A Prospective Randomised Controlled Trial of the Effect of Magnesium Sulphate Administration on Red Cell Transketolase Activity in Alcohol Dependent Patients at Risk of Wernicke Korsakoff Syndrome Treated With Thiamine
Phase: PHASE2
Conditions: Alcohol Withdrawal, Lactic Acidosis, Vitamin B1 Deficiency, Magnesium Deficiency, Wernicke Encephalopathy
Sponsor: Glasgow Royal Infirmary

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A prospective randomised controlled trial of the effect of 
Magnesium 
Sulphate administration 
on 
Red 
Cell 
Transketolase Activity in Alcohol dependent patients at 
risk of Wernicke Korsakoff Syndrome treated with 
Thiamine 
 
 
 
Running title: 
Effect of Magnesium and Thiamine on red cell 
transketolase activity 
Protocol Version: 
 
 
 1.0 
Date:  
 
 
 
13.07.2016 
REC Reference Number: 
 
TBC 
Clinical trial.gov: 
 
 
TBC 
Sponsor’s Protocol Number:  
GN16ME174 
Sponsor: 
NHS Greater Glasgow & Clyde 
Funder: 
Supported 
by 
A&E 
and 
Biochemistry 
departments of NHS Greater Glasgow and 
Clyde 
 
 
 
 
 
Amendment number 
Date 
Protocol version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be performed according to the Research Governance Framework for Health 
and Community Care (Second edition, 2006) and WORLD MEDICAL ASSOCIATION 
DECLARATION OF HELSINKI  Ethical Principles for Medical Research Involving Human 
Subjects 1964 (as amended). 

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CONTACTS 
Chief Investigator 
 
Dr Donogh Maguire 
Emergency Care Consultant 
Glasgow Royal Infirmary 
Emergency Department 
Alexandra Parade 
Glasgow G4 0SF 
Tel: 0141 211 4294 
E-mail: donogh.maguire@ggc.scot.nhs.uk   
 
Co-investigators   
 
Dr Fiona Stefanowicz 
Clinical Biochemist 
Trace Elements Laboratory 
McEwan Building 
Glasgow Royal Infirmary 
G4 0SF 
Tel: 1041 2115178 
E-mail: Fiona.stefanowicz@ggc.scot.nhs.uk 
 
Dr Dinesh Talwar 
Clinical Biochemist 
Trace Elements Laboratory 
McEwan Building 
Glasgow Royal Infirmary 
G4 0SF 
Tel: 1041 2115178 
E-mail: dinesh.talwar@ggc.scot.nhs.uk 
 
Professor Mike Lean 
Department of Human Nutrition 
Glasgow University Medical School 
Glasgow Royal Infirmary 
G4 0SF 
Tel: 0141 2018604 
Email: mike.lean@glasgow.ac.uk  
 
Study Statistician 
 
David Young 
Senior Lecturer and Consultant Statistician 
Department of Mathematics and Statistics, University of Strathclyde 
NHS, Greater Glasgow and Clyde 
Tel: <Number> 
E-mail: david.young@strath.ac.uk   
 
 
Pharmacy  
 
Elizabeth Douglas 
Clinical Trials Pharmacist 
NHS Greater Glasgow & Clyde 
Senior Clinical Trials Pharmacist R&D 
Clinical Research & Development, NHS Greater Glasgow & Clyde 

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West Glasgow Ambulatory Care Hospital 
Dalnair Street 
Glasgow, UK 
G3 8SJ 
 
Tel: 0141 232 1792 
E-mail: elizabeth.douglas@ggc.scot.nhs.uk  
 
Sponsor  - NHS Greater Glasgow and Clyde 
 
Sponsor’s representative – 
 
Dr Maureen Travers, 
Research Coordinator, 
R&D Management Office, 
Clinical Research & Development 
West Glasgow Ambulatory Care Hospital 
Dalnair Street 
Glasgow G3 8SW 
 
Tel: 0141 232 1813 
Email: Maureen.Travers@ggc.scot.nhs.uk   
 
Funding Body  
 
No external funding sought.  
Study is supported by A&E and Biochemistry departments of NHS Greater Glasgow and Clyde 

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PROTOCOL APPROVAL 
 
Effect of Magnesium and Thiamine on red cell transketolase activity 
 
Chief Investigator 
Dr Donogh Maguire 
Emergency Care Consultant 
Glasgow Royal Infirmary 
Emergency Department 
Alexandra Parade 
Glasgow G4 0SF 
 
 
Signature: 
 
 
 
 
Date: 
12/07/16 
 
 
 
 
Sponsor’s representative 
Dr Maureen Travers, 
Research Coordinator, 
R&D Management Office, 
Clinical Research & Development 
West Glasgow Ambulatory Care Hospital 
Dalnair Street 
Glasgow G3 8SW 
 
Signature: 
 
 
 
 
Date: 
 
 
 
18.07.2016 
 
 
 

