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Trial registered on ANZCTR


Registration number
ACTRN12614000327684
Ethics application status
Approved
Date submitted
5/03/2014
Date registered
26/03/2014
Date last updated
23/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimum Thiamine Intervention for Treatment and Prevention of Wernicke-Korsakoff Syndrome (WKS): A Randomised Controlled Trial.
Scientific title
Optimum Thiamine Intervention for Treatment and Prevention of Wernicke-Korsakoff Syndrome (WKS): A Randomised Controlled Trial.
Secondary ID [1] 284156 0
Nil known
Universal Trial Number (UTN)
U1111-1153-7696
Trial acronym
OpT In
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Wernicke-Korsakoff Syndrome (WKS) 291243 0
Condition category
Condition code
Neurological 291586 291586 0 0
Other neurological disorders
Diet and Nutrition 291846 291846 0 0
Other diet and nutrition disorders
Mental Health 291847 291847 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Thiamine Hydrochloride

On the first day of the trial, following baseline assessment, participants will be randomised to one of three parenteral thiamine dose conditions.

Acute Symptomatic WKS Group:
i. 300mg daily (i.e. 100mg 3 times/day) for 5 days
ii. 900mg daily (i.e. 300mg 3 times/day) for 5 days or
iii. 1500mg daily (i.e. 500mg 3 times/day) for 5 days.

High-risk of subclinical WKS-related brain damage:
i. 100mg once daily for 3 days,
ii. 300mg (i.e. 100mg 3 times/day) for 3 days or
iii. 900mg (i.e. 300mg 3 times/day) for 3 days.

Thiamine Hydrochloride will be prescribed by the Addiction Medicine physician (also a trial Investigator) using standard hospital prescribing. The thiamine will be provided by the hospital pharmacy and administered by the registered nurse caring for the patient. Administration will be intravenously in a 100ml bag of normal saline (0.9%) infused over 30 minutes. Adherence will be recorded by reviewing medication chart.
Intervention code [1] 288849 0
Treatment: Drugs
Intervention code [2] 289048 0
Prevention
Comparator / control treatment
Thiamine Hydrochloride

Active - Standard treatment

Acute Symptomatic WKS Group:
300mg thiamine hydrochloride daily (i.e. 100mg 3 times/day) for 5 days administered intravenously in 100ml bag of normal saline (0.9%) infused over 30 minutes

High-risk of subclinical WKS-related brain damage:
100mg thiamine hydrochloride once daily for 3 days,
administered intravenously in 100ml bag of normal saline (0.9%) infused over 30 minutes
Control group
Dose comparison

Outcomes
Primary outcome [1] 291537 0
Evaluate differences in cognitive outcomes among acute symptomatic WKS patients under three parenteral thiamine treatment conditions (300mg/day for 5 days, versus 900mg/day for 5 days, versus 1500mg/day for 5 days);and among patients at high- risk of subclinical WKS-related brain damage under three parenteral thiamine treatment conditions (100mg/day for 3 days, versus 300mg/day for 3 days, versus 900mg/day for 3 days);
Standardised cognitive assessments (RUDAS)
Timepoint [1] 291537 0
Days 1 and 5 for acute symptomatic patients; Days 1 and 3 for at risk patients
Primary outcome [2] 291761 0
Evaluate differences in neurological outcomes among acute symptomatic WKS patients under three parenteral thiamine treatment conditions (300mg/day for 5 days, versus 900mg/day for 5 days, versus 1500mg/day for 5 days); and among patients at high-risk of subclinical WKS-related brain damage under three parenteral thiamine treatment conditions (100mg/day for 3 days, versus 300mg/day for 3 days, versus 900mg/day for 3 days);
Standardised neurological examination
Timepoint [2] 291761 0
Days 1 and 5 for acute symptomatic patients; Days 1 and 3 for at risk patients
Secondary outcome [1] 306998 0
Correlate changes in red cell thiamine test results (blood test) with cognitive (RUDAS scores) and neurological functioning (Standardised Neurological examiniation)
Timepoint [1] 306998 0
Days 1 and 5 for acute symptomatic patients; Days 1 and 3 for at risk patients
Secondary outcome [2] 307002 0
Examine the impact of magnesium deficiency (magnesium blood test) on thiamine treatment response (cognition as measured by RUDAS and thiamine pyrophosphate levels as measured by blood test)
Timepoint [2] 307002 0
Days 1 and 5 for acute symptomatic patients; Days 1 and 3 for at risk patients
Secondary outcome [3] 307003 0
Assess independent predictors of WKS including nutritional factors, substance use history and demographic factors
assessed by questionaire items including Nutritional Risk Assessment and AUDIT-C.
Timepoint [3] 307003 0
Day 1
Secondary outcome [4] 307004 0
Examine the impact of patient re-admission on red cell thiamine pyrophosphate levels (blood test) and cognitive (RUDAS) and neurological functioning (standardised neurological exam)
Timepoint [4] 307004 0
Day 1

