[Summary text]
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention
Control
Included criteria: Both boys and girls, aged 6-12years, who were diagnosed with AD, using the Hanifin and Rajka criteria, were recruited for this study.
Excluded criteria: Children diagnosed with acquired im-munosuppressive disease or other chronic conditions and patients who were receiving any systemic corticosteroid or other immuno-suppressive drugs or taking antihistamines within the last 3months before the study were excluded.
Pretreatment:
Intervention Characteristics
Intervention
Bivirkninger
Sponsorship source: The present study was supported by a grant from the Vice-chancellor for Research, KAUMS, Kashan, and Iran (grant no. 96110)
Country: Iran
Authors name: Zatollah Asemi
Institution: Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
Email: asemi_r@yahoo.com
RCT
Børn + unge med hjernerystelse
2 uger med melatonin 10 mg
Bivirkninger
RCT Cross-over
Atopic dermatitis
4 uger melatonin 3 mg
Bivirkninger
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
RCT - cross-over
developmental disabilities
4-6 weeks with melatonin 5mg
Bivirkninger
Fundet i Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
RCT - cros-over
isiopathic sleep, sleep onset difficulties
2 uger med melatonin 1 mg
Bivirkninger
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
See McDaid 2019 "Outcome domains and outcome measures used in studies assessing the effectiveness of interventions to manage non-respiratory sleep disturbances in children with neurodisabilities: a systematic review".
RCT
RCT cross-over
Epilepsi
4 uger med melatonin 9 mg
Bivirkninger
See McSee McDaid 2019 "Outcome domains and outcome measures used in studies assessing the effectiveness of interventions to manage non-respiratory sleep disturbances in children with neurodisabilities: a systematic review".
RCT cross-over
Rett Syndrome
4 uger med melatonin 2,5-7,5 mg
Bivirkninger
RCT
Idiopathic Chronic Sleep onset insomnia (komorbiditet primært ADHD)
4 uger med melatonin 5 mg
Bivirkninger
RCT
Idiopathic Chronic Sleep onset insomnia (komorbiditet primært ADHD)
4 uger med melatonin 5 mg
Bivirkninger
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention
Control
Inclusion criteria: Inclusion criteria were 6 to 12 years old, diagnosis of ADHD and SOI, and written informed consent obtained from parents.
Exclusion criteria: Exclusion criteria were total IQ <80, pervasive developmental disorder, chronic pain, known disturbed hepatic or renal function, epilepsy, earlier use of melatonin, and use of stimulants, neuroleptics, benzodiazepines, clonidine, antidepressants, hypnotics, or " -blockers" within 4 weeks before enrollment.
Intervention Characteristics
Intervention
Control
Indsovningstid (Lights out) (målt med actigraph)
Total sovetid (minutes) (målt med Actigraph)
Livskvalitet
Sponsorship source: This study was supported by the Maarten Kapelle Foundation and Foundation De Drie Lichten.
The authors thank Pharma Nord for making available the trial medication.
Country: Holland
Authors name: Kristiaan B. Van der Heijden
Institution: Epilepsy Center Kempenhaeghe, Heeze;
Van der Heijden is also with the Maastricht Institute of Brain and Behavior, Maastricht.
RCT (Meldos study)
70 children with Chronic Sleep Onset Insomnia
1 uge med hhv 0,05, 0.10, 0.15 mg melatonin pr kg legemsvægt (3 IV arme - 1 kon)
Bivirkninger
RCT cross-over
Neurodevelopmental disabilities
10 dage med melatonin 5 mg
Bivirkninger
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Inclusion criteria: This two-phase treatment study began with sleep hygieneintervention. Only children who continued to have initial insomnia of 960 minutes were eligible to enter the double-blind, randomized, crossover trial of melatonin versus placebo. Inclusion criteria for participation in the study required that the child be taking stimulant medication with no change in dose for at least 2 months and be willing to maintain the current dose for the duration of the protocol. Parents had to demonstrate competence at completing the somnolog and children had to be willing and able to wear an actigraph wrist monitor and assent to the demands of the sleep hygiene program of a fixed bedtime and awakening time.
Exclusion criteria: Exclusion criteria included children who were in stressful life circumstances that could account for new onset sleep difficulties or children who could or would not comply with sleep hygiene recommendations because they were sharing a bed or had some other environmental factor that would account for their sleep deficits. This included children who had comorbid medical or psychiatric illness that could be associated with insomnia or required treatment with a medication other than a stimulant at dosages known to cause insomnia or sedation. Children living in multiple households were excluded unless all of the caregivers could reliably participate in the program. The resulting sample was nonetheless comorbid for difficulties with oppositional disorder, enuresis, learning problems, and some degree of anxiety or depressive symptoms. We did not accept children with known diagnoses of other major sleep disorders but neither were these children evaluated in a sleep laboratory to rule out these conditions with a polysomnogram.
