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Trial registered on ANZCTR
Registration number
ACTRN12613000647730
Ethics application status
Approved
Date submitted
2/06/2013
Date registered
11/06/2013
Date last updated
2/11/2018
Date data sharing statement initially provided
2/11/2018
Type of registration
Prospectively registered
Titles & IDs
Public title
Efficacy of melatonin in idiopathic rapid eye movement (REM) sleep behaviour disorder
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Scientific title
Efficacy of melatonin in idiopathic rapid eye movement (REM) sleep behaviour disorder: A double-blind, randomised controlled trial
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Secondary ID [1]
282354
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Nil
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Universal Trial Number (UTN)
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Trial acronym
M-iRBD
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
REM sleep behaviour disorder
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Efficacy of melatonin
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Condition category
Condition code
Neurological
289264
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0
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Other neurological disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Circadin prolonged release tablet 2 mg (prolonged release melatonin 2mg) - 1x2tablets (total of 4mg per day), orally ingested , after food, within 1 hour bedtime for 8 weeks
Total duration of the trial is 16 weeks: 4 weeks of screening period, 8 weeks of treatment period, 4 weeks of followup period.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
Two matched placebo tablets (lactose monohydrate) ingested orally once a day after food within 1 hour of bedtime for 8 weeks
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Control group
Placebo
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Outcomes
Primary outcome [1]
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The efficacy of melatonin will be assessed by the difference in the mean of the total number of recorded events of all kinds as captured by the "weekly CIRUS RBD questionnaire" which measures the frequency and the severity of symptoms of REM sleep behaviour disorder.
Improvement over the last 4 weeks of treatment compared to the 4 weeks prior to treatment whilst including statistical information collected during the intervening period to characterize individual phenotype
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Assessment method [1]
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Timepoint [1]
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Aggregate of all incidents measured within weeks 5 to 8 of treatment
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Secondary outcome [1]
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Improvement in the index of REM sleep without atonia (RWAI) on a polysomnogram as described by Ferri R. et al. in
"A quantitative statistical analysis of the submentalis muscle EMG amplitude during sleep in normal controls and patients with REM sleep behavior disorder. Journal of sleep research. 2008;17(1):89-100."
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Assessment method [1]
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Timepoint [1]
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the timepoint is before end of treatment, week 8 to 12 versus prior to treatment, week 1 to 4.
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Secondary outcome [2]
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The efficacy of melatonin will be assessed by the difference in the mean of the total number and severity of injuries and bedroom environment damage incidents as captured by the "weekly CIRUS RBD questionnaire" which measures the frequency and the severity of symptoms of REM sleep behaviour disorder.
Improvement over the last 4 weeks of treatment compared to the 4 weeks prior to treatment whilst including statistical information collected during the intervening period to characterize individual phenotype
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Assessment method [2]
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Timepoint [2]
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Aggregate of all incidents measured within weeks 5 to 8 of treatment
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Secondary outcome [3]
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The efficacy of melatonin will be assessed by the difference in the mean of the total number and severity of vivid dreams as captured by the "weekly CIRUS RBD questionnaire" which measures the frequency and the severity of symptoms of REM sleep behaviour disorder.Improvement over the last 4 weeks of treatment compared to the 4 weeks prior to treatment whilst including statistical information collected during the intervening period to characterize individual phenotype
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Assessment method [3]
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Timepoint [3]
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Aggregate of all incidents measured within weeks 5 to 8 of treatment
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Secondary outcome [4]
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Improvement in self-reported quality of sleep (Pittsburg sleep quality index)
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Assessment method [4]
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Timepoint [4]
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at week 12 (end of treatment) versus week 4 (night prior to randomization)
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Secondary outcome [5]
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Comparison of Leeds Sleep Evaluation Questionnaire between melatonin and placebo. The Leeds questionnaire is a side-effect of hypnotics questionnaire with 4 sub-scales measured on 10 visual analogue scales
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Assessment method [5]
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Timepoint [5]
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at week 12 (end of treatment), at week 8 (mid-treatment) and using information from week 4 (prior to randomization)
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Secondary outcome [6]
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SUB-ANALYSES. The validity of the weekly CIRUS RBDQ will also be investigated using these clinical trial data. We will correlate aggregate events on the wCIRUS-RBDQ questionnaire to other potential measures of RBD such as actigraphy, CGI, RWAI.