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TABLE OF CONTENTS 
 
CONTACTS ................................................................................................................. 2 
PROTOCOL APPROVAL ............................................................................................... 4 
TABLE OF CONTENTS ................................................................................................. 5 
ABBREVIATIONS ....................................................................................................... 7 
STUDY SYNOPSIS ...................................................................................................... 8 
1. 
INTRODUCTION ......................................................................................... 9 
1.1 
Background .................................................................................................... 9 
1.2 
Rationale ........................................................................................................ 9 
1.3 
Study hypothesis .......................................................................................... 11 
2. 
STUDY OBJECTIVES .................................................................................. 11 
3. 
STUDY DESIGN ......................................................................................... 11 
3.1 
Study Population .......................................................................................... 12 
3.2 
Inclusion criteria ........................................................................................... 12 
3.3 
Exclusion criteria........................................................................................... 12 
3.4 
Withdrawal of subjects .................................................................................. 12 
3.5 
Assessment and management of risk ............................................................. 13 
4 
TRIAL PROCEDURES ..................................................................................... 13 
4.1 
Patient identification and consent .................................................................. 13 
4.2 
Randomisation .............................................................................................. 14 
4.3 
Trial assessments ......................................................................................... 14 
4.4 
Study Outcome Measures .............................................................................. 15 
4.4.1 
Primary Outcome Measure ......................................................................... 15 
4.4.2 
Secondary Outcome Measure ..................................................................... 15 
5 
LABORATORY TESTS ..................................................................................... 16 
6. 
DRUG INFORMATION ............................................................................... 16 
6.1 
Blinding arrangements ............................................................................... 1716 
6.2 
Prescribing, preparation and administration arrangements ........................... 1716 
6.3 
Thiamine (Pabrinex) ..................................................................................... 17 
6.3.1 
Thiamine (Pabrinex) treatment schedule .................................................... 17 
6.3.2 
Rationale for chosen dose.......................................................................... 17 
6.3.3 
Administration .......................................................................................... 17 
6.4 
Magnesium sulphate .................................................................................. 1817 
6.4.1 
Magnesium sulphate treatment schedule ................................................. 1817 
6.4.2 
Rationale for chosen dose....................................................................... 1817 
6.4.3 
Administration ....................................................................................... 1817 
6.5 
Study supplies .............................................................................................. 18 
6.5.1 
Supply of study treatment ......................................................................... 18 
6.5.2 
Labelling of study treatment ...................................................................... 18 
6.5.3 
Storage of study treatments ...................................................................... 18 
6.5.4 
Drug accountability ................................................................................... 18 
7. 
PHARMACOVIGILANCE- ........................................................................... 19 
7.1 
Definitions of adverse events ......................................................................... 19 
7.2 
Serious Adverse Event (SAE) ......................................................................... 19 
7.3 
Recording and reporting of Adverse Events .................................................... 19 
8. 
STATISTICS AND DATA ANALYSIS- .......................................................... 20 
8.2 
Statistical analysis plan ................................................................................. 21 
9.0 
STUDY CLOSURE / DEFINITION OF END OF TRIAL ................................. 21 
10 
DATA HANDLING .................................................................................. 2221 
10.1 Record Retention ........................................................................................... 2221 
11.0 
TRIAL MANAGEMENT ............................................................................... 22 
11.1 
Routine management of trial: Trial Management Group .................................. 22 
12. 
STUDY AUDITING ..................................................................................... 22 
13. 
PROTOCOL AMENDMENTS ........................................................................ 22 
14. 
ETHICAL CONSIDERATIONS................................................................. 2322 
14.1 
Ethical conduct of the study ....................................................................... 2322 

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15. 
INSURANCE AND INDEMNITY .................................................................. 23 
16. 
FUNDING .................................................................................................. 23 
17. 
ANNUAL REPORTS .................................................................................... 23 
18. 
DISSEMINATION OF FINDINGS ........................................................... 2423 
19. 
REFERENCES ......................................................................................... 2524 
APPENDIX A: 
GMAWS: assessment ............................................................... 2625 
 

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ABBREVIATIONS 
 
 
A&E 
Accident and Emergency 
AE 
Adverse event 
CRF 
Case Report Form 
ED 
Emergency Department 
FAST 
Fast Alcohol Screening Test 
GMAWS 
Glasgow Modified Alcohol Withdrawal Scale 
GRI 
Glasgow Royal Infirmary 
IV 
Intravenous 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SmPC 
Summary of Product Characteristics 
TKA 
Transketolase 
WE 
Wernicke’s Encephalopathy 
 

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STUDY SYNOPSIS 
Title of Study: 
Effect of Magnesium and Thiamine on red cell 
transketolase activity 
Study Centre: 
Glasgow Royal Infirmary 
Duration of Study: 
12 months 
Primary Objective: 
Does magnesium administration enhance the biochemical 
response to thiamine as measured by the activity of the 
enzyme transketolase in red blood cells? 
Secondary Objective: 
What  is the effect of the administration of thiamine alone, 
Magnesium alone, or both together on 
- 
Plasma lactate concentrations 
- 
Biomarkers of ageing 
Primary Endpoint: 
Change in erythrocyte transketolase activity after treatment 
with  
- 
Thiamine 
- 
Magnesium 
- 
Thiamine plus magnesium 
Rationale: 
Chronic alcoholics have a 30-80% incidence of thiamine 
deficiency causing Wernicke’s Encephalopathy (WE).  
Intravenous (IV) thiamine replacement is standard practice in 
the treatment of alcoholic patients presenting to the Accident 
& Emergency (A&E) department, however routine co-
supplementation 
with 
magnesium 
(administered 
IV 
as 
magnesium sulphate ), a co-factor for thiamine in some 
metabolic processes, e. g. on the activity of the enzyme 
transketolase in red blood cells, is not routine practice in the 
treatment of these patients. Without correction of concomitant 
magnesium deficiency there may be impaired utilisation of 
thiamine resulting in a failure to treat WE. 
This study is designed to determine if administration of 
Magnesium to alcoholic patients affects red cell transketolasae 
by itself, or only acts to increase the effect of thiamine  on the 
activity of this enzyme.  
Methodology: 
Open label, randomised controlled study 
Sample Size: 
120 
Screening: 
Confirmation of chronic alcoholism (FAST questionnaire. 
GMAWS score) 
Registration/Randomisation: Randomisation will be performed using individually numbered 
opaque envelopes. 
Main Inclusion Criteria: 
 