Intervention Characteristics
Intervention
Placebo
Indsovningstid (Lights out) (sleep latency) (målt med somnolog), (mean, SD)
Sponsorship source: This study was sponsored as an investigator-initiated trial by Circa Dia BV. (melatonin-producent).
Country: Canada
Authors name: Margaret Weiss
Institution: UBC
Email: weiss@cw.bc.ca
RCT
Delayed sleep phase disorder (DSPD)
2 uger med melatonin 3 mg
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Reference: Abdelgadir et al. 2018
Quote: "Randomization assignment was conducted using computer- generated random numbers."
Randomization was performed with a computer-generated sequence by special- ized personnel who had no further involvement in the rest of the trial.
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
The capsules were dispensed in numbered sets of three bottles, labelled 1, 2 and 3, each containing six capsules. The sets had been randomized and were delivered together with sealed data in envelopes, separate for each set.
Reference: Abdelgadir et al. 2018
Quote: "the pharmacy department of the Royal United Hospital, which was responsible for generating random numbers and using these to deter- mine whether to start with 5 or 10 mg of melatonin."
Judgement Comment: Insufficient information on sequence generation
Medidata Balance® (Medidata Solu-tion, Inc.; New York, NY, USA) was used to allocate the random numbers to eligible children that had been generated by an independent manager. The minimization method for randomization used a history of ramelteon treatment and the median SOL during the last 7 days of the screening phase in an attempt to avoid the skew randomization to either of the 3 study groups of children with the history or a biased median SOL, if any.
The Investigational Pharmacy at CCHMC performed the randomization by random number generators in www.randomization.com
Judgement Comment: Insufficient information on sequence generation
Not stated
No information on randomization method
Method not mentioned
Quote: "Randomization was performed by a hospital pharmacist not connected to the study in blocks of four to keep the number of patients in each treatment group closely balanced at all times. The following stratification criteria were used: (1) presence of psychiatric comorbidity (disruptive behavior disorder [n = 59]; anxiety disorder [n = 16]; depressive disorder [n = 1]), (2) age category (6-9 years [n = 66]; 10-12 years [n = 39]), and (3) body weight (<40 kg [n = 88]; = 40 kg [n = 17]). Investigators and participants were unaware of treatment allocation. The code was broken after all of the children completed treatment and data were recorded (October 2005)."
For this trial, a specialized internet software application (Medsys/De Nieuwe Coster/2004) was developed for randomization of participants, for calculation of the assigned dose (based on body weight), and for collection of sleep log data.
A blocked randomization method was employed in which every four patients had equal probability of receiving either of the two treatment sequences.Patients were randomly assigned by the hospital pharmacy to receive either melatonin or placebo first.
Quote: "Subjects were randomly assigned by the pharmacy in blocks of four to receive either melatonin and then placebo or the reverse. All of the patients and study"
Judgement Comment: Insufficient information on sequence generation
The randomization lists were created (4 groups for the 2-week intervention and 2 groups for the 3-month follow-up) using the Internet-based program Research Randomizer
Reference: Abdelgadir et al. 2018
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Reference: Abdelgadir et al. 2018
Quote: "Melatonin and placebo tablets were produced in the same shape and package by Webber Naturals Pharmaceutical Company (Coquitlam, Canada) and Barij Essence Pharmaceutical Company (Kashan, Iran), respectively. Randomization assignment was conducted using computer- generated random numbers. Randomization and alloca- tion concealment for both the researchers and participants were carried out by a trained staff at the pediatric clinic."
Allocation codes were disclosed only after the entire clinical trial was completed.The melatonin and placebo tablets were identical in appearance.
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
The melatonin and PL were administered to the students as hard- gelatin capsules, which were indistinguishable from one another by appearance, taste and smell. The capsules were dispensed in numbered sets of three bottles, labelled 1, 2 and 3, each containing six capsules. The sets had been randomized and were delivered together with sealed data in envelopes, separate for each set.
Reference: Abdelgadir et al. 2018
Quote: "Identical capsules of 5 mg of melatonin and placebo were used (two capsules per dose), dis- pensed by the pharmacy department of the Royal United Hospital, which was responsible for generating random numbers and using these to deter- mine whether to start with 5 or 10 mg of melatonin. The dosage regimens were revealed to the investigators and parents or carers only after all of the patients had completed the trial."
Judgement Comment: Identical capsules
Information on allocation concealment was not provided
Random number generators in www.randomization.com, <b>ensured blinding via over- encapsulation of both the melatonin and placebo pills to have the same appearance, and dispensed the study medications.
Quote: "Then the 16 subjects were randomly prescribed CR or FR melatonin in a bubble pack, each for 11 days, following which the drugs were crossed over."
