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Trial registered on ANZCTR
Registration number
ACTRN12624001404516p
Ethics application status
Submitted, not yet approved
Date submitted
29/10/2024
Date registered
27/11/2024
Date last updated
27/11/2024
Date data sharing statement initially provided
27/11/2024
Type of registration
Prospectively registered
Titles & IDs
Public title
Rapid eye movement sleep & extinction trial in post-traumatic stress disorder
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Scientific title
A randomised, double-blind, placebo-controlled trial on the effect of lemborexant on sleep and emotional memories in adults aged 18 to 50 with PTSD.
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Secondary ID [1]
313265
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None
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Universal Trial Number (UTN)
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Trial acronym
Trauma RESET
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
PTSD
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Trauma
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Condition category
Condition code
Mental Health
332161
332161
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0
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Other mental health disorders
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Neurological
332356
332356
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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
This Randomized Controlled Trial (RCT) investigates whether the dual orexin receptor antagonist lemborexant increases rapid eye movement (REM) sleep and improves fear extinction recall compared to a placebo control.
Participant with previous trauma exposure and PTSD will be recruited and randomly assigned to the double-blinded drug condition. The intervention group receives one dose of 10mg lemborexant orally about 1h before bedtime.
On the test day, participants will complete a standardized and well-validated fear conditioning and extinction task which examines their capacity to acquire conditioned fear (via recording skin conductance response [SCR] reflecting physiological arousal to stimuli paired with a mild electric shock) and extinguishing fear. Prior to the task, the level of shock will be individually set at a level that is uncomfortable, but not painful. For the fear acquisition phase, they will look at visual images of a scene containing a desktop lamp which lights up with a color. One color will be associated with a mild electrical shock (the CS+), the other colored circle is never associated with shock (the CS-). This will be followed immediately by the fear extinction phase in which they will look at both colored lights which will never be followed by shock. This paradigm is adapted from Milad, Orr, Pitman, & Rauch (2005) and the approximate duration of the task is 20 minutes. SCR will be recorded to reflect sympathetic arousal. SCR amplitude typically increases to the CS+ compared to the CS- in the acquisition phase, and then gradually reduces over the extinction phase. The slope of decline of SCR over the fear extinction phase reflects how well an individual can inhibit/regulate their fear and reflects their capacity for fear extinction learning. Next, participants view emotive and neutral images selected from the International Affective Picture System (IAPS, task duration approximately 10 minutes). Then, participants will take the drug (oral tablet) under direct supervision by research staff and sleep at the lab while polysomnography (PSG) records sleep including REM sleep during the test night. This is followed by a recovery night at home to allow full drug washout (an ambulatory PSG records REM sleep during the recovery night). The participants return to the lab the next morning for the follow up. First they are asked to remember, recognized and rate the IAPS images they have seen two days before. Then, they complete the extinction phase again while SCR is recorded to measure recall of fear extinction. The extent that their fear returns reflects how well they remember the fear extinction from the first test day. The following week, participants record any intrusive memories that they have of the IAPS images.
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Intervention code [1]
329845
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Treatment: Drugs
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Intervention code [2]
329981
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Treatment: Other
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Comparator / control treatment
The participants in the placebo control group will receive the tablet in the form of a capsule (ingredient: hypromellose) filled with sugar 1h before bedtime.
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Fear extinction recall
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Assessment method [1]
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Skin conductance response from electrodes placed on the hands.
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Timepoint [1]
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Follow up (about 48h after drug intake).
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Primary outcome [2]
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Rapid eye movement sleep
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Assessment method [2]
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Overnight in-lab polysomnography
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Timepoint [2]
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Test night (night after drug intake)
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Primary outcome [3]
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Emotional memory
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Assessment method [3]
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Spontaneous recall
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Timepoint [3]
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Follow up (about 48h after drug intake).
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Secondary outcome [1]
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Emotional memory This is an additional primary outcome
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Assessment method [1]
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Recognition
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Timepoint [1]
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Follow up (about 48h after drug intake).
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Secondary outcome [2]
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Rapid eye movement sleep
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Assessment method [2]
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Home sleep recording using Somfit device and app
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Timepoint [2]
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Sleep during second night after drug intake (recovery night)
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Secondary outcome [3]
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Number and description of intrusive memories (assessed from the open-ended question of the intrusive memory diary).
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Assessment method [3]
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Daily diary
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Timepoint [3]
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Daily for 7 days post follow-up (about 48h after drug intake)
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Secondary outcome [4]
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Emotional memory This is an additional primary outcome
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Assessment method [4]
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Image rating
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Timepoint [4]
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Follow up (about 48h after drug intake).