Eligibility
Key inclusion criteria
Aged between 18-65
History of heavy alcohol use AUDIT-C score >4 or consumption >60mg/day or >80mg/binge
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Pregnant women.
Under the age of 18 or over 65 years old
Known pre-existing neurological or cognitive impairment unrelated to thiamine deficiency or WKS.
Intubated
on vasopressor therapy for hypotension
on Renal dialysis

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 Clinical Investigator or medical registrar will be provided with opaque sealed envelopes (for Symtomatic and At-Risk groups separately) following recruitment and completion of informed consent documentation. The envelopes will be provided in consecutive order of participant recruitment and indicate the thiamine dose condition allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The Menzies biostatistics group (independent statistician) will draw up the randomisation schedule using a computerised random number generator, with restricted randomisation (blocks of varying sizes) to ensure that equal numbers of participants are allocated to each treatment condition. The study medicines will be administered according to the randomisation code. The independent statistician will keep the randomisation code on file, kept securely at Menzies School of Health Research.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving 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
450 participants (total N=225 participants to each patient group)

We wish to detect the smallest experimental effect that will lead to a clinically useful outcome, even if this effect is modest (ie Cohen's d of 0.5) Sample size calculations using Stata version 12.1 for ANCOVA dictate that to detect the above difference with 90% power, an alpha of 0.05 and three dosage conditions, we will require a sample size of 51 per dosage condition (assuming baseline data are correlated r=0.7 to final day of treatment data). Allowing for approximately 30% attrition, we will recruit 75 participants to each dosage condition. Therefore we aim to recruit total N= 225 participants to each patient group.

Continuous outcome measures on the final day of treatment will be compared between the dosage conditions, adjusted for the outcome measure at baseline level using an ANCOVA approach

Binary neuological data will be analysed using logisitc regression adjusting for the outcome measure at baseline

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
22/09/2014
Actual
22/09/2014
Date of last participant enrolment
Anticipated
30/11/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
450
Accrual to date
322
Final
Recruitment in Australia
Recruitment state(s)
NT
Recruitment hospital [1] 2132 0
Alice Springs Hospital - Alice Springs
Recruitment postcode(s) [1] 7821 0
0870 - Alice Springs

Funding & Sponsors
Funding source category [1] 288782 0
Government body
Name [1] 288782 0
National Health and Medical Research Council (NHMRC)
Country [1] 288782 0
Australia
Primary sponsor type
Individual
Name
Dr Kylie Dingwall
Address
Menzies School of Health Research
c/o Centre for Remote Health
Cnr Simpson and Skinner Street
Alice Springs NT 0870
Country
Australia
Secondary sponsor category [1] 287480 0
Other
Name [1] 287480 0
Menzies School of Health Research
Address [1] 287480 0
Royal Darwin Hospital Campus
John Mathews Building
Building 58, Royal Darwin Hospital Campus
Rocklands Drive
TIWI NT 0810
Country [1] 287480 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290624 0
Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [1] 290624 0
PO Box 41096
Casuarina NT 0811
Ethics committee country [1] 290624 0
Australia
Date submitted for ethics approval [1] 290624 0
15/01/2014
Approval date [1] 290624 0
07/07/2014
Ethics approval number [1] 290624 0
HREC-2014-2151
Ethics committee name [2] 291720 0
Central Australian Human Research Ethics Committee
Ethics committee address [2] 291720 0
PO Box 4066
Alice Springs, NT 0871
Ethics committee country [2] 291720 0
Australia
Date submitted for ethics approval [2] 291720 0
27/03/2014
Approval date [2] 291720 0
27/08/2014
Ethics approval number [2] 291720 0
14-226