Chronic alcohol dependence  
Main Exclusion Criteria: 
 
Known chronic renal failure 
Product, Dose, Modes of 
Administration:  
Participants will be randomised to: 
 Arm 1:Thiamine  
 Arm 2: Thiamine and magnesium sulphate  
 
Arm 3: Magnesium sulphate with delayed thiamine  
where thiamine will be administered as Pabrinex.  
Duration of Treatment: 
Each infusion will be administered over 30 minutes 
Statistical Analysis: 
A three group study was designed to detect a minimum 
biochemically significant difference of 0.16 in the change from 
baseline between the groups, with 80% power and a 5% 
significance level. total sample size = 120. Methodology: One 
way ANOVA 
 
 

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1. 
INTRODUCTION 
1.1 
Background 
Alcohol related conditions account for up to 40% of weekday Emergency Department 
attendances.1  II  Socioeconomic deprivation has a well-proven association with rates of 
alcoholism in the community.2  Glasgow Royal Infirmary serves the north and east of 
Glasgow, parts of which have been designated by the WHO to be among the most deprived 
areas in Europe.2 
Between 30-80% of chronic alcoholics have thiamine deficiency.  The incidence of Korsakoff’s 
psychosis has been noted to be steadily increasing in the East End of Glasgow since 
1990.3   Wernicke-Korsakoff Psychosis has also been shown to be related to Thiamine 
deficiency. Magnesium (Mg2+) is known to be an essential cofactor for Thiamine, though its 
effect on the enzyme transketolase, in the Pentose Phosphate Shunt and as such is 
advocated by core Emergency Medicine texts in the treatment of alcoholic or malnourished 
patients.4 
The aim of this project is to further clarify the effect of concurrent magnesium 
supplementation with thiamine administration on Red Cell Transketolase (TKA)  Activity in a 
cohort of alcoholic patients admitted through ED. Patients will be determined to be alcohol 
dependant from history (FAST questionnaire) or in alcohol withdrawal as determined by the 
GMAWS scale (appendix). 
 
1.2 
Rationale 
Thiamine and Magnesium in the Alcohol Withdrawal Patient 
Chronic alcoholics have a 30-80% incidence of clinical or biochemical signs of thiamine 
deficiency.5 Wernicke’s Encephalopathy (WE) is not a rare disorder. Autopsy studies have 
revealed a prevalence of 2% in western society among the general population.5 Untreated WE 
has a mortality rate of 20% and a progression along its clinical spectrum to Korsakoff 
psychosis of 85%.5 
Parenteral thiamine replacement is standard practice in the treatment of alcoholic patients 
presenting to the A&E department. However despite the fact that routine co-supplementation 
with magnesium sulphate is practiced by many doctor’s in the treatment of these patients 

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(authors own experience and peer consensus), the underlying mechanism and efficacy is not 
yet fully understood. 
Low total body magnesium results from the direct effect of alcohol on the nephron, which 
causes urinary Mg2+ wastage.  Malnutrition and poor dietary intake of magnesium also 
contribute to poor levels of total body magnesium.8  
Clinician’s often fail to recognise the presence of magnesium deficiency in their patients as 
they rely on serum values of magnesium. The measureable serum value reflects only 0.15% 
of total body magnesium, as magnesium is predominantly intracellular and protein bound. 
Serum values do not drop until critical deficiency exists. Without correction of baseline 
magnesium deficiency there may be impaired utilisation of thiamine.10 
The Cochrane review states that there is insufficient evidence as to the duration of treatment 
and dosages of Thiamine required for the treatment of Wernicke-Korsakoff Syndrome, while 
acknowledging that thiamine utilization in patients experiencing alcohol withdrawal is 
probably influenced by Mg2+ status.9, 11 
Current evidence consists mainly of case reports and clinical observations. Given the weight 
of biochemical evidence available it is surprising that this role has not been clarified in a 
clinical study context. A comprehensive search of the literature revealed only one clinical 
study (co-written by this author) comparing effects of thiamine alone versus thiamine and 
magnesium sulphate on Red Cell Transketolase (TKA) in alcoholic patients. 12  In this study, a 
more rapid recovery of the thiamine dependent enzyme Red Cell TKA occurred, when 2 
grams magnesium sulphate was delivered simultaneously with thiamine than in a similar 
patient group treated with thiamine alone, however this study was not fully controlled. 
The Scottish Intercollegiate Guidelines Network (SIGN) also identify the dosage and duration 
of Thiamine administration as an area of research to be encouraged.13 The role of Mg2+ as an 
essential cofactor has a definite relevance to this question as Mg2+ may be influential in 
determining efficacy. 
In this study we would like to extend out previous work by randomising alcoholic patients to 
treatment with either thiamine alone, magnesium sulphate alone (with delayed thiamine), or 

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concurrent administration of thiamine plus magnesium sulphate, to determine whether 
treatment with magnesium sulphate has any effect on its own on red blood cell transketolase 
activity, or only acts to increase the effect of thiamine. 
1.3 
Study hypothesis 
Hypothesis: That magnesium administration enhances the biochemical response to thiamine. 
 