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Eligibility
Key inclusion criteria
Previous trauma-exposure and PTSD Checklist for DSM-5 (PCL-5) score >30
Proficient in English
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Minimum age
18
Years
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Maximum age
50
Years
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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
- Severe mental disorders: personality disorder and bipolar disorder, actively suicidal, experiencing psychosis, schizophrenia, or major addiction
- Physical disorder including severe hepatic or renal impairment, neurological disorders including narcolepsy, epilepsy or seizures, and/or cardiac disorders including hypo- or hypertensions (blood pressure outside 90/60mmHg - 140/90mmHg)
- Sleep disorder (unmanaged), or sleep disturbance including jetlag or recent shift work
- Currently taking medication that interacts with the study drug. Contraceptive pills are ok.
- Regular smokers (social smokers are ok)
- BMI outside 18.5 – 30kg m2
- Participants who routinely go to bed after 1am
- Biologically female participants: pregnant, breastfeeding and/or trying to get pregnant
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Study design
Purpose of the study
Prevention
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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 drug will be administered in a white, opaque, numbered plastic bottle.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation stratified by sex will be done by a non-involved third party that has no contact with participants and will prepare the randomisation list for the researcher.
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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
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
Data will be analysed using a variety of methodologies depending on the dependent variable.
T-test and effect size analyses will test difference in REM sleep amount and fear extinction amongst drug conditions.
To assess group differences on fear conditioning and extinction learning, 2 (Drug Condition: lemborexant, placebo) x 2 (Condition: CS+/CS-) x 5 (trial) mixed model ANOVAs will be conducted. To assess group differences on extinction recall, the average SCR to the first two trials at recall will be compared between drugs. To assess the drug effect on sleep and extinction recall, multple linear regressions will be conducted.
To examine group differences in emotion memory data (memory recall, intrusive memories), a 2 (Drug: lemborexant/placebo) x 3 (Valence: Negative, Neutral, Positive) mixed model ANOVA or linear regressions when including REM sleep will be used.
The significance level is set to a = 0.05, indicating a p-value < a to be statistically significant.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
2/12/2024
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Actual
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Date of last participant enrolment
Anticipated
7/12/2026
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Actual
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Date of last data collection
Anticipated
31/12/2026
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Actual
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Sample size
Target
80
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
VIC
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Funding & Sponsors
Funding source category [1]
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University
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Name [1]
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the University of Melbourne
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Address [1]
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Country [1]
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Australia
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Primary sponsor type
University
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Name
the University of Melbourne
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Address
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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]
320034
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Address [1]
320034
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Country [1]
320034
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Ethics approval
Ethics application status
Submitted, not yet approved
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Ethics committee name [1]
316408
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University of Melbourne Central Human Research Ethics Committee
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Ethics committee address [1]
316408
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https://research.unimelb.edu.au/work-with-us/ethics-and-integrity/our-ethics-committees
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Ethics committee country [1]
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Australia
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Date submitted for ethics approval [1]
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29/10/2024
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Approval date [1]
316408
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Ethics approval number [1]
316408
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31292
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Summary
Brief summary
Dysregulated fear memory processing as well as disrupted sleep (particularly rapid eye movement [REM] sleep) are important factors in the development of posttraumatic stress disorder (PTSD). Sleep is one of the few modifiable variables in the aftermath of a traumatic event, which might be utilized to prevent PTSD onset. Therefore, the aim of this project is to examine the effect of the insomnia drug lemborexant, that increases rapid eye movement (REM) sleep in primary insomnia, on fear extinction learning and extinction recall, as well as emotional memory consolidation compared to placebo in individuals with PTSD. We recently completed a similar pilot study in healthy controls using suvorexant (same mechanism of action like lemborexant but lower clinical effect, and safe in PTSD) and found increased REM sleep was associated with better extinction recall (ACTRN12619001694101). This study will provide evidence for the potential of enhancing REM sleep as a therapeutic target for improving PTSD onset.
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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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Prof Kim Felmingham
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Address
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The University of Melbourne's School of Psychological Sciences, Level 12, 17 Spencer Street, Parkville VIC 3010
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Country
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Australia
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Phone
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+61 03 8344 1523
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Fax
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Email
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[email protected]
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Contact person for public queries
Name
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Maya Schenker
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Address
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The University of Melbourne's School of Psychological Sciences, Level 9, 17 Spencer Street, Parkville VIC 3010
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Country
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Australia
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Phone
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+61390354863
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Name
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Maya Schenker
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Address
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The University of Melbourne's School of Psychological Sciences, Level 9, 17 Spencer Street, Parkville VIC 3010
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Country
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Australia
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Phone
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+61390354863
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Fax
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Email
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[email protected]
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Data sharing statement
Will the study consider sharing individual participant data?
No
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
No additional documents have been identified.
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