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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

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]

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

Wernicke-Korsakoff syndrome (WKS)

Condition category

Condition code

Mental Health

Addiction

Neurological

Other neurological disorders

Diet and Nutrition

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]

Treatment: Drugs

Intervention code [2]

Prevention

Comparator / control treatment

Group 1 (Standard dose group – see above) serves as the control group.

Control group

Dose comparison

Outcomes

Primary outcome [1]

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]

Day 1 baseline (prior to treatment) and Day 3 (after all treatments)

Primary outcome [2]

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]

Day 1 baseline (prior to treatment) and Day 3 (after all treatments)

Primary outcome [3]

Comparison between Standard and High dose groups on neurological signs.
Neurological signs (ii): Ataxia total score – derived from same structured neurologic examination.

Timepoint [3]

Day 1 baseline (prior to treatment) and Day 3 (after all treatments)

Secondary outcome [1]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

Actual

19/02/2013

Date of last participant enrolment

Anticipated

30/11/2019

Actual

21/08/2018

Date of last data collection

Anticipated

2/12/2019

Actual

23/08/2018

Sample size

Target

140

Accrual to date

Final

128

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment postcode(s) [1]

3065 - Fitzroy

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council (NHMRC)

Address [1]

414 La Trobe St
Melbourne VIC 3000

Country [1]

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]

University

Name [1]

University of Melbourne

Address [1]

Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital Melbourne Human Research Ethics Committee D

Ethics committee address [1]

Research Governance Unit
Level 5
Mary Aikenhead Building
27 Victoria Parade
FITZROY VIC 3065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

03/10/2011

Approval date [1]

24/11/2011

Ethics approval number [1]

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

Prof Stephen Bowden

Address

Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010

Country

Australia

Phone

+61 3 8344 6373

Fax

+61 3 9347 6618

sbowden@unimelb.edu.au

Contact person for public queries

Name

Stephen Bowden

Address

Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010

Country

Australia

Phone

+61 3 8344 6373

Fax

+61 3 9347 6618

sbowden@unimelb.edu.au

Contact person for scientific queries

Name

Stephen Bowden

Address

Melbourne School of Psychological Sciences
Redmond Barry Building
UNIVERSITY OF MELBOURNE VIC 3010

Country

Australia

Phone

+61 3 8344 6373

Fax

+61 3 9347 6618

sbowden@unimelb.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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No additional documents have been identified.

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