Judgement Comment: Insufficient information on allocation concealment
Identical looking capsules
Melatonin and placebo provided in identical packages. Code was broken when all data was recorded
All investigators were unaware of treatment allocation. Code broken when all data were recorded
Judgement Comment: Insufficient information on allocation concealment
The capsules were packed in unit dose strips, labeled with “Melatonine×mg” masked with an X to keep participants blind to the treatment allocation and subject number.
placebo was prepared by the hospital pharmacy in identical capsules as melatonin
Judgement Comment: Insufficient information on allocation concealment Insufficient information on allocation concealment
Participants were further informed that the capsules contained either melato- nin or maize starch. The melatonin and placebo capsules were packed in identical containers differ- entiated by a number code (1 and 2).
Reference: Abdelgadir et al. 2018
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Reference: Abdelgadir et al. 2018
Quote: "Melatonin and placebo tablets were produced in the same shape and package by Webber Naturals Pharmaceutical Company (Coquitlam, Canada) and Barij Essence Pharmaceutical Company (Kashan, Iran), respectively."
Judgement Comment: Double-blinded. Participants likely blinded (see quote). Tablets packed by two independent companies, personnel likely blinded.
The participants and their caregivers, treating phy- sicians, those assessing outcomes, and those analyzing the data were all masked to group assignment.
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
The randomization of the first two bottles was blind to students and study team and the code was broken only after all study procedures were terminated.
Reference: Abdelgadir et al. 2018
Judgement Comment: Double-blinded, so likely that the participants and personnel were blinded
Patients and personnel who were involved in the present study were blinded to treatment assignments.
Participants and the rest of the study team was blinded to the allocation throughout data collection
Quote: "Both investigators and caregivers were blinded as to the order of the medications."
Nothing mentioned
Nothing mentioned
As above
Quote: "A 4-week randomized, double-blind, placebo-controlled study, immediately following a 1-week baseline period, was conducted between November 2001 and June 2005."
All participants, care providers, and investigators involved in the study were unaware of the treatment allocation.
Patients, caregivers, study investigator, and clinical staff were blind to the medication randomization.
Judgement Comment: double-blinded
The 2-week treatment study was double blinded.
Reference: Abdelgadir et al. 2018
Detection bias due to knowledge of the allocated interventions by outcome assessors
Reference: Abdelgadir et al. 2018
Judgement Comment: Double-blinded
The participants and their caregivers, treating phy- sicians, those assessing outcomes, and those analyzing the data were all masked to group assignment.
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
The randomization of the first two bottles was blind to students and study team and the code was broken only after all study procedures were terminated.
Reference: Abdelgadir et al. 2018
Quote: "The dosage regimens were revealed to the investigators and parents or carers only after all of the patients had completed the trial. The"
Judgement Comment: Outcomes were parent/carer reported, and these were likely blinded.
Patients and personnel who were involved in the present study were blinded to treatment assignments.
The pharmacy and the statistician were unblinded
Quote: "Both investigators and caregivers were blinded as to the order of the medications."
Nothing mentioned
All investigators were blinded
All investigators were unaware of treatment allocation. Code broken when all data were recorded
Judgement Comment: Double-blinded og Actigrafmåling er ikke i risiko for at være under indflydelse af dette
All participants, care providers, and investigators involved in the study were unaware of the treatment allocation.
Patients, caregivers, study investigator, and clinical staff were blind to the medication randomization.
Judgement Comment: double-blinded
Unclear who was blinded
Reference: Abdelgadir et al. 2018
Attrition bias due to amount, nature or handling of incomplete outcome data
Reference: Abdelgadir et al. 2018
Quote: "Overall, there were nine participants who discontinued the study, four in the melatonin intervention group and five in the placebo group, all due to personal reasons (Figure 1). However, using ITT, all 70 participants who had been recruited for the study were included in the final analysis."
Quote: "The intention- to- treat (ITT) analysis was applied to all randomly allocated subjects."
Uklart hvilken impact hhv 4 (melatonin gruppen) og 6 (placebo gruppen) har i dette cross over study, idet alle deltagere EoT har modtaget intervention og placebo. 79% gennemfører hele studiet
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
No apparent sources of bias
Reference: Abdelgadir et al. 2018
Quote: "One patient completed the study, but the diaries were lost in the mail, and we had not thought to ask to have them photocopied before they were posted to us."
Data missing did not occur during the screening and randomization phases. Information on all outcomes seem sufficient to use in further analyses although main outcome data could be more clearly presented
No apparent sources of bias
Judgement Comment: No information on missing data
No drop outs
No apparent sources of bias
No drop outs
Quote: "Analyses were conducted using SPSS, 12.0.1 (SPSS, Inc., Chicago, IL) on an intention-to-treat basis (significance p = .05, two-sided)."