Summary
Brief summary
Wernicke-Korsakoff syndrome (WKS), once thought to be a rare condition, is now known to be common in people with nutritional deficiencies or alcohol dependence. The primary cause of WKS is thiamine deficiency, and more than 90% of cases are reported in alcohol dependent patients because alcohol dependence predisposes to severe nutritional deficiency. WKS may lead to significant, long-term brain dysfunction with severe effects on work, personal and social function. Whilst effective treatment may greatly reduce severe disability and the human and social costs of this illness, almost no evidence exists on optimal dosing regimens. This project proposes to develop quality evidence for effective treatment of WKS in an Aboriginal setting.

The need for evidence-based thiamine treatment protocols is of great clinical importance for two related reasons. First, in relation to acute symptomatic WKS, a failure to treat immediately or adequately may result in profound and often permanent cognitive and neurological disability. Secondly, the need for evidence-based treatment guidelines is greatly magnified when it is recognised that milder, subclinical WKS may be preventable with adequate thiamine treatment.

The aims of this study are to determine the optimal thiamine dose required for:
A. Treatment of acute symptomatic Wernicke-Korsakoff syndrome (WKS) among Aboriginal and non-Aboriginal alcohol-dependent patients.
B. Reducing or preventing subclinical WKS-related brain damage in at-risk Aboriginal and non-Aboriginal alcohol-dependent patients.

Primary Hypotheses
1. Among alcohol-dependent patients with acute symptomatic WKS, higher doses of parenteral thiamine (1500mg) will lead to greater improvements in specific cognition and neurological functions than lower doses (900mg or 300mg).
2. Among alcohol-dependent patients that are at high risk for subclinical WKS-related brain damage, higher doses of parenteral thiamine (900mg) will lead to greater improvements in specific cognition and neurological functions compared to lower doses (300mg or 100mg).

Secondary Hypotheses
1. Thiamine deficient patients will show poorer performance on cognitive and neurological measures
2. Patients with concurrent magnesium deficiency will show greater impairment at baseline
3. Nutritional risk and alcohol frequency will correlate with thiamine pyrophosphate levels.
4. Number of previous admissions with thiamine supplementation in the past 3 months will correlate with thiamine pyrophosphate levels.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46486 0
Dr Kylie Dingwall
Address 46486 0
c/o Centre for Remote Health
Cnr Simpson and Skinner Street
Alice Springs NT 0870
Country 46486 0
Australia
Phone 46486 0
+61 8 89514753
Fax 46486 0
+61 8 89514777
Email 46486 0
[email protected]
Contact person for public queries
Name 46487 0
Kylie Dingwall
Address 46487 0
c/o Centre for Remote Health
Cnr Simpson and Skinner Street
Alice Springs NT 0870
Country 46487 0
Australia
Phone 46487 0
+61 8 89514753
Fax 46487 0
+61 8 89514777
Email 46487 0
[email protected]
Contact person for scientific queries
Name 46488 0
Kylie Dingwall
Address 46488 0
c/o Centre for Remote Health
Cnr Simpson and Skinner Street
Alice Springs NT 0870
Country 46488 0
Australia
Phone 46488 0
+61 8 89514753
Fax 46488 0
+61 8 89514777
Email 46488 0
[email protected]

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