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Assessment method [6]
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Timepoint [6]
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Baseline, end of treatment and change during treatment values will all be investigated for the purposes of establishing validity of various methods of measuring RBD
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Secondary outcome [7]
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The clinical global improvement impression score
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Assessment method [7]
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Timepoint [7]
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At week 12 (end of treatment) and a comparison of secondary importance at week 16
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Secondary outcome [8]
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Change in the self-reported sleepiness (ESS),
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Assessment method [8]
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Timepoint [8]
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at week 12 (end of treatment) versus week 4 (night prior to randomization)
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Secondary outcome [9]
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A change in the Depression, Anxiety, Stress scales (the DASS), a 42-item self-report instrument for measuring depression, anxiety and tension/stress
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Assessment method [9]
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Timepoint [9]
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at week 12 (end of treatment) versus week 4 (night prior to randomization)
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Secondary outcome [10]
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A change in the short form 36 health survey questionnaire (SF-36),a 36-item scale measuring eight-health concepts. It is useful in assessing the health benefits produces by a treatment
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Assessment method [10]
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Timepoint [10]
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at week 12 (end of treatment) versus week 4 (night prior to randomization)
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Eligibility
Key inclusion criteria
1) Age over 18
2) MiniMental State Examination>/=24
3) REM sleep Behaviour Disorde (RBD)r as defined by the International Classification for Sleep Disorder criteria (ICSD-2)
4) Screening questionnaire criteria (RBDSQ) with a score equal or greater than 5/13 confirmed by bed partner
5) Two or more events of RBD defined by dream enactment behaviour and/or sleep related injuries (question 2 and 4 of the wCIRUS-RBDQ) during the 4 weeks (screening period) prior to randomisation.
6) Stable medications for 1 month prior to randomisation.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1) Untreated Obstructive sleep apnea with Apnea Hypopnea Index >20
2) Significant psychiatric disorder or cognitive impairment (MMSE< 24)
3) Any significant liver, kidney or autoimmune disease.
4) Current use of benzodiazepines or other non-benzodiazepine hypnotics (e.g. zaleplon, zolpidem, zopiclone), native compounds of melatonin, other melatoninergic agonists,, unless washout of more than four weeks
5) Drug-induced RBD (antidepressants) with clear relation between RBD onset and medication
6) Excessive alcohol consumption (>25 Unit/week)
7) Pregnancy or lactation
8) Use of light therapy (for treatment of sleep-wake disorders) within the last 6 months
9) Galactose intolerance, LAPP lactase deficiency or glucose-galactose malabsorption
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The patients need to meet the eligibility criteria at the screening visit (week 0) and at the end of the screening period at visit study-2 (end of week 4) prior to randomisation in order to have fullfilled the definite inclusion criteria of having at least 2 RBD events in the last 4 weeks.
More precisely, the following assessments and procedures need to be completed:
- Medical history and examination (quality of life as well as medical, psychiatric and family history, medication and substance abuse, caffeine and alcohol included.)
- Mini Mental State Examination
- RBDSQ (RBD screening questionnaire)
- Current medication
- Exclusion criteria
- A previously recorded nocturnal polysomnogram (PSG) report is required to confirm patient eligibility and exclude OSA. If a PSG has not already been performed within the last 12 months or the patient has recently lost or gained a substantial amount of weight, the PSG done prior to randomisation would define the apnea-hypopnea index (AHI). If AHI>20, the participant will be withdrawn. After 4 weeks (screening period), the patient need to meet all the inclusion criteria, including to have presented at least
two or more events of RBD defined by dream enactment and/or sleep related injuries as stated by the weekly CIRUS- RBD questionnaire on the question 2 and 4 of the wCIRUS-RBDQ.
Patients who meet the eligibility criteria will be randomised. Patients will be randomly assigned to receive melatonin or placebo in a 1:1 ratio in random blocks. Patients will be allocated a unique ID code in sequential, ascending chronological order. The ID code will be a three-digit number prefixed by “I-RBD” (e.g. I-RBD001, I-RBD002, etc...;)The only way to match an individual’s name with their code is with a password protected excel file.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment assignment will be determined according to a computer generated randomisation list prepared by an individual not directly involved in patients’ recruitment or assessment.
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Single group
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Other design features
phase II
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Phase
Phase 2
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
M-iRBD trial and M-PD.RBD trial are two clinical trials with the same protocol in two different subtypes of patient with RBD, i.e idiopathic RBD and the Parkinsonian related form of RBD (RBD patients with Parkinsonian syndrome).
Because of the potential longer duration of recruitment in the idiopathic group (I-RBD) in comparison to the PD group (PD-RBD), the analyses are designed to be stratified with equal or separate statistical power for both Idiopathic and Parkinsonian-related subtypes and these subtypes will be registered as separate clinical trials with 2 clinical trial registrations in the ANZCTR.
We need to randomise 30 patients in each strata to have 56 completers in this efficacy trial assuming a dropout rate of 7% to detect a drop from 2.25 RBD events per week to 1 event per week with a standard deviation in events of 1 per week (measured by the wCIRUS-RBDQ averaged over the 2 month treatment period and employing all measurements made in all patients in the statistical model). With 28 completers in each strata we will have 90% power with alpha set at 5% to detect this 56% relative improvement.
Raw data will not be analysed at the participating sites but will be collected via electronic case report forms via a secure website to the central study coordinating site under the control of the Woolcock Institute for Medical Research.
Statistical analyses will be undertaken by the trial epidemiologist or under their direction and supervision. The analysts will be blinded to treatment allocation. Reductions in the number of RBD events reported by patients and their observers will be analysed for statistical difference via mixed model analyses of variance using the patient and the centre they were recruited from as random effects. Drug randomisation and time (weeks into the trial) will be fixed effects. The primary endpoint will be the last 4 weeks of therapy versus the 4 weeks prior to therapy compared with a least means square test within the interaction between time and treatment (regardless of the significance of that main interaction). The model will employ all interim measures of the primary outcome to reduce measurement error within patients.
All other measures will be regarded as secondary in importance. The actigraphy data will be compared to the diary and primary outcome data for the purposes of aiding in the validation of these diagnostic and monitoring approaches.
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Recruitment
Recruitment status
Stopped early
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Data analysis
No data analysis planned
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Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
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Date of first participant enrolment
Anticipated
1/08/2013
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Actual
20/10/2014
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Date of last participant enrolment
Anticipated
1/03/2016
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Actual
18/01/2016
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Date of last data collection
Anticipated
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Actual
15/05/2016
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Sample size
Target
30
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Accrual to date
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Final
5
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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Royal Prince Alfred Hospital - Camperdown
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Recruitment postcode(s) [1]
6908
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2050 - Missenden Road
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Funding & Sponsors
Funding source category [1]
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Other Collaborative groups
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Name [1]
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Swiss Medical Science Foundation
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Address [1]
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Swiss National Science Foundation SNSF
Wildhainweg 3
P.O. Box 8232
CH-3001 Berne
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Country [1]
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Switzerland
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Funding source category [2]
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Hospital
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Name [2]
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Royal Prince Alfred Hospital
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Address [2]
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Missenden road, Camperdown, NSW 2050
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Country [2]
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Australia
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Primary sponsor type
Other Collaborative groups
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Name
The Woolcock Institute of Medical Research
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Address
The Woolcock Institute for Medical Research and the Centre for Integrated Research and Understanding of Sleep (CIRUS)
PO Box M77, Missenden Road NSW 2050
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
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Address [1]
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Country [1]
286073
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Other collaborator category [1]
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Individual
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Name [1]
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A/Prof Simon GJ Lewis
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Address [1]
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The Brain and Mind Research Institute
Sydney Mallet Street Campus
The University of Sydney
NSW 2006
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Country [1]
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Australia
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Other collaborator category [2]
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Individual
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Name [2]
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A/Prof Brendon Yee
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Address [2]
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Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road
Camperdown NSW 2050
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Country [2]
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Australia
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Other collaborator category [3]
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Individual