Judgement Comment: af 107 patienter er der to drop-outs (1 i hver gruppe)
Afhængig af outcome er der en samlet dropout rate på 5-10 deltagere
One patient (1%) withdrew and was hence excluded from the analysis.
Quote: "Parents of 33 patients seen in the ADHD clinic at British Columbia Children’s Hospital consented to their child’s participation and all of the children provided written accept. Five parents/patients later with- drew consent or were unable to continue participating in the study. Five patients were sleep hygiene responders and did not continue into randomization. Of the 23 patients eligible for randomization, 1 with- drew consent. Three patients were discontinued because of protocol violations during the randomized treatment phases, which left 19 cases that were able to be evaluated. There were no major differences in outcomes if these patients were or were not included; thus, the results presented include the data for the patients who completed as per protocol (N = 19)."
No apparent sources of bias
Reference: Abdelgadir et al. 2018
Reporting bias due to selective outcome reporting
Reference: Abdelgadir et al. 2018
Quote: "DS 2.1 | Participants and ethics statements <b>This randomized, double- blinded, placebo- controlled trial was ini- tially registered in the Iranian registry of clinical trials (http://www.</b> irct.ir: IRCT2017082733941N12). The study was"
Judgement Comment: There are reported on more outcomes that are stated a priori in the study protocol, thus they do not match on the reported outcomes,
No apparent sources of bias
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
Reference: Abdelgadir et al. 2018
No apparent sources of bias
Reference: Abdelgadir et al. 2018
Quote: "The sleep diaries were used to monitor the sleep latency (ie, time taken to fall asleep), the total sleep time, and the number of awakenings each night. The seizure diaries were used to monitor the frequency and type of seizures (if any) experienced by the patients during the study period. The carers were also asked to record any illnesses the child had or any possible side effects that they suffered during the trial period."
Judgement Comment: No reference to study protocol, but appears to report on all outcomes of interest
No reference to study protocol, but appears to report on outcomes of interest
No apparent sources of bias
Judgement Comment: No reference to study protocol, but appears to report on all outcomes of interest
No apparent sources of bias
No apparent sources of bias
No apparent sources of bias
Quote: "The protocol was approved by the institutional review board at each center, as a multicenter trial by the Central Committee on Research Involving Human Subjects, and registered in the International Standard Randomized Controlled Trial Number Register (ISRCTN- 47283236). The trial was performed according to the 1997 European Guidelines for Good Clinical Research Practice in children and followed the 1983 revised provisions of the 1975 Declaration of Helsinki."
Judgement Comment: Study protocol and reported outcomes match
No apparent sources of bias
No apparent sources of bias
Judgement Comment: No reference to study protocol, but the study appears to report on all outcomes of interest.
No apparent sources of bias
Reference: Abdelgadir et al. 2018
Bias due to problems not covered elsewhere in the table
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
Quote: "The present study was supported by a grant from the Vice- chancellor for Research, KAUMS, Kashan, and Iran (grant no. 96110). C O N FL I C T O F I N T E R E S T None."
Judgement Comment: The study appears to be free from other sources of bias
No apparent sources of bias
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
No apparent sources of bias
Reference: Abdelgadir et al. 2018
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
Quote: "Supported by a grant from the Bath Unit for Research in Paediatrics. E.H. was funded by the Tuberous Sclerosis Association and Cow and Gate. F.O. was in receipt of a Wellcome Trust research training fellowship in epidemiology."
Judgement Comment: The study appears to be free from other sources of bias
The study sponsor, Nobelpharma Co., Ltd., provided investigational drugs for this study—melatonin granules and placebo. Nobelpharma Co., Ltd. manufac-tured placebo, and an independent third party organization ensured indistinguishability between active drug—1- and 4-mg melatonin granules—and placebo. Not clearly stated that funder was not involved in any processes.
No apparent sources of bias
Quote: "NEURIM Pharmaceuticals, Tel Aviv, Israel"
Judgement Comment: Last author from the pharma industry. Conflicts of interest not reported nor how the study was funded. The study appears otherwise to be free from other sources of bias
No apparent sources of bias
No apparent sources of bias
No apparent sources of bias
Judgement Comment: The study appears to be free from other sources of bias
No apparent sources of bias
Study sponsoring in favour of melatonin?
Quote: "Disclosure: Dr. Weiss is a consultant, an advisory board and speaker’s bureau member, and holds research contracts/grants with Eli Lilly, Shire, and Janssen Ortho; she is a consultant to and an advisory board and a speaker’s bureau member of Novartis; she holds a research contract with and is a consultant to Purdue; she is a consultant to and an advisory board member of Johnson & Johnson; and holds a research contract/grant with Circa Dia. The other authors have no financial relationships to disclose."
Judgement Comment: The study appears to be free from other sources of bias
No apparent sources of bias
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."
See Abdelgadir 2018 "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: A systematic review and meta-analysis."