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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
Scientific title
Efficacy of melatonin in idiopathic rapid eye movement (REM) sleep behaviour disorder: A double-blind, randomised controlled trial
Secondary ID [1] 282354 0
Nil
Universal Trial Number (UTN)
Trial acronym
M-iRBD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
REM sleep behaviour disorder
288920 0
Efficacy of melatonin 289336 0
Condition category
Condition code
Neurological 289264 289264 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 286978 0
Treatment: Drugs
Comparator / control treatment
Two matched placebo tablets (lactose monohydrate) ingested orally once a day after food within 1 hour of bedtime for 8 weeks
Control group
Placebo

Outcomes
Primary outcome [1] 289369 0
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
Timepoint [1] 289369 0
Aggregate of all incidents measured within weeks 5 to 8 of treatment
Secondary outcome [1] 302340 0
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."
Timepoint [1] 302340 0
the timepoint is before end of treatment, week 8 to 12 versus prior to treatment, week 1 to 4.
Secondary outcome [2] 302341 0
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
Timepoint [2] 302341 0
Aggregate of all incidents measured within weeks 5 to 8 of treatment
Secondary outcome [3] 302342 0
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
Timepoint [3] 302342 0
Aggregate of all incidents measured within weeks 5 to 8 of treatment
Secondary outcome [4] 302343 0
Improvement in self-reported quality of sleep (Pittsburg sleep quality index)
Timepoint [4] 302343 0
at week 12 (end of treatment) versus week 4 (night prior to randomization)
Secondary outcome [5] 302344 0
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
Timepoint [5] 302344 0
at week 12 (end of treatment), at week 8 (mid-treatment) and using information from week 4 (prior to randomization)
Secondary outcome [6] 302882 0
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.
Timepoint [6] 302882 0
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
Secondary outcome [7] 302883 0
The clinical global improvement impression score
Timepoint [7] 302883 0
At week 12 (end of treatment) and a comparison of secondary importance at week 16
Secondary outcome [8] 303086 0
Change in the self-reported sleepiness (ESS),
Timepoint [8] 303086 0
at week 12 (end of treatment) versus week 4 (night prior to randomization)
Secondary outcome [9] 303088 0
A change in the Depression, Anxiety, Stress scales (the DASS), a 42-item self-report instrument for measuring depression, anxiety and tension/stress
Timepoint [9] 303088 0
at week 12 (end of treatment) versus week 4 (night prior to randomization)
Secondary outcome [10] 303090 0
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
Timepoint [10] 303090 0
at week 12 (end of treatment) versus week 4 (night prior to randomization)

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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
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.
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.
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Single group
Other design features
phase II
Phase
Phase 2
Type of endpoint(s)
Efficacy
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.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 1045 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 6908 0
2050 - Missenden Road

Funding & Sponsors
Funding source category [1] 287327 0
Other Collaborative groups
Name [1] 287327 0
Swiss Medical Science Foundation
Address [1] 287327 0
Swiss National Science Foundation SNSF
Wildhainweg 3
P.O. Box 8232
CH-3001 Berne
Country [1] 287327 0
Switzerland
Funding source category [2] 287384 0
Hospital
Name [2] 287384 0
Royal Prince Alfred Hospital
Address [2] 287384 0
Missenden road, Camperdown, NSW 2050
Country [2] 287384 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The Woolcock Institute of Medical Research
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
Country
Australia
Secondary sponsor category [1] 286073 0
None
Name [1] 286073 0
Address [1] 286073 0
Country [1] 286073 0
Other collaborator category [1] 277419 0
Individual
Name [1] 277419 0
A/Prof Simon GJ Lewis

Address [1] 277419 0
The Brain and Mind Research Institute
Sydney Mallet Street Campus
The University of Sydney
NSW 2006
Country [1] 277419 0
Australia
Other collaborator category [2] 277421 0
Individual
Name [2] 277421 0
A/Prof Brendon Yee
Address [2] 277421 0
Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road
Camperdown NSW 2050
Country [2] 277421 0
Australia
Other collaborator category [3] 277422 0
Individual
Name [3] 277422 0
Prof. Ron Grunstein
Address [3] 277422 0
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
Country [3] 277422 0
Australia
Other collaborator category [4] 277423 0
Individual
Name [4] 277423 0
Dr. Alessandra Coeytaux Jackson
Address [4] 277423 0
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
Country [4] 277423 0
Australia
Other collaborator category [5] 277424 0
Individual
Name [5] 277424 0
Dr Nathaniel Marshall
Address [5] 277424 0
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
Country [5] 277424 0
Australia
Other collaborator category [6] 277425 0
Individual
Name [6] 277425 0
Dr. Keith Wong
Address [6] 277425 0
The Woolcock Institute of Medical Research
Glebe Point road 431
Glebe 2037 NSW
Country [6] 277425 0
Australia
Other collaborator category [7] 277426 0
Individual
Name [7] 277426 0
Dr. Samuel Bolitho
Address [7] 277426 0
The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
Country [7] 277426 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289125 0
Human Research Ethics Committee - Royal Prince Alfred (HREC RPA) zone
Ethics committee address [1] 289125 0
Research Development Office - Royal Prince Alfred Hospital. Missenden Road, Camperdown. NSW. 2050
Ethics committee country [1] 289125 0
Australia
Date submitted for ethics approval [1] 289125 0
21/01/2013
Approval date [1] 289125 0
21/03/2013
Ethics approval number [1] 289125 0
X13-0010

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39362 0
A/Prof Simon JG Lewis
Address 39362 0
The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
Country 39362 0
Australia
Phone 39362 0
+61 2 9515 7565
Fax 39362 0
+61 2 9515 7564
Email 39362 0
simonl@med.usyd.edu.au
Contact person for public queries
Name 39363 0
A/Prof Simon JG Lewis
Address 39363 0
The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
Country 39363 0
Australia
Phone 39363 0
+61 2 9515 7565
Fax 39363 0
+61 2 9515 7564
Email 39363 0
simonl@med.usyd.edu.au
Contact person for scientific queries
Name 39364 0
A/Prof Simon JG Lewis
Address 39364 0
The Brain & Mind Research Institute,
Sydney Mallet Street Campus
The University of Sydney NSW 2006
Country 39364 0
Australia
Phone 39364 0
+61 2 9515 7565
Fax 39364 0
+61 2 9515 7564
Email 39364 0
simonl@med.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Deidentified trial data will be available
When will data be available (start and end dates)?
Now until indefinite
Available to whom?
Suitably qualified investigators
Available for what types of analyses?
Individual level meta-analysis
How or where can data be obtained?
Emailed by the PI
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
Analytic code
Summary results
No Results