 
2. 
STUDY OBJECTIVES 
This is a single-centre, randomised, parallel group study to determine the effects of 
- 
IV thiamine 
- 
IV magnesium sulphate 
- 
IV thiamine plus IV magnesium sulphate 
on red blood cell TKA in a cohort of alcoholic patients admitted through A&E. 
 
 
Primary Objective 
To determine whether Magnesium administration enhances the biochemical response to 
thiamine as measured by the activity of the enzyme transketolase in red blood cells 
 
 
Secondary Objectives 
 
To determine effect of the administration of thiamine alone, magnesium sulphate 
alone, or both together on plasma lactate concentrations, vitamins  A, B1, B2, B6, B9 
B12, C, D, E and K and trace elements (copper, manganese, copper and zinc) 
 
3. 
STUDY DESIGN 
This is a 3- arm randomised, open label, controlled study in a cohort of alcoholic patients 
admitted through A&E.  Patients will be randomised to concurrent infusion of one of the 
following:  
 
Arm 1: IV thiamine  
 
Arm 2: IV magnesium sulphate followed by delayed IV thiamine 
 
Arm 3: IV thiamine and IV magnesium sulphate 
Thiamine will be administered as IV Pabrinex, a compound preparation which also contains B 
vitamins and vitamin C. Administration of IV Pabrinex is standard care in this patient group 
and magnesium sulphate is routinely co-administered at Glasgow Royal Infirmary.   

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3.1 
Study Population 
A total of 120 patients will be recruited to this study, with 40 being randomised to each arm 
i.e.  
 
Arm 1: IV thiamine (Pabrinex)  
 
Arm 2: IV magnesium sulphate followed by delayed thiamine (Pabrinex) 
 
Arm 3: IV thiamine (Pabrinex) and IV magnesium sulphate 
Patients will be identified by ED staff on presentation to the ED.   
 
3.2 
Inclusion criteria 
 
Written informed consent 
 
Male or non-pregnant or breastfeeding females ≥18 years of age For women of child-
bearing potential a negative pregnancy test will be required prior to treatment.   
(Women of non-childbearing potential are defined as those defined as women who are 
post-menopausal or permanently sterilised (e.g. hysterectomy, tubal occlusion, bilateral 
salpingectomy). 
 
Chronic alcohol dependence as confirmed by 
o 
FAST questionnaire 
o 
GMAWS scale 
 
3.3 
Exclusion criteria 
 
Unable to give consent 
 
Less than 18 years of age 
 
Chronic renal or hepatic failure/hepatic encephalopathy (investigator assessment as 
documented in past medical history i.e. Clinical Portal.) 
 
Known hypersensitivity or previous allergy to any of the active substances in either 
trial medication, or to excipients  
 
Severe concurrent medical condition that would prevent participation in study 
procedures (e.g. myasthenia gravis, clinically significant cardiac disease, or cardiac 
failure with severe pulmonary oedema) 
 
3.4 
Withdrawal of subjects 
Participants have the right to withdraw from the trial at any point for any reason.  Data 
collected up to the point of withdrawal will be retained.  The investigator can also withdraw 
patients from the study intervention in the event of inter-current illness, protocol violations or 
any other relevant reasons. 

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3.5 
Assessment and management of risk 
As above, there are three arms to this study. Our previous study examined the effect of 
thiamine and magnesium, as compared to thiamine alone, on TKA activity. This demonstrated 
a significant increase in TKA activity in the magnesium and thiamine group as compared to 
the thiamine group. It is therefore necessary to include the magnesium sulphate arm to this 
study to confirm this effect was not directly attributable to Magnesium separately, and to 
elucidate the degree of synergism that may exist between magnesium and thiamine. 
 
Alcoholism is a disease of malnutrition. Dietary deficiencies develop over weeks, months and 
years.  We appreciate that the two hour delay to Pabrinex administration, represents a delay 
to standard treatment in the Magnesium group (with delayed Pabrinex).  However there is no 
evidence in the literature to indicate that a real time delay of two hours may disadvantage a 
patient, or that a single treatment of Pabrinex can reverse the chronic changes associated 
with Vitamin B1 (Thiamine) deficiency.  It is our view therefore that a two hour delay will not 
disadvantage the patients randomised to this group.  Indeed a 2 hour delay is not uncommon 
in the Emergency Department (ED) for any treatment due to the acuity and volume of 
patients attending a busy inner city ED.  All patients attending the ED should be treated and 
discharged within the 4 hour window, as dictated by the national access target for emergency 
care. 
 
Patients will be identified at triage in order to ensure adequate time to recruit, consent and 
obtain repeat samples at the 2 hour time interval post administration of treatment whilst still 
meeting national targets. Eligible patients may therefore be seen earlier in their patient 
journey which may offset potential delays due to study involvement. The net effect will be 
that patients randomised to the Magnesium group, will therefore receive their Pabrinex at 
approximately the same point in their patient journey, as if the study were not ongoing. 
 