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Name [3]
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Prof. Ron Grunstein
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Address [3]
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The Woolcock Institute for Medical Research and the Centre for Integrated Research and Understanding of Sleep (CIRUS)
University of Sydney and Royal Prince Alfred Hospital
PO Box M77, Missenden Road NSW 2050
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Country [3]
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Australia
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Other collaborator category [4]
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Individual
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Name [4]
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Dr. Alessandra Coeytaux Jackson
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Address [4]
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The Woolcock Institute for Medical Research and the Centre for Integrated Research and Understanding of sleep (CIRUS)
Royal Prince Alfred Hospital
PO BOX M77, Missenden Road NSW 2050
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Country [4]
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Australia
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Other collaborator category [5]
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Individual
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Name [5]
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Dr Nathaniel Marshall
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Address [5]
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The Woolcock Institute of Medical Research and the Centre for Integrated Research and Understanding of Sleep (CIRUS)
and the Sydney Nursing School,
University of Sydney NSW 2006
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Country [5]
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Australia
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Other collaborator category [6]
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Individual
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Name [6]
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Dr. Keith Wong
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Address [6]
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The Woolcock Institute of Medical Research
Glebe Point road 431
Glebe 2037 NSW
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Country [6]
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Australia
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Other collaborator category [7]
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Individual
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Name [7]
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Dr. Samuel Bolitho
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Address [7]
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The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
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Country [7]
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Australia
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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Human Research Ethics Committee - Royal Prince Alfred (HREC RPA) zone
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Ethics committee address [1]
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Research Development Office - Royal Prince Alfred Hospital. Missenden Road, Camperdown. NSW. 2050
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Ethics committee country [1]
289125
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Australia
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Date submitted for ethics approval [1]
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21/01/2013
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Approval date [1]
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21/03/2013
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Ethics approval number [1]
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X13-0010
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Summary
Brief summary
The primary aim of the study is to test in a randomised, double blind, placebo controlled trial the efficacy of melatonin in patients with REM sleep behaviour disorder over 8 weeks of treatment
Specifically, we will test the hypothesis that, compared to placebo, melatonin treatment will result in a reduction in the frequency of patients' self reported events.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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A/Prof Simon JG Lewis
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Address
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The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
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Country
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Australia
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Phone
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+61 2 9515 7565
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Fax
39362
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+61 2 9515 7564
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Email
39362
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[email protected]
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Contact person for public queries
Name
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A/Prof Simon JG Lewis
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Address
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The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
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Country
39363
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Australia
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Phone
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+61 2 9515 7565
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Fax
39363
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+61 2 9515 7564
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Email
39363
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[email protected]
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Contact person for scientific queries
Name
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A/Prof Simon JG Lewis
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Address
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The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
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Country
39364
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Australia
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Phone
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+61 2 9515 7565
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Fax
39364
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+61 2 9515 7564
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Email
39364
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Deidentified trial data will be available
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When will data be available (start and end dates)?
Now until indefinite
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Available to whom?
Suitably qualified investigators
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Available for what types of analyses?
Individual level meta-analysis
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How or where can data be obtained?
Emailed by the PI
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials.
2022
https://dx.doi.org/10.1007/s00415-020-10353-0
N.B. These documents automatically identified may not have been verified by the study sponsor.
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