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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
16/07/2019
Date data sharing statement initially provided
16/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Treatment of alcohol dependent patients at-risk for subclinical Wernicke-Korsakoff syndrome
Scientific title
Treatment of alcohol dependent patients at-risk for subclinical Wernicke-Korsakoff syndrome: effect of thiamine dosage on neurological and cognitive symptoms
Secondary ID [1] 292464 0
1011141 (NHMRC Grant ID)
Universal Trial Number (UTN)
U1111-1199-4826
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alcohol use disorder 304311 0
Wernicke-Korsakoff syndrome (WKS) 304312 0
Condition category
Condition code
Mental Health 303665 303665 0 0
Addiction
Neurological 303666 303666 0 0
Other neurological disorders
Diet and Nutrition 303667 303667 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 298844 0
Treatment: Drugs
Intervention code [2] 298845 0
Prevention
Comparator / control treatment
Group 1 (Standard dose group – see above) serves as the control group.
Control group
Dose comparison

Outcomes
Primary outcome [1] 303031 0
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.
Timepoint [1] 303031 0
Day 1 baseline (prior to treatment) and Day 3 (after all treatments)
Primary outcome [2] 303053 0
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).
Timepoint [2] 303053 0
Day 1 baseline (prior to treatment) and Day 3 (after all treatments)
Primary outcome [3] 303054 0
Comparison between Standard and High dose groups on neurological signs.
Neurological signs (ii): Ataxia total score – derived from same structured neurologic examination.
Timepoint [3] 303054 0
Day 1 baseline (prior to treatment) and Day 3 (after all treatments)
Secondary outcome [1] 337723 0
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.
Timepoint [1] 337723 0
Day 1 baseline (prior to treatment) and Day 3 (after all treatments)

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

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 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.
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.
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
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
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.

Recruitment
Recruitment status
Recruiting
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)
VIC
Recruitment hospital [1] 8569 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 16674 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 297032 0
Government body
Name [1] 297032 0
National Health and Medical Research Council (NHMRC)
Address [1] 297032 0
414 La Trobe St
Melbourne VIC 3000
Country [1] 297032 0
Australia
Primary sponsor type
Individual
Name
Prof Stephen Bowden
Address
Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
Country
Australia
Secondary sponsor category [1] 296034 0
University
Name [1] 296034 0
University of Melbourne
Address [1] 296034 0
Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
Country [1] 296034 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298217 0
St Vincent's Hospital Melbourne Human Research Ethics Committee D
Ethics committee address [1] 298217 0
Research Governance Unit
Level 5
Mary Aikenhead Building
27 Victoria Parade
FITZROY VIC 3065
Ethics committee country [1] 298217 0
Australia
Date submitted for ethics approval [1] 298217 0
03/10/2011
Approval date [1] 298217 0
24/11/2011
Ethics approval number [1] 298217 0
117/11

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76374 0
Prof Stephen Bowden
Address 76374 0
Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
Country 76374 0
Australia
Phone 76374 0
+61 3 8344 6373
Fax 76374 0
+61 3 9347 6618
Email 76374 0
sbowden@unimelb.edu.au
Contact person for public queries
Name 76375 0
Prof Stephen Bowden
Address 76375 0
Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
Country 76375 0
Australia
Phone 76375 0
+61 3 8344 6373
Fax 76375 0
+61 3 9347 6618
Email 76375 0
sbowden@unimelb.edu.au
Contact person for scientific queries
Name 76376 0
Prof Stephen Bowden
Address 76376 0
Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010
Country 76376 0
Australia
Phone 76376 0
+61 3 8344 6373
Fax 76376 0
+61 3 9347 6618
Email 76376 0
sbowden@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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.
What supporting documents are/will be available?
No other documents available
Summary results
No Results