Magnesium sulphate and pabrinex are routinely administered to this patient group in the ED 
at GRI.   
 
 
4 
TRIAL PROCEDURES 
4.1 
Patient identification and consent 
Patients will be identified by ED staff on presentation and will be determined to be alcohol 
dependent (Fast Alcohol Screening Test questionnaire) or in alcohol withdrawal as 
determined by the GMAWS scale (appendix) as per standard practice.  Patients will then be 

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approached about the study by a trained and appropriately delegated member of the ED 
team who will provide a Patient Information Sheet and go through the purpose of the study 
and what it would require of them, and have any questions they may have addressed.  
Patients will then be given up to 30 minutes to decide whether they wish to take part. If they 
agree to participate patients will then be asked to sign a study consent form by a member of 
ED/research team.  Eligibility to participate in the study will be confirmed by appropriately 
trained and delegated medical staff.   
 
4.2 
Randomisation 
Randomisation will be performed in advance by the study statistician and opaque envelopes 
detailing the subject number and treatment allocation prepared.  Patients will be sequentially 
assigned a subject number once eligibility is confirmed and the corresponding treatment 
assignment envelope opened.  The opened enveloped will be retained and attached to the 
patient’s case report form (CRF)   
 
4.3 
Trial assessments 
Patients who have consented to participate in the study will have all study procedures carried 
out in a single visit. Where the procedure differs for the respective groups this will be 
indicated in the schedule below 
 
Part 1: Baseline Assessments 
 
Medical history 
 
Pregnancy test for female participants of child-bearing potential.    
 
Randomisation 
 
Blood samples for biochemistry 
o 
Standard care: FBC, U&E, LFT, Gamma GT, CRP, serum Magnesium, 
glucose and lactate, random cortisol and nutritional markers 
o 
Study specific: erthyrocyte TKA, thiamine and magnesium trace elements 
copper, manganese, and zinc and vitamin A, B1, B2, B6, B9, B12 C, D, E and 
K 
 
Blood sample eGFR and blood glucose 
 
Weight  
 
Physical examination 
 
Part 2: Administration of study medicines 
Patients will be randomised to one of the following regimes and infusions administered: 
 
Arm 1: IV thiamine (Pabrinex)  

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 
Arm 2: IV magnesium sulphate and delayed Pabrinex  
 
Arm 3: IV thiamine (Pabrinex) and IV magnesium sulphate 
 
Part 3: Post-intervention Assessments 
Patients in all groups will then have repeat blood samples 2 hours (+/- 30mins) for 
biochemistry  
 
serum magnesium, glucose, cortisol and lactate  
 
erthyrocyte TKA, thiamine and magnesium,  
 
trace elements copper, manganese, copper and zinc  
 
vitamins A, B1, B2, B6, B9, B12, C, D, E and K  
 
Part 4: Administration of delayed Pabrinex (Arm 2 only) 
For patients randomised to Arm 2, (IV magnesium sulphate and delayed thiamine), Pabrinex 
will be administered after the second blood samples have been taken, approximately 2 hours 
(+/- 30mins) after completion of magnesium sulphate infusion.   
 
Case report forms will be updated as appropriate.   
4.4 
Study Outcome Measures 
4.4.1 Primary Outcome Measure 
 
The relative change in TKA pre- and 2 hours (+/- 30mins) post-administration of  
o 
IV thiamine  
o 
IV magnesium sulphate  
o 
IV thiamine +  IV magnesium sulphate 
4.4.2 Secondary Outcome Measure 
 
The relative change in lactate  pre- and 2 hours (+/_ 30mins) post administration of  
o 
IV thiamine  
o 
IV magnesium sulphate  
o 
IV thiamine +  IV magnesium sulphate 
 
Review of levels of routine biochemical, trace elements (copper, manganese, 
selenium, zinc) and vitamin (A, B1, B2, B6,  C, D, E and K) markers pre- and 2 
hours (+/- 30 mins) post administration of  
o 
IV thiamine alone  
o 
IV magnesium sulphate 
o 
IV thiamine +  IV magnesium sulphate 
 

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5 
LABORATORY TESTS 
Analysis of U&E, LFT, gamma GT, CRP, serum magnesium, glucose and lactate will be carried 
out be the Core Biochemistry section in the Biochemistry department of Glasgow Royal 
Infirmary. The FBC will be carried out by the Haematology department of Glasgow Royal 
Infirmary. Samples will be transported to the laboratory using standard means and analysed 
routinely. 
A full micronutrient screen will be carried out by the Scottish Trace Element and Micronutrient 
Diagnostic and Research Laboratory located within the Biochemistry department at Glasgow 
Royal Infirmary. A standard micronutrient screen includes vitamin A, E, C and K and copper, 
zinc and selenium in plasma, vitamin B1 and Mn in whole blood and vitamins B2 and B6 and 
selenium in red cells. Additional tests will be carried out to assess micronutrient status that 
are not part of a standard micronutrient screen. Non-standard tests include magnesium, zinc 
and selenium in red cells and red cell transketolase activity. Non gel, lithium heparin tubes 
will be required. Samples will be taken and clearly labelled “AToM Study”. Samples will then 
be transported to the laboratory within four hours of collection using standard means. 
Laboratory reception staff will prepare the whole blood, plasma and packed red cell fractions 
for the standard micronutrient tests within 30 mins of sample arriving in specimen reception. 
The red cell samples for magnesium, zinc, selenium and transketolase activity will be 
prepared and stored at    -70 ˚C until analysis. Standard micronutrient tests will be analysed 
within laboratory turnaround times (6-10 days) and results will be entered into telepath. Non-
standard tests will be stored until enough are accumulated to constitute a batch at which 
time they will be analysed. Results will be stored by the laboratory. 
Results of both standard and additional assays will be copied to the Care Report 
Form (CRF). 
 
6. 
DRUG INFORMATION 
Patients who are eligible for the study will be randomised to receive one of the following 
arms:  
 
Arm 1: IV thiamine (Pabrinex)  
 
Arm 2: IV magnesium sulphate followed by delayed thiamine (Pabrinex) 
administered after completion of post-intervention assessments. 
 
Arm 3: IV thiamine (Pabrinex) and IV magnesium sulphate 
In Arm 3 IV Pabrinex and IV magnesium sulphate will be administered concurrently.  There is 
limited data available on Y-site compatibility for Pabrinex and magnesium sulphate infusions 

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however, it has been standard practice at GRI to administer in this way for a number of 
years.   
All study drug administration will be completed within the ED where full resuscitation facilities 
are available.   
 
6.1 
Blinding arrangements 
This is an open label study.  No participant blinding will be necessary as the outcome 
measures are biochemical.. 
6.2 
Prescribing, preparation and administration arrangements 
All study treatments will be prescribed on a hospital Kardex and administration documented 
in accordance with standard practice in NHS Greater Glasgow.  Only those who are trained on 
the study protocol and delegated prescribing responsibilities by the PI may prescribe study 
medication.   
 
Pabrinex and magnesium sulphate are routinely prepared in ED with the latter currently used 
at physician discretion for treatment in alcohol dependent patients and also in treatment of 
asthma, pre-eclampsia, heart arrhythmias.  Nursing staff experienced in preparation of 
magnesium sulphate and Pabrinex may prepare either infusions.  There is no requirement 
that they be delegated this task on the study delegation log as this is within the remit of 
routine practice within the GRI ED department. 
 
6.3 
Thiamine (Pabrinex) 
6.3.1 Thiamine (Pabrinex) treatment schedule 
Participants will be treated once only with Pabrinex Intravenous High Potency Solution for 
injection as per standard care in this patient group as detailed above.  Any further treatment 
with Pabrinex will be in accordance with standard care and will fall outwith this study.   
6.3.2 Rationale for chosen dose 
Administration of Pabrinex on admission to ED is standard care for this patient group.   
6.3.3 Administration 
Pabrinex will be administered as an intravenous infusion.  Two pairs  (1 pair = ampoule no 1 
+ ampoule no 2 )of 5ml ampoules will be added to 100ml of sodium chloride 0.9% and 
administered IV over 30 minutes.  The prepared infusion should be inspected prior to 
administration to ensure absence of particulates.  No dose modifications are permitted.  The 
infusion rate may be adjusted as per standard practice.   

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6.4 
Magnesium sulphate 
6.4.1 Magnesium sulphate treatment schedule  
Participants will be treated once only with magnesium sulphate.  
6.4.2 Rationale for chosen dose 
Magnesium sulphate is currently used at physician discretion for treatment in alcohol 
dependent patients in GRI as part of standard treatment approach 
6.4.3 Administration 
Magnesium sulphate will be administered an intravenous infusion.  Two grams of magnesium 
sulphate will be added to 100ml of sodium chloride 0.9% and administered IV over 30 
minutes.  The infusion should be inspected prior to administration to ensure absence of 
particulates.   No dose modifications are permitted.  The infusion rate may be adjusted as per 
standard practice.   
 
6.5 
Study supplies  
6.5.1 Supply of study treatment 
Magnesium sulphate and Pabrinex  are already routinely available within the ED department.  
Supplies for the study will be sourced from usual ED hospital stock.   
6.5.2 Labelling of study treatment 
Prepared infusions should be labelled in accordance with standard practice.  
6.5.3 Storage of study treatments 
All supplies will be stored in accordance with the current Summary of Product Characteristics 
(SmPC).   
6.5.4 Drug accountability 
For traceability purposes, batch details for Pabrinex, thiamine and infusion fluid will be 
recorded on the CRF.  No other accountability will be required.   

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7. 
PHARMACOVIGILANCE-  
7.1 
Definitions of adverse events 
Adverse Event (AE) – Any untoward medical occurrence in a subject to whom a medicinal 
product has been administered, including occurrences which are not necessarily caused by or 
related to that product. 
 
7.2 
Serious Adverse Event (SAE) 
Any adverse event or adverse reaction that: 
a. results in death  
b. is life threatening  
c. requires hospitalisation or prolongation of existing hospitalisation  
d. results in persistent or significant disability or incapacity  
e. consists of a congenital anomaly or birth defect 
f. 
is otherwise considered medically significant by the investigator  
g. Important adverse events/ reactions that are not immediately life-threatening or do 
not result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
7.3 
Recording and reporting of Adverse Events 
AEs must be recorded, assessed, reported, analysed and managed in accordance with the 
Research Governance Framework for Health and Community Care and the study protocol.  All 
AEs must be assessed for seriousness.   
 
7.4 Serious adverse event and serious adverse reactions recording and 
reporting 
Where an SAE requires recording, full details  including the nature of the event, start and 
stop dates severity, relationship to research product and/or procedures. Outcome will be 
recorded in the patient’s CRF (and medical notes where available).  These events will be 
monitored and followed up until satisfactory resolution and stabilisation.  SAEs must be 
assessed to determine if related to the research procedures (includes administration of study 
medicines) and expectedness.    
 
Related: that is, it resulted from administration of study medicines or any of the 
research procedures, 
 
Expectedness for SAR: that is, the expectedness of an adverse reaction to 
administered research products is assessed against the SmPC for Pabrinex and 
Magnesium sulphate.   

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 
Expectedness for SAEs: is against the research procedure events listed in the 
study protocol as an expected occurrence.  
 
All SAEs and SARs must be reported to the Pharmacovigilance Office immediately (within 24 
hours) 
using 
the 
generic 
non-CTIMP 
SAE 
form 
which 
is 
available 
from 
http://www.glasgowctu.org/data/SAE_non-CTIMP.pdf . The SAE form should be completed 
and signed by appropriately delegated staff.  The form should be faxed or e-mailed to the PV 
Office (pharmacovig@glasgowctu.org) and a copy placed in the Study Site File.  If necessary 
a verbal report can be given by contacting the PV Office on 0141 330 4744. This must be 
followed up as soon as possible with a signed written (or electronic) report.   
 
If all of the required information is not available at the time of initial reporting, the CI (or 
designee) must ensure that any missing information is forwarded to the PV Office as soon as 
this becomes available. The report should indicate that this information is follow-up 
information for a previously reported event. 
 
7.5 
 Reporting of SARs and SAEs to the Ethics Committee 
Reports of SARS and SAEs should be submitted within 15 days of the Chief Investigator 
becoming aware of the event, using the ‘report of serious adverse event form’ for non-
CTIMPs 
published 
on 
the 
Health 
Research 
Authority 
web 
site. 
http://www.hra.nhs.uk/documents/2015/02/safety-report-form-non-ctimp.docx 
The 
form 
should be completed in typescript and signed by the Chief Investigator.   
 
7.6 
 Annual progress reports 
The Chief Investigator must also provide an annual progress report to the REC. A report on 
the safety of participants will be included as part of this report.  
 
7.7 
 Reporting to the MHRA 
Whilst there is no statutory requirement to report to the MHRA adverse reactions to Pabrinex 
and 
thiamine 
may 
be 
reported 
to 
the 
MHRA 
Yellow 
Card 
Scheme 
(www.mhra.gov.uk/yellowcard). 
 
 
8. 
STATISTICS AND DATA ANALYSIS- 
8.1 Power and Sample Size  
Choosing the higher standard deviation to be more conservative, a three group study was 
designed to detect a minimum biochemically significant difference of 0.16 in the change from 

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baseline between the groups, with 80% power and a 5% significance level. This requires 37 
participants to be randomised to each arm of the study. We therefore propose a total sample 
of 120 to account for any drop-outs or missing data. 
 
8.2 
Statistical analysis plan 
 
The following data was available from a pilot study for a two group design: 
 
Descriptive Statistics: Combined, Thiamine  
 
Variable   N    Mean  SE Mean   StDev  Minimum  Maximum 
Combined  18  0.3211   0.0513  0.2176   0.0200   0.7500 
Thiamine  12  0.1433   0.0350  0.1214   0.0100   0.4500 
 
Power and Sample Size  
 
Choosing the higher st dev to be more conservative, a three group study was designed to 
detect a minimum biochemically significant difference of 0.16 in the change from baseline 
between the groups, with 80% power and a 5% significance level. This requires 37 
participants to be randomised to each arm of the study. We therefore propose a total sample 
of 120 to account for any drop-outs or missing data. 
 
 
 
 
9.0 
STUDY CLOSURE / DEFINITION OF END OF TRIAL 
The study will end when one or more of the following situations applies: 
 
Last patient last study visit; 
OR 
i. 
There is insufficient funding to support further recruitment, and no reasonable 
prospect of additional support being obtained; 
ii. 
New information makes it inappropriate to continue to randomise patients to one or 
other arm of the trial; 
iii. 
Recruitment is so poor that completion of the trial cannot reasonably be anticipated. 
 
 

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10 
DATA HANDLING 
A paper case report form (CRF) will be used to collect study data.  The paper CRF will be 
developed and managed by the study team.  It is the investigator's responsibility to ensure 
completion and to review and approve all data captured in the CRF.  
 
10.1 Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to 
keep records, including the identity of all participating subjects (sufficient information to link 
records), all original signed informed consent forms, serious adverse event forms, source 
documents, and detailed records of treatment disposition in accordance with ICH GCP, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer.  Data will be 
retained for a minimum of 5 years. 
 
11.0 TRIAL MANAGEMENT 
11.1 Routine management of trial: Trial Management Group 
The trial will be coordinated by the chief investigator. A Trial Management Group consisting of 
chief investigator R&D coordinator, R&D pharmacy staff and others as appropriate will be 
convened on an ad hoc basis.  The role of the group is to monitor all aspects of the conduct 
and progress of the trial, ensure that the protocol is adhered to and take appropriate action 
to safeguard participants and the quality of the trial itself. 
 
