent for participation in the RECRUIT study. Recordings from families who decline RECRUIT will be erased as soon as practicable. All families who express an interest in RECRUIT but are not selected for follow-up interview will be contacted by letter to thank them and inform them that their recordings have been erased. Audio-recordings of the recruitment consultations will only be released to the RECRUIT RAs after the consent of participants has been obtained. |
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E.3 | Principal inclusion criteria |
1. Children aged 3 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: a. developmental delay alone b. developmental delay and epilepsy* c. developmental delay and autistic spectrum disorder* (ASD) d. developmental delay with ‘other’ (‘other’ is defined as the child having a specific genetic/chromosomal disorder). or 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: a. not falling asleep within one hour of 'lights off' or 'snuggling down to sleep' at age-appropriate times for the child**, and/or: b. 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 family’s normal routine
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E.4 | Principal exclusion criteria |
1. Children treated with melatonin within 5 months prior to screening 2. Any plans to commence the following medication: • any benzodiazepines • amisulpride (Solian) • chlorpromazine (Largactil) • haloperidol (Haldol) • olanzapine (Zyprexa) • risperidone (Risperdal) • sertindole (Serdolect) • sulpiride (Sulpidil, Sulpor) • thioridazine (Melleril) • 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, Triclofos and alimemazine tartrate (Vallergan) (minimum of 14 days washout required) 5. Children with a known allergy to melatonin 6. Regular consumption of alcohol (> 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
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Total duration of night-time sleep. 2. Sleep onset latency (the time taken to fall asleep). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |