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Trial registered on ANZCTR
Registration number
ACTRN12617001182381
Ethics application status
Approved
Date submitted
9/08/2017
Date registered
11/08/2017
Date last updated
3/12/2020
Date data sharing statement initially provided
16/07/2019
Date results information initially provided
3/12/2020
Type of registration
Retrospectively registered
Titles & IDs
Public title
Treatment of alcohol dependent patients at-risk for subclinical Wernicke-Korsakoff syndrome
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Scientific title
Treatment of alcohol dependent patients at-risk for subclinical Wernicke-Korsakoff syndrome: effect of thiamine dosage on neurological and cognitive symptoms
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Secondary ID [1]
292464
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1011141 (NHMRC Grant ID)
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Universal Trial Number (UTN)
U1111-1199-4826
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Alcohol use disorder
304311
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Wernicke-Korsakoff syndrome (WKS)
304312
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Condition category
Condition code
Mental Health
303665
303665
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0
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Addiction
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Neurological
303666
303666
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0
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Other neurological disorders
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Diet and Nutrition
303667
303667
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0
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Other diet and nutrition disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Thiamine Hydrochloride
Day one of trial
Patient admitted for inpatient detoxification for alcohol withdrawal.
Eligible patients randomly allocated to one of two groups (see below for group descriptions).
Participant completes baseline neurological and cognitive assessment, as well as screening questionnaires regarding alcohol use and mental health.
On same day, but only after baseline assessment, participant receives first dose of thiamine treatment.
Day two
Participant receives second dose of thiamine.
Day three
Participant receives third dose of thiamine.
On same day, but only after third and final dose of thiamine, participant repeats neurological and cognitive assessment.
Two groups, randomly allocated.
Group 1 (Standard dose group): 300mg once daily for three days, intravenous infusion.
Group 2 (High dose group): 1,000mg once daily for three days, intravenous infusion.
For both groups, thiamine will be added to 100ml of normal saline and infused over 1 hour. Thiamine hydrochloride provided by St Vincent’s Hospital as part of routine care. Thiamine administered by nursing staff who are not members of the research team and who are blind to dose amount.
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Intervention code [1]
298844
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Treatment: Drugs
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Intervention code [2]
298845
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Prevention
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Comparator / control treatment
Group 1 (Standard dose group – see above) serves as the control group.
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Control group
Dose comparison
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Outcomes
Primary outcome [1]
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Comparison between Standard and High dose groups on cognitive measures.
Cognitive measure (i): Working memory – Digit span task, which is a modified version of the Wechsler Adult Intelligence Scale Fourth Edition (WAIS-IV) Digit Span subtest. Modified so that each item contains three, rather than two, trials.
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Assessment method [1]
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Timepoint [1]
303031
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Day 1 baseline (prior to treatment) and Day 3 (after all treatments)
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Primary outcome [2]
303053
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Comparison between Standard and High dose groups on neurological signs.
Neurological signs (i): Eye movement abnormalities total score – derived from a structured quantitative neurologic examination based on the Ataxia Staging and Scoring system (Pourcher & Barbeau, 1980) and previously validated by members of the research team for the evaluation of neurological impairment in drug and alcohol-related cognitive impairment and encephalopathies (Cairney et al., 2004; Wood et al., 1986).
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Assessment method [2]
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Timepoint [2]
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Day 1 baseline (prior to treatment) and Day 3 (after all treatments)
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Primary outcome [3]
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Comparison between Standard and High dose groups on neurological signs.
Neurological signs (ii): Ataxia total score – derived from same structured neurologic examination.
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Assessment method [3]
303054
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Timepoint [3]
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Day 1 baseline (prior to treatment) and Day 3 (after all treatments)
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Secondary outcome [1]
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Additional primary outcome.
Comparison between Standard and High dose groups on cognitive measures.
Cognitive measure (ii): Anterograde memory – Wechsler Memory Scale Fourth Edition (WMS-IV) Logical Memory subtest.
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Assessment method [1]
337723
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Timepoint [1]
337723
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Day 1 baseline (prior to treatment) and Day 3 (after all treatments)
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Eligibility
Key inclusion criteria
Alcohol dependent patients presenting to Depaul House residential withdrawal unit.
Meet DSM-IV criteria for Alcohol dependence or alcohol abuse, as assessed with the Mini International Neuropsychiatric Interview (MINI) version 6.0.0 (Sheehan & Lecrubier, 2009).
Consumption of at least six standard drinks daily for a period of at least three months.
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Minimum age
18
Years
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Maximum age
65
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
Difficulties with language comprehension.
Significant pre-existing cognitive impairment due to a cause other than alcohol abuse or dependence.
Recent regular use of any non-prescription drug other than alcohol.
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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 order of allocation is determined by a randomisation chart. This chart is kept in an opaque envelope and is not seen by those involved in assessing for eligibility or recruitment. The holder of the allocation schedule, who is “on-site”, checks the schedule only after recruitment is made.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Non-stratified, blocked randomisation using large block sizes of either 10 or 20 in size and randomly varied to maximise unpredictability. The allocation ratio per block was 1:1. An online true random number generator was used to select order of block sizes and treatment allocation sequence.
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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
Power analysis sought to detect a minimal experimental effect that will lead to a clinically useful outcome. Small but clinically useful effects have been described as corresponding to a difference between groups of about one-half of one standard deviation or a Cohen’s d of .5 (Cohen, 1988; Wolf & Cornell, 1986). This cautious estimate is also in line with the effect observed in our previous study (Ambrose, Bowden, & Whelan, 2001). Power calculations based on two treatment groups indicate n=70 per group and a univariate analysis of variance model with one response variable are required for adequate design power to have a high chance (.9 or greater) of rejecting the null hypothesis (at alpha = .05) of no difference between means (GPower: Faul et al., 2009). Therefore we will aim to collect 140 participants in total.
Outcome measures to be analysed with univariate analysis of variance with dose as the independent variable. Dependent variables include working memory, anterograde memory, eye movement abnormalities total score, and ataxia total score. A number-needed-to-treat analysis will also be conducted with intention-to-treat corrections.
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
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Actual
19/02/2013
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Date of last participant enrolment
Anticipated
30/11/2019
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Actual
21/08/2018
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Date of last data collection
Anticipated
2/12/2019
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Actual
23/08/2018
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Sample size
Target
140
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Accrual to date
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Final
128
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
8569
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St Vincent's Hospital (Melbourne) Ltd - Fitzroy
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Recruitment postcode(s) [1]
16674
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3065 - Fitzroy
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Funding & Sponsors
Funding source category [1]
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Government body
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Name [1]
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National Health and Medical Research Council (NHMRC)
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Address [1]
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414 La Trobe St
Melbourne VIC 3000
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Country [1]
297032
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Australia
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Primary sponsor type
Individual
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Name
Prof Stephen Bowden
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Address
Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
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Country
Australia
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Secondary sponsor category [1]
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University
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Name [1]
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University of Melbourne
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Address [1]
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Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
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Country [1]
296034
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Australia
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
298217
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St Vincent's Hospital Melbourne Human Research Ethics Committee D
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Ethics committee address [1]
298217
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Research Governance Unit
Level 5
Mary Aikenhead Building
27 Victoria Parade
FITZROY VIC 3065
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Ethics committee country [1]
298217
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Australia
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Date submitted for ethics approval [1]
298217
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03/10/2011
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Approval date [1]
298217
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24/11/2011
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Ethics approval number [1]
298217
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117/11
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Summary
Brief summary
Wernicke-Korsakoff syndrome (WKS) is a neurological disorder caused by thiamine deficiency associated with alcohol dependence or other causes of malnutrition. Although WKS is a common condition, there are currently no universally accepted, national or international, evidence-based guidelines for thiamine dosing for the treatment of either acute symptomatic WKS or for prevention of subclinical WKS-related brain damage in at-risk people. WKS is most commonly seen in alcohol dependent people who therefore constitute a major at-risk population. In the absence of agreed treatment guidelines, different clinical groups or hospital settings tend to maintain their own protocols based on experience or tradition, and in general the dosage levels of thiamine prescribed in Australia for symptomatic WKS varies from lower doses (100-300mg daily) to higher doses (1000mg daily). Australian Department of Health and Aging treatment guidelines recommend 300mg per day for at risk patients (DoHA, 2009). The main aim of this study is to evaluate whether high dose (1000mg daily) thiamine is more effective than Australian standard dose (300mg daily) thiamine for treating subclinical WKS-related brain damage in at-risk alcohol dependent patients admitted for management of their alcohol dependence. The study has direct implications for how this common condition should be treated in the future.
In this study, patients will not have acute symptomatic WKS, rather, they will be alcohol dependent patients at risk of subclinical WKS-related brain damage. Patients will be treated as per usual hospital protocols, except that they will be randomly allocated to one of two treatment groups that differ only on dosage amount of thiamine (300mg or 1000mg per day for 3 days) administered via intravenous (IV) infusion. All patients admitted to Depaul House and receiving “treatment as usual” for alcohol withdrawal would routinely have received at least 3 days of thiamine (200mg x two times per day administered intramuscularly) as part of that treatment.
Baseline measures, to be obtained before treatment on day 1 and outcome measures obtained after treatment on day 3, include structured examinations of mental health and neurological symptoms, particularly signs associated with WKS such as lack of coordination and irregularity of muscle movement (ataxia) and abnormal eye movements (nystagmus, ophthalmoplegia). Cognitive function will be assessed via standardised tests of working memory and anterograde memory. All participants will receive full hospital care during and after data collection, as per usual hospital protocols for such patients.
It was hypothesised that higher doses of parenteral thiamine (1000 mg daily) will lead to greater improvements in specific aspects of cognition and neurological function than lower doses (300mg) in alcohol dependent patients undergoing alcohol withdrawal who are at risk for subclinical WKS-related brain damage.
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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 Stephen Bowden
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Address
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Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
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Country
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Australia
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Phone
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+61 3 8344 6373
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Fax
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+61 3 9347 6618
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Email
76374
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[email protected]
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Contact person for public queries
Name
76375
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Prof Stephen Bowden
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Address
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Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
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Country
76375
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Australia
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Phone
76375
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+61 3 8344 6373
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Fax
76375
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+61 3 9347 6618
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Email
76375
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[email protected]
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Contact person for scientific queries
Name
76376
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Prof Stephen Bowden
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Address
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Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
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Country
76376
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Australia
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Phone
76376
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+61 3 8344 6373
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Fax
76376
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+61 3 9347 6618
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Email
76376
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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)?
No
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No/undecided IPD sharing reason/comment
Patient confidentiality. All participants were recruited in a public hospital detoxification unit. Plus, information regarding potential data sharing was not included on the Patient Information and Consent Form.
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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
No additional documents have been identified.
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