 
12. 
STUDY AUDITING 
The Sponsor, NHS GG&C, carries out risk assessment on all studies to determine requirement 
ofr monitoring/auditing, and in addition carried out audit of studies on a random basis 
(approximately 10% of sponsored studies per annum). 
 
 
13. 
PROTOCOL AMENDMENTS 
Any change in the study protocol will require an amendment.  Any proposed protocol 
amendments will be initiated by the CI following discussion with the Sponsor and any 
required amendment forms will be submitted to the regulatory authority, ethics committee 
and sponsor.  The CI will liaise with study sponsor to determine whether an amendment is 
non-substantial or substantial.  All amended versions of the protocol will be signed by the CI 

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and Sponsor representative.  Before the amended protocol can be implemented favourable 
opinion/approval must be sought from the original reviewing REC and Research and 
Development (R&D) office(s). 
 
 
14. 
ETHICAL CONSIDERATIONS 
14.1 Ethical conduct of the study 
General: 
 
The study will be carried out in accordance with the World Medical Association Declaration of 
Helsinki (1964) and its revisions (Tokyo [1975], Venice [1983], Hong Kong [1989], South 
Africa [1996] and Edinburgh[2000]). 
Favourable ethical opinion will be sought from an appropriate REC  before patients are 
entered into this clinical trial.  Patients will only be allowed to enter the study once either they 
have provided written informed consent. The CI will be responsible for updating the Ethics 
committee of any new information related to the study. 
 
 
15. 
INSURANCE AND INDEMNITY 
This study is sponsored by NHS Greater Glasgow & Clyde.  The sponsor will be liable for 
negligent harm caused by the design of the trial.  NHS indemnity is provided under the 
Clinical Negligence and Other Risks Indemnity Scheme (CNORIS). 
 
The NHS has a duty of care to patients treated, whether or not the patient is taking part in a 
clinical trial, and the NHS remains liable for clinical negligence and other negligent harm to 
patients under its duty of care. 
 
 
16. 
FUNDING 
No external funding has been sought. The study is supported by the A&E and Biochemistry 
departments of NHS Greater Glasgow and Clyde. 
 
 
 
17. 
ANNUAL REPORTS 
Annual reports will be submitted to the ethics committee and sponsor with the first submitted 
one year after the date that all trial related approvals are in place. 

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18. 
DISSEMINATION OF FINDINGS 
It is hoped to publish study results in a peer reviewed journal and present at scientific 
meetings. 
 
 
 
 

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19. 
REFERENCES 
1. 
Ramayya A, Jauhar P. Increasing incidence of Korsakoff’s Psychosis in the East End of 
Glasgow. Alcohol and Alcoholism 1997;32:281-285 
2. 
Pollack C, Pollack E, Seizures Rosen Emergency Medicine 5th Edition Vol.2 Chapter 90 Pg. 
1787-1805 
3. 
Christina Viola. Seizure and Status Epilepticus in Adults. Tintinalli JE, Kelen GD, 
Stapczynski JS. Emergency Medicine - A Comprehensive Study Guide. McGraw Hill 
Publications.2000: Ch.224. Pg. 463-4. 
4. 
Tso EL, Barish RA. Magnesium clinical considerations. The Journal of Emergency 
Medicine.:10;735-745. 1992 
5. 
Flink E.M. Magnesium deficiency in Alcoholism.  Alcoholism: Clinical Experimental 
Research.:10(6);  590-4. 1986 
6. 
Harrison’s Medical Textbook. 4th Edition, Magnesium Chapter 357, pg2263-226 
7. 
McClean RM. Magnesium and its therapeutic uses: A Review. The American Journal of 
Medicine.: 96(1);63-76. 1994 
8. 
Shane SR. Flink EB, Magnesium deficiency in alcohol addiction and withdrawal. 
Magnesium & Trace Elements. 10(2-4):263-8, 1991-92. 
9. 
Wernicke-Korsakoff Syndrome - Literature review. The Cochrane Library.2004:2 
10. Harper C, Manchip S. Wernicke’s Encephalopathy induced by Magnesium depletion. 
Lancet 1999;353:1768 
11. Wood B, Currie J, Presentation of Wernicke’s Encephalopathy and treatment with 
thiamine. Metabolic Brain Disease 1995;10(1):57-72 
12. Peake RW, Godber IM, Maguire D.  The effect of magnesium administration on 
erythrocyte transketolase activity in alcoholic patients treated with thiamine. Scott Med J. 
2013 Aug;58(3):139-42  
13. The Scottish Intercollegiate  Guidelines Network (SIGN) 74 The Management of Harmful 
Drinking and Alcohol Dependence in Primary Care 

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APPENDIX A: 
 
 
 
 
Patient details : CHI / age 
P/C: alcohol withdrawal, seizure, fall, recurrent falls , head 
injury, sepsis 
PM/SH: 
Have you been prescribed thiamine?  
Do you regularly take thiamine or multi-vitamin tablets? 
Medications: 
Antacid 
stomach 
medication 
PPi/H2 
antagonist , Loop diuretics, Digoxin 
Approximate Time of last alcoholic drink: 
Predisposing poor nutritional status: Eating disorder, 
Opiate dependence 
GMAWS score: