Conditions: Primary Alcohol Use Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
96 recently detoxified alcoholics will be randomized to receive either 3 sessions ketamine (0.8 mg/kg IV over 45 minutes) or placebo plus manualised psychological therapy, or 3 sessions of ketamine or placebo plus simple psychoeducation. Patients will be assessed at 3 and 6 months on a range of psychological and biological variables. Primary endpoints will be % days abstinent at 6 months and relapse rates at 6 months. Secondary endpoints include depressive symptoms, craving, quality of life.

Detailed description:

Arms:
arm 1: Ketamine with psychological therapy arm 2: ketamine with alcohol education arm 3: placebo with psychological therapy arm 4: placebo with simple alcohol education

Interventions: intervention 1: Ketamine intervention 2: Placebo intervention 3: Psychological Therapy intervention 4: Alcohol Education
Intervention descriptions: intervention 1: 0.8 mg/kg ketamine intervention 2: 0.9% saline intervention 3: Manualised relapse prevention based CBT intervention 4: Simple education about alcohol effects

Protocol document:
Prot_000.pdf: 
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Full title of trial 
 
A phase II, randomised, double-blind, 
placebo- controlled, multi-site, parallel group 
clinical trial to examine ketamine as a 
pharmacological treatment for alcohol 
dependence in an alcohol dependent 
population. 
Short title 
 
KARE: Ketamine for reduction of Alcoholic 
RElapse  
Version and date of protocol 
Final Version 12,  20 January 2020 
 
Sponsor: 
University College London (UCL) 
Sponsor protocol number 
13/0253 
Funder (s) : 
Medical Research Council 
EudraCT no 
2015-000222-11 
ACTIVE IMP(s): 
Ketamine 
PLACEBO IMP(s): 
Placebo (Saline)  
Phase of trial 
Phase II 
Sites(s) 
Multisite 
Chief investigator: 
Dr Brigitta Brandner 
Consultant Anaesthetist 
UCL Centre for Anaesthesia 
University College London Hospital 
Sponsor Representative: 
Samim Patel 
Email: samim.patel@ucl.ac.uk 
Tel: 020 76799320 
Joint Research Office, 1st Floor Maple 
House, 


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LONDON NW1 2BU 
Email: brigitta.brandner@nhs.net 
Tel: 020 3447 3343 fax: 020 3447 9604 
 
 
149 Tottenham Court Road, 
London W1T 7DN. 
Postal address: 
Joint Research Office, UCL 
Gower Street, 
 London 
London WC1E 6BT 


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Signatures 
The Chief Investigator and the JRO have discussed this protocol. The 
investigators agree to perform the investigations and to abide by this protocol.  
The investigator agrees to conduct the trial in compliance with the approved 
protocol, EU GCP and UK Regulations for CTIMPs (SI 2004/1031; as amended), 
the UK Data Protection Act (1998), the Trust Information Governance Policy (or 
other local equivalent), the Research Governance Framework (2005’ 2nd Edition; 
as amended), the Sponsor’s SOPs, and other regulatory requirements as 
amended. 
 
Chief investigator 
Dr Brigitta Brandner 
Signature
Date
Sponsor Representative 
 Dr Nick McNally, Director of 
Research Support 
UCL
Signature
Date
 
This Protocol template is intended for use with UK sites only. 
 


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Contents 
Signatures ................................................................................................................................. 3 
Contents .................................................................................................................................... 4 
List of abbreviations ................................................................................................................. 7 
Trial personnel ........................................................................................................................ 11 
Summary ................................................................................................................................. 14 
 
Introduction..................................................................................................................... 17 
 
Background ................................................................................................... 17 
 
Preclinical data ............................................................................................. 18 
 
Clinical data .................................................................................................. 19 
 
Rationale and risks/benefits ....................................................................... 20 
 
Assessment and management of risk ...................................................... 24 
 
Objectives ....................................................................................................................... 35 
 
Trial design ..................................................................................................................... 35 
 
Overall design ............................................................................................... 35 
 
Selection of Subjects .................................................................................................... 38 
 
Inclusion criteria ........................................................................................... 38 
 
Exclusion criteria .......................................................................................... 38 
 
Recruitment .................................................................................................................... 40 
 
Study procedures and schedule of assessments .................................................... 41 
 
Informed consent procedure ...................................................................... 41 
 
Randomisation procedures ........................................................................ 42 
 
Unblinding ..................................................................................................... 42 
 
Screening Period ......................................................................................... 44 
 
Baseline assessments (Visit 2, 1 to 28 days after screening): ............. 47 
 
Treatment procedures (visits 2 (i.e. baseline; 1 to 28 days after 
screening), visit 4 (4 to 21 days after visit 2) and 6 (4 to 21 days after visit 4)) 48 
 
Subsequent assessments .......................................................................... 49 
 
Table of study assessments ....................................................................... 52 
 
Methods ......................................................................................................... 52 
 
Non laboratory procedures ...................................................................... 52 


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Laboratory procedures ............................................................................ 55 
 
Definition of end of trial ............................................................................... 56 
 
Discontinuation/withdrawal of participants and ‘stopping rules’ ........... 57 
All efforts will be made to maintain participants in the study where possible and to 
continue assessments as intended. However, there are circumstances under which 
treatment may be discontinued and/or participants withdrawn from the trial. .............. 57 
 
Discontinuation from treatment ................................................................ 57 
 
Withdrawal from the trial .......................................................................... 57 
 
Stopping rules ......................................................................................... 58 
 
Name and description of all drugs used in the trial .................................................. 58 
 
Treatment of subjects .................................................................................. 58 
 
Concomitant medication ............................................................................. 59 
 
Investigational Medicinal Product ............................................................................... 59 
 
Name and description of investigational medicinal product(s) ............. 59 
 
Name and description of each NIMP ........................................................ 59 
 
Summary of findings from non-clinical studies ........................................ 59 
 
Summary of findings from clinical studies ................................................ 59 
 
Summary of known and potential risks and benefits .............................. 60 
 
Description and justification of route of administration and dosage .... 60 
 
Dosages, dosage modifications and method of administration ............ 60 
 
Preparation and labelling of Investigational Medicinal Product ............ 60 
 
Drug accountability ...................................................................................... 61 
9.10 Source of IMPs including placebo .................................................................... 61 
 
Dose modifications ...................................................................................... 62 
 
Assessment of compliance......................................................................... 62 
 
Post-trial IMP arrangements ...................................................................... 62 
 
Recording and reporting of adverse events and reactions ..................................... 63 
 
Definitions ..................................................................................................... 63 
 
Recording adverse events .......................................................................... 63 
 
Assessments of Adverse Events ..................................................................... 65 
10.3.1 Severity ........................................................................................................... 65 
10.3.2   Causality ....................................................................................................... 65 


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Expectedness ......................................................................................... 66 
 
Procedures for recording and reporting Serious Adverse Events ................... 66 
 
Notification of deaths ................................................................................... 67 
 
Reporting SUSARs ................................................................................. 67 
 
Development Safety Update Reports ...................................................... 67 
 
Annual progress reports .......................................................................... 67 
 
Pregnancy (If applicable) ......................................................................... 67 
 
Overdose ................................................................................................ 68 
 
Reporting Urgent Safety Measures ......................................................... 68 
 
The type and duration of the follow-up of subjects after adverse events.
 
68 
 
Notification of Serious Breaches to GCP and/or the protocol (SPON/S15)69 
 
Data management and quality assurance................................................................. 69 
 
Confidentiality ............................................................................................... 69 
 
Data collection tools and source document identification ..................... 69 
 
Data handling and analysis ........................................................................ 71 
 
Record keeping and archiving..................................................................................... 72 
 
Statistical Considerations............................................................................................. 73 
13.1 
Outcomes ...................................................................................................... 73 
13.1.1 
Primary outcomes ................................................................................... 73 
13.1.2 
Secondary outcomes .............................................................................. 73 
13.2 
Sample size and recruitment ..................................................................... 73 
13.2.1 
Sample size calculation ........................................................................... 73 
13.2.2 
Planned recruitment rate ......................................................................... 74 
13.3 
Statistical analysis plan ............................................................................... 74 
13.3.1 
Summary of baseline data and flow of patients ....................................... 74 
13.3.2 
Primary outcome analysis ....................................................................... 74 
13.3.3 
Secondary outcome analysis .................................................................. 75 
13.3.4 
Sensitivity and other planned analyses ................................................... 75 
13.4 
Randomisation methods ............................................................................. 75 
13.5 
Interim analysis ............................................................................................ 76 


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13.6 
Other statistical considerations .................................................................. 76 
14 
Name of Committees involved in trial ........................................................................ 76 
15 
Direct Access to Source Data/Documents ................................................................ 76 
16 
Ethics and regulatory requirements ........................................................................... 76 
17 
Monitoring requirement for the trial ............................................................................ 77 
18 
Finance ........................................................................................................................... 77 
19 
Insurance ........................................................................................................................ 77 
20 
Publication policy........................................................................................................... 78 
21 
Statement of compliance ............................................................................................. 78 
22 
References ..................................................................................................................... 78 
 
 
List of abbreviations 
 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AR 
Adverse Reaction 
AST 
Aspartate aminotransferase 
ACQ-NOW 
Alcohol Craving Questionnaire 
BDI 
Beck Depression Inventory 
BDNF 
Brain-derived neurotrophic factor 
BMI 
Body Mass Index 
BPRS 
Brief Psychiatric Rating Scale 
CA 
Competent Authority 
CBT 
Cognitive Behavioural Therapy 
CI 
Chief Investigator 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 


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CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal 
Product 
 
DMC 
Data Monitoring Committee 
DSM 
Diagnostic and Statistical Manual of Mental 
Disorders 
DSUR 
Development Safety Update Report 
EC 
European Commission 
ECRF 
Exeter Clinical Research Facility 
ECT 
Electro-convulsive therapy 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
GAfREC 
Governance Arrangements for NHS Research 
Ethics 
GCP 
Good Clinical Practice 
GGT 
Gamma-GT 
GMP 
Good Manufacturing Practice  
HAM-D 
Hamilton Depression Scale 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised   
LFT 
Liver Function Test 
MA 
Marketing Authorisation 
MDD 
Major Depressive Disorder 


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MHRA 
Medicines 
and 
Healthcare 
products 
Regulatory Agency 
MS 
Member State 
Main REC 
Main Research Ethics Committee 
NHS R&D 
National 
Health 
Service 
Research 
& 
Development   
NMDA 
N-methyl-d-aspartate 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
POMS 
Profile of Mood States 
PSI 
Psychotomimetic States Inventory 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person for release of trial drug 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SCID 
Structured Clinical Interview for Diagnostic 
and Statistical Manual of Mental Disorders 
SDV 
Source Document Verification 
SOP 
Standard Operating Procedure  
SPC 
Summary of Product Characteristics  
SSA 
Site Specific Assessment 
STAI 
State-Trait Anxiety Inventory 
SUSAR 
Suspected 
Unexpected 
Serious 
Adverse 
Reaction  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UCLH 
University College London Hospitals NHS 
Foundation Trust 
VAS 
Visual Analogue Scale 
WOCBP 
Women of Child-Bearing Potential 


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Trial personnel 
Chief Investigator (CI): 
Dr Brigitta Brandner 
Anaesthetics Department 
Podium 3, Maple Link corridor 
University College Hospital 
235 Euston Road 
London 
NW1 2BU 
e-mail: brigitta.brandner@nhs.net 
tel:  020 3447 3343 fax: 020 3447 9604 
 
Sponsor’s representative:  Samim Patel 
Joint Research Office, UCL,  
Gower Street,  
London, WC1E 6BT. 
e-mail:  samim.patel@ucl.ac.uk 
tel:  020 76799320 
fax: 020 3108 2312 
 
Statistician: Dr Fiona Warren 
Lecturer in Medical Statistics 
University of Exeter 
Smeall Building 
St Luke's Campus 
Exeter 
EX1 2LU 
e-mail:  f.warren@exeter.ac.uk 
tel:  +44 (0) 1392 722749 fax: +44 (0) 1392 722894 
 
Central laboratories: ABS Laboratories 
Mira Doig 
ABS Laboratories Ltd 
BioPark, 


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Broadwater Road, 
Welwyn Garden City, 
AL7 3AX 
Hertfordshire 
e-mail: info@abslabs.com 
Tel: 01707 358669 fax: 0207 916-1989 
 
SCRAM-X Providers: Alere Toxicology 
Charter House II 
Links Business Park 
St Mellons 
Cardiff 
CF3 0LT 
e-mail: james.rowe@alere.com  
tel: +44 (0)2920 540 542   fax: 44 (0)8452 991 410 
 
Study Centre:  NIHR/Wellcome UCLH Research Facility 
University College Hospital 
Clinical Research Facility 
Ground floor 
Elizabeth Garrett Anderson Wing 
235 Euston Road 
London NW1 2BU 
email: generalcrf@uclh.nhs.uk 
tel: 0203 447 6036  fax: 020 3447 6094 
 
Study Centre: NIHR Exeter Clinical Research Facility 
University of Exeter Medical School 
Royal Devon & Exeter Foundation NHS Trust 
Barrack Road 
Exeter 
Devon 
EX4 5DW 


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Email: crf@exeter.ac.uk 
Tel: 01392408182 
 
Lead Researcher (PI):  Dr Celia Morgan 
Centre for Clinical Psychopharmacology 
Department of Psychology 
Washington Singer Laboratories 
Perry Rd 
Exeter 
EX4 4QG 
email: celia.morgan@exeter.ac.uk 
tel: 01392 724 649 fax:01392 724 623 
 
 


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Summary 
 
Title: 
A 
phase 
II, 
randomised, 
double-blind, 
placebo-
controlled, multi-site, parallel group clinical trial to 
examine ketamine as a pharmacological treatment for 
alcohol 
dependence 
in 
an 
alcohol 
dependent 
population. 
Short title:
KARE: Ketamine for the reduction of Alcoholic RElapse 
Trial medication:
Ketamine Hydrochloride and Placebo (Saline)
Phase of trial:
Phase II
Objectives: 
Primary objectives: 
 
1) To obtain preliminary data on whether ketamine is 
effective in promoting and prolonging abstinence in 
alcohol dependent patients following detoxification. 
2) To assess safety and tolerability of ketamine in 
alcohol dependence 
 
Secondary objectives: 
1) To make an early assessment on likely compliance to 
a combined ketamine and relapse prevention based 
cognitive behavioural therapy (CBT) 
2) To obtain preliminary data as to whether ketamine 
alone is as effective as a combined ketamine and 
psychotherapy treatment.  
Type of trial: 
Phase IIa/b, double-blind, randomised, parallel group, 
multi-site trial in an alcohol dependent population
Trial 
design 
and 
methods: 
96 recently detoxified alcoholics will be randomised to 
receive either 3 sessions of ketamine (0.8 mg/kg IV over 
40 minutes) or placebo (50ml Saline 0.9% IV over 40 
minutes) plus either manualised psychological therapy 
or psychoeducation control. Patients will be assessed at 
3 and 6 months on a range of psychological and 
biological variables. The primary endpoint is relapse 
rate at 6 months. Secondary endpoints include 3 and 6 
month 
percentage 
days 
abstinence, 
tolerability 
(indicated by drop-out), adverse events, depressive 
symptoms, craving and quality of life. 
Application/exploitation: The findings would have broad 
application 
given 
the 
worldwide 
prevalence 
of 
alcoholism and associated medical, psychological and 
social problems.  
Trial duration per 
participant:
24 weeks 


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Estimated total trial 
duration:
30 months 
Planned trial sites:
Multi-site 
Total 
number 
of 
participants 
planned:
96 
Main 
inclusion/exclusion 
criteria: 
Main Inclusion Criteria:  
 18 to 65 years old;  
 Meet either a) DSM-5 criteria for moderate/severe 
alcohol use disorder or b) DSM-IV criteria for alcohol 
abuse/dependence within the last 12 months;  
 Currently abstinent from alcohol (breathlyser BAC 
level 
0.00) 
and 
negative 
urine 
drug 
screen 
(participants testing positive for THC  who do not 
have a history or current cannabis dependency may 
be 
included; 
participants 
testing 
positive 
for 
benzodiazepines and who do not have a history or 
current dependency for benzodiazepines may be 
included);  
 Capacity to give informed consent as defined by GCP 
guidelines;  
 Willing to wear SCRAM-X bracelet for active 
treatment;  
 Females of childbearing potential and males must be 
willing to use an effective method of contraception 
(hormonal or barrier method of birth control; True 
abstinence) from the time consent is signed until 6 
weeks after treatment discontinuation and inform the 
trial if pregnancy occurs. For the purpose of clarity, 
True abstinence is when this is in line with the 
preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence, 
spermicides 
only, 
withdrawal 
or 
lactational 
amenorrhoea method for the duration of a trial, are 
not acceptable methods of contraception;  
 Females of childbearing potential must have a 
negative pregnancy test within 7 days prior to being 
registered for trial treatment and on day of first 
treatment.  
 
Main Exclusion Criteria:  
 Currently taking any other relapse prevention 
medication or anti-depressants; 
 Current uncontrolled hypertension (systolic 140mm 
Hg or greater and diastolic 90mm Hg or greater); 
 Currently has BMI outside normal limits <16 or > 35  
 Any relevant mental or physical health issues as 
determined by medically qualified personnel, which 
may include:


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o Current 
or 
history 
of 
psychosis 
as 
identified by DSM-5 or DSM-IV SCID;  
o Current 
or 
historical 
diagnosis 
of 
schizophrenia in a first degree relative; 
o Current co-morbid psychiatric diagnosis 
excluding depression and anxiety;  
o Previous or current diagnosis of substance 
dependence /  severe substance misuse 
disorder as confirmed by the participant’s 
GP  or if the participant has sought 
professional help for their dependence;  
o Clinically 
relevant 
history 
of 
neuropsychological difficulties. One or 
more 
previous 
medically 
confirmed 
seizures, including seizures witnessed by 
an 
appropriate 
clinician, 
documented 
evidence from an EEG or a history 
consistent 
with 
a 
diagnosis 
of 
an 
epileptiform illness;  
o Current 
suicidal 
ideation, 
as 
judged 
clinically.  
 Any medication deemed, by the trial medical 
professionals, to pose risk combined with ketamine 
which may include daily prescribed use of;  
a. Barbiturates and/or narcotics 
b. Atracurium and tubocurarine 
c. Central nervous system (CNS) depressants 
(e.g. phenothiazines, sedating H1 – blockers 
or skeletal muscle relaxants) 
d. Thiopental  
e. Thyroid hormones  
f. Antihypertensive agents 
g. Theophylline and methylxanthines. 
 Liver function tests that assess chronic liver damage 
(namely bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST)) > 3 times normal 
levels 
 Where there are special warnings or precautions for 
use according to the SPC where the risk benefit ratio 
is not in favour of giving ketamine with assessment 
made by physical examination by medically qualified 
trial personnel, self-report or inspection of the 
medical notes. Current diagnosis of: 
a. Acute intermittent porphyria 
b. Dehydration or hypovolemia 
c. Hyperthyroidism  
d. Pulmonary or upper respitatory tract infection 
e. Severe Coronary artery disease, 
Cerebrovascular accident or cerebral trauma 
f. Known glaucoma or globe injuries


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g. Cirrhosis 
h. Epilepsy 
 i. Intracranial mass lesions, hydrocephalus, or 
presence of head injury (i.e. evidence of lasting 
impact of head injury that is affecting everyday 
functioning)  
 Not willing to use effective contraception or (females) 
take pregnancy test;  
 Allergic reaction to ketamine;  
 >10  previous inpatient detoxifications from alcohol;  
 Pregnant or breastfeeding 
 Allergies to excipients of IMP or placebo;  
 Use of another IMP that is likely to interfere with the 
study medication within 3 months of study enrolment. 
Statistical 
methodology 
and 
analysis:        
The primary outcomes are relapse in alcohol use and 
percentage of days abstinent at 6-month follow-up. 
Relapse in alcohol use will be analysed descriptively 
using proportions per arm and as relative risks with 95% 
confidence 
intervals 
for 
selected 
comparisons. 
Percentage of days abstinent will be analysed 
descriptively and as between-group mean differences 
with 95% confidence intervals for selected comparisons. 
The primary analysis will be on an intention-to-treat 
complete case basis. Secondary analysis will be 
conducted using a per protocol approach. Sensitivity 
analyses using multiple imputation methods will be 
conducted for relapse at 6-month follow-up only.  
Secondary outcomes will be analysed descriptively on 
an intention-to-treat complete case basis and reported 
as 
between-group 
mean 
differences 
with 
95% 
confidence intervals for ketamine versus non-ketamine 
participants.
 
 
Introduction 
 
Background 
Worldwide, alcohol abuse is a burgeoning problem. In the UK alone, 
nearly 9% of men and 4% of women today meet criteria for alcohol 
dependence – in all ~ 3.9 million British adults [1].  Alcohol misuse globally 
accounts for roughly 4% of all deaths and 5% of the burden of disease [2]. 
Here in the UK 22,000 people die annually because of alcohol misuse, 
which can produce severe and enduring physical and neurological 
problems.  Costs to the NHS from alcohol abuse are estimated at £2.7 
billion annually [2]. Abstinence is key to allow recovery of physical and 
mental health as well as quality of life, but treatment for alcohol 
dependence is associated with high relapse rates of around 50% at 3 


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months, 70% at 6 months [3, 40].  Despite the huge burden on the NHS 
and UK economy, treating alcohol dependence and prolonging abstinence 
remains an unmet need. 
 
The end users of our intervention are ultimately alcohol dependent 
patients. The proposed treatment would be a brief intervention to reduce 
relapse rates and concurrent depressive symptoms that are rife in alcohol 
dependent individuals. Benefits of no longer being dependent on alcohol 
for end-users are considerable and wide-ranging. Physical health would 
improve, and risks of alcohol-related diseases such as cirrhosis of the liver 
would decrease. Benefits would also be observed in terms of end users’ 
mental health (depression, anxiety) and improved cognitive function 
resulting in an overall increase in quality of life. Considering the high toll 
alcohol abuse has on the health system [9], benefits would accrue in a 
reduction in burden on the NHS and its workforce, in alcohol-related 
deaths and in other non-fatal acute harms. Economic benefits would not 
only be reflected in a reduction in burden to the NHS but in more frequent 
and regular engagement in work activities, and a reduction in crime. 
Importantly for end users, the brief nature of our pharmacological 
intervention will be less stigmatising than current treatments that require 
taking pharmacotherapies for prolonged periods of time. 
 
Preclinical data 
Ketamine is a lipid soluble molecule that readily crosses the blood-brain 
barrier 
following 
peripheral 
administration. 
Preclinical 
work 
has 
demonstrated that ketamine is stored in adipose tissue and then slowly 
released back into the plasma compartment [7]. The alpha phase of 
ketamine distribution lasts about 45 minutes, with a half-life of 10 to 15 
minutes. The first phase corresponds clinically to the anaesthetic effect of 
the drug. When administered intravenously for anaesthesia, a sensation of 
dissociation occurs within 15 seconds and anaesthesia occurs within 30 
seconds (in 3-4 minutes for intra-muscular (IM) route). The anaesthetic 
effects are terminated by a combination of redistribution and hepatic 
biotransformation to an active metabolite, norketamine [8]. Norketamine 
has itself been suggested to have some psychotomimetic effects [9]. The 
terminal half-life of ketamine is about 2-3 hours.   
 
In preclinical models, ketamine has been shown to be highly effective in 
depression [see 10 for a review]; these include forced swim [11; 1213; - 
see also 14 for a review), novelty suppressed feeding test [15; 16; 17] and 
the tail suspension test [12; 19]. Ketamine pre-treatment blocks alcohol 
seeking in alcohol preferring rats [14; 34], but this effect is reversed by co-
administration 
of 
rapamycin 
[13], 
which 
blocks 
increases 
in 
synaptogenesis. Similarly the antidepressant effects of ketamine are 
blocked by this same compound [21].  Thus the mechanism for reduction 
in alcohol seeking following ketamine may be the same mechanism of the 
anti-depressant effects of ketamine: an increase in synaptogenesis.    


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Clinical data 
A review of several studies administering ketamine to 450 healthy 
humans, found no serious adverse events. Out of the 450 infusions, 9 
participants reported adverse mental status events (high levels of 
hallucinations and dysphoria) during the infusion, all of which ended with 
discontinuation of the infusion [20].  3 of these became unresponsive to 
verbal stimuli and six reported mild distress at the dissociative effects of 
ketamine. 
 
Over 2000 patients with treatment-resistant depression have been 
involved  worldwide in clinical trials using ketamine as a treatment for 
depression [46]. These include several with repeated dosing [98;  Collins 
et al. 2010] including one repeated dosing study recently completed in the 
UK [21; 22]. 
 
The first study to draw attention to ketamine as an antidepressant was of 
17 treatment-resistant patients with Major Depressive Disorder [MDD; 23]. 
This placebo-controlled, randomized, crossover study found 71% of the 
participants to have a greater than 50% reduction in depressive symptoms 
within 24 hours of ketamine administration, while the same participants 
showed almost no change in symptoms following the placebo saline 
injection. Moreover, the response was sustained for the 1-week follow-up 
in approximately one-third of the participants. There have been several 
subsequent placebo-controlled crossover studies that showed very similar 
findings of rapid onset of robust antidepressant activity lasting for several 
days to weeks after a single subanaesthetic dose of ketamine in the 
treatment of major depressive episodes associated with both MDD and 
bipolar disorder [e.g. 94; 21]. 
 
Numerous open-label studies and case series provide additional evidence 
of ketamine’s antidepressant effect and further characterize its effects in 
unique patient populations. Rapid reductions in suicidal ideation in 
depressed patients who received ketamine have been reported [25]. Other 
studies have begun to examine the potential benefits of adding ketamine 
to the anesthetic regimen of patients undergoing ECT [26; 27]. Still other 
reports have begun to evaluate the potential use of ketamine in palliative 
care settings, where the drug’s pain-reducing effects may provide an 
additional benefit [28; 29]. 
 
Pilot work conducted in the 1980s, found unprecedented reductions in 
relapse rates in alcoholism following ketamine treatment. Three weekly 
doses (2.5mg/kg bolus I.M.) of ketamine were given alongside sessions of 
psychotherapy before and after the administration of the drug to 111 
recently detoxified alcohol dependent patients. Of a control group of 100 
similar recently detoxified alcohol dependent patients, 24% were abstinent 
after 1 year compared with 66% of those who had undergone ketamine 
therapy [5]. A 40% reduction in relapse rate is much greater than anything 
previously been observed with any other relapse prevention method in 
alcohol dependence. These preliminary findings have been supported by 


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case studies of the successful use of ketamine, alongside transpersonal 
therapy, in the treatment of alcoholism, where 15 patients had 70% 
abstinence rates at 1 year [30].  
 
Importantly, ketamine has a very favourable safety profile. One concern 
with this therapy may be that ketamine can also be abused but we have 
shown that higher subanaesthetic doses of ketamine, such as that 
proposed in this study, are not rewarding, [68] and recently detoxified 
alcoholics given ketamine did not go on to abuse the drug [51, 69] and 
alcohol craving did not increase following ketamine in this group [51]. A 
clinical trial is underway at Yale University in the US using ketamine for 
the treatment of depression in alcoholism [31] and the study team have 
reported the treatment to be well tolerated with no adverse events [32]. 
Further, as discussed above in section 2.2 there has been no evidence of 
subsequent drug abuse, or any persisting problems when ketamine was 
administered to a large sample of psychologically-prepared patients in a 
supportive research setting [38] and similar absences of subsequent drug 
abuse have been observed in smaller samples of depressed patients [71]. 
 
 
Rationale and risks/benefits 
 
The research question is whether ketamine can reduce relapse in alcohol 
dependence. 
 
Scientific Rationale 
 
Exsiting treatments in alcohol use disorder are of limited efficacy and are 
poorly adhered to. In the UK only acamprosate and disulfiram are licensed 
for relapse prevention with naltrexone used but not licensed for this 
purpose (unlike in the US). Various other antidepressants and 
anticonvulsants have been trialled (e.g. trazadone, gabapentin) but any 
effects disappear as soon as treatment is discontinued. While 
psychosocial interventions are recommended as first line treatments [84], 
for example couples’ therapy, CBT and motivational enhancement 
therapy; their effects are, at best, modest. 
 
These current pharmacological treatments for relapse prevention have 
limited efficacy and require daily dosing.  Naltrexone has  side effects, 
disulfiram is  associated with adverse events and toxicity. Other drugs that 
have shown some minor efficacy (e.g. gabapentin) cease to be effective 
as soon as active treatment is discontinued. If this study confirms the long-
lasting effect of ketamine on relapse, then it would mean it was 6 times 
more efficacious than any existing therapy [2]. Ketamine has a significantly 
better safety profile compared to disulfuram, and as our proposed solution 
requires only 3 sessions of ketamine-assisted therapy and one extra 
psychological therapy session, treatment adherance [42] – which has 
been a problem with all existing pharmacotherapies - would likely be good. 


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Further, all competing solutions require being maintained on medication 
for a minimum of 6 months but likely longer, whereas ketamine-assisted 
therapy requires only 3 weeks making the treatment more tolerable and 
less stigmatising. 
 
Ketamine has been extraordinarily successful in treating depression [4; 11; 
43], such that it has recently been hailed ‘..a wonder drug…’ in the journal 
Science by some researchers and clinicians [44]. Similarly, pilot work 
conducted in the 1980s, found unprecedented reductions in relapse rates 
in alcoholism following ketamine treatment [33].  
 
At the time of the pilot work in alcohol dependence in Russia, any potential 
biological mechanism was unclear. However the remarkable recent 
success of isolated doses of ketamine in the treatment of depression [4; 
43] suggests that a similar biological mechanism could be in operation in 
this observed reduction of relapse in alcoholism following ketamine. The 
proposed biological mechanism behind the anti-depressant effects of 
ketamine is increased synaptogenesis and recent empirical evidence  
suggests that blocking synaptogenesis also blocks ketamine-induced 
reductions in alcohol consumption [45]. We are proposing that ketamine 
may improve relapse in alcoholism via a three-way mechanism: 
stimuliating the growth of neurons and synapses; targeting depressive 
symptoms; and enhancing the uptake of psychological therapy. 
 
Stimulating neurogenesis and synaptogenesis 
The birth of new neurons and synapses in the human brain is now widely 
accepted as an ‘ordinary process with extraordinary implications’ [52]. For 
many years neurogenesis and synaptogenesis have been suggested to be 
fundamentally impaired in depression. Preclinical research [53] and 
human case studies [54] now suggest that ketamine exerts its anti-
depressant effects by stimulating the growth of new synapses and 
promoting synaptic transmission in the prefrontal cortex.  
 
Recent theoretical accounts have also proposed a role for impaired 
neurogenesis and synaptogenesis in addiction [52; 55]. These accounts 
are supported by vast numbers of preclinical studies that suggest that 
these processes are blocked following administration of addictive 
substances, in particular alcohol [e.g. 56-61]. Changes in potential indices 
of neurogenesis, such as serum BDNF, are observed in alcoholics [62], 
with levels increasing the longer their sobriety [39].  Reducing the numbers 
of newborn neurons and synapses has been suggested as a means of  
making the addicted brain less able to learn about non-drug rewards and 
unable to project into the future [52].  
 
Ketamine pre-treatment blocks alcohol seeking in alcohol preferring rats 
[46; 66], but this effect is reversed by co-administration of rapamycin [45], 
which blocks increases in synaptogenesis. Similarly the antidepressant 
effects of ketamine are blocked by this same compound [53].  Thus the 
mechanism for reduction in alcohol seeking following ketamine may be the 


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same mechanism of the anti-depressant effects of ketamine: an increase 
in synaptogenesis.    
 
Alleviating depressive symptoms 
Depression is almost ubiquitous in alcoholism and nearly all alcoholics 
have depressive symptoms upon entry into detoxification programmes 
[47].  Conventional anti-depressants have no impact on drinking, which is 
problematic as depressive symptoms are thought to precipitate relapse 
[48; 49]. Over 50% of alcoholics will have relapsed 3 months post-
treatment [3]. Given the fast-acting and impressive antidepressant profile 
of ketamine, its impact on early depressive symptoms during this 
vulnerable period post-detoxifcation may explain why our preliminary data 
suggest that ketamine is a far more effective treatment than any other 
relapse prevention medication in alcoholism. 
Ketamine also has been found to produce a more robust anti-depressant 
effect in treatment-refractory depressed individuals with a family history of 
alcoholism compared to those without [50]. It has been suggested that this 
is due to genetic variation in density of NMDA-receptors, hence it is 
possible that ketamine may work more effectively as an antidepressant in 
alcohol-dependent individuals. When administered to recently detoxified 
alcoholics, our collaborator (IP) has shown that ketamine can reduce 
dysphoria [51], supporting our hypothesis that it will be an effective 
treatment of low mood in this sample. 
 
Enhancing the uptake of psychological therapy 
Psychosocial therapies are currently the mainstays of treatment for alcohol 
dependence but are of limited effectiveness, which may partly be because 
they depend on the brain’s capacity for neuroplastic change [63]. 
Psychological therapies in alcoholism are also less effective in individuals 
with cognitive impairment [64]. Undergoing learning based psychological 
therapy during the period of neurogenesis and synaptogenesis, which 
commences around two hours after an acute dose of ketamine [53], may 
facilitate its uptake as the brain is primed to make new connections and 
learn new information. Increased synaptogenesis has been linked with 
improved memory [e.g. 65; 69]. Therefore ketamine may enhance the 
uptake of psychological therapy in the hours following an acute dose by 
making the brain more receptive to new learning.  
 
The 
notion 
that 
treatments 
that 
stimulate 
neurogenesis 
and 
synaptogenesis in this manner may work synergistically with psychological 
therapies is becoming more accepted [90] and may represent a future 
paradigm shift in the treatment of mental health problems. Historically, 
approaches to treating alcoholism that involve psychological therapy and 
provoke neurogenesis have enjoyed some success [see e.g. 91 for a 
review] but it is only recently that the biological mechanisms have been 
elucidated.  In order to examine whether enhancing the uptake of therapy 
is the mechanism by which ketamine is effective in alcoholism we have 
included a ketamine + 'no therapy' arm in the trial. These data will have 
considerable implications not only for alcohol dependence, but also 


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depression as this may suggest a similar psychotherapy plus ketamine 
approach may enhance the effectiveness of ketamine treatment. 
 
Additional advantages of ketamine: glutamatergic actions 
Ketamine also acts as an antagonist of the glutamatergic N-methyl-d-
aspartate receptor. Glutamatergic activation and glutamate receptor up-
regulation contribute to alcohol dependence and withdrawal [66]. Acute 
detoxification is associated with a hyperglutmatergic effect that NMDA-
receptor antagonists have been shown to normalise [66]. Excess 
glutamate is known to have toxic effects, and ketamine may protect 
against some of these adverse effects. 
 
Risks / Benefits 
 
Excellent safety and tolerability data suggest that the risks of ketamine 
treatment would be low. Ketamine is currently indicated as an anaesthetic 
agent for diagnostic and surgical procedures. The use of ketamine for this 
anaesthetic purpose administers much higher doses (1 mg/kg to 4.5 
mg/kg over 60 seconds) than our proposed dose of 0.8 mg/kg over 40 
minutes, and even at these higher doses ketamine has a very good safety 
profile [34]. Use of ketamine is indicated with caution in the chronic 
alcoholic and the acutely alcohol-intoxicated patient. This is because 
ketamine is metabolised in the liver and hepatic clearance is required for 
termination of clinical effects. A prolonged duration of action may occur in 
patients with cirrhosis or other types of liver impairment. For this reason 
exclusion criteria will be liver function tests (LFTs, specifically bilirubin, 
ALT, AST) 3 times> the upper limit of normal. These are the same criteria 
used in the clinical trial for ketamine for depression in alcoholism in the US 
[31] by our collaborator at Yale. Her current study, and previous work 
which has administered ketamine to the same population (recently 
detoxified alcoholics) has shown good tolerability and safety in this group 
at a similar dose (0.5mg/kg IV over 40 minutes) [35; 36]. Further, 
breathalyser readings  taken at infusion visits will be used to ensure that 
the visit is terminated where patients are currently intoxicated with alcohol.  
 
The SPC states that dose reductions should be considered in alcoholic 
patients: our study does intend to use less than the minimum clinical dose 
of 1mg/kg. The SPC also states that abnormal liver function tests 
associated with ketamine use have been reported, particularly with 
extended use (>3 days) or drug abuse. Ketamine will be used at a lower 
dose than anaesthetic levels and will only be given in 3 isolated low doses, 
spaced at weekly intervals. Ketamine has a very short half-life and so will 
be quickly eliminated from the system. Benefits of no longer being 
dependent on alcohol for end-users are considerable and wide-ranging. 
Physical health would improve, and risks of alcohol-related diseases such 
as cirrhosis of the liver would decrease. Benefits would also be observed 
in terms of end users’ mental health (depression, anxiety) and improved 
cognitive function, as well as quality of life. Benefits would be reflected 
economically, not only in a reduction in burden to the NHS but in more 
frequent and regular engagement in work activities, and a reduction in 


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crime. Alcohol is also associated with considerable acute harms. In 2012, 
15,401 deaths in England and 1.24 million hospital admissions are 
attributable to alcohol consumption [41], therefore benefits would also 
acrue in a reduction in burden on the NHS and its workforce, in alcohol-
related deaths  and in other non-fatal acute harms. Importantly for end 
users, the brief nature of our pharmacological intervention will be less 
stigmatising than current treatments that require taking pharmacotherapies 
for prolonged periods. Data therefore suggest that the potential 
benefits to this group of patients far outweigh the risks.  
 
 
 
Assessment and management of risk 
This trial is categorised as TYPE B suggesting that the risk is somewhat 
higher than the risk of standard medical care. The IMP is licenced in the 
EU but is being trialled in a new indication  
 
The table below summarises the risks, frequencies and mitigations of the 
IMP: 
Potential risk 
Risk 
Frequency
*  
Risk Management 
Elevation of 
blood 
pressure, 
respiratory 
and heart rate 
Common 
IMP will be administered at site. Vital signs 
will be monitored throughout the infusion of 
ketamine. Patients will not leave the site 
until they are judged ‘street ready’ by an 
anaesthetist, all signs of acute intoxication 
are absent and they will be advised to be 
collected by a responsible adult or 
transportation will be arranged for them.  At 
discharge patients will be given a 24 hour 
contact card for emergencies. 
Patients with uncontrolled hypertension, 
eclampsia or pre-eclampsia, severe 
coronary or myocardial disease, 
cerebrovascular accident or cerebral trauma 
will be excluded from the study (see section 
5.2). 
Patients taking thyroid hormones have an 
increased risk of developing hypertension 
and tachycardia when given with ketamine 
and therefore we will exclude these patients 
(see section 5.2).
Bradycardia, 
Arrhythmia, 
Uncommon 
IMP will be administered at site. Vital signs 
(heart rate, blood pressure, pulse oximetry) 


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Hypotension 
will be monitored throughout the infusion of 
ketamine. Patients will not leave the site 
until they are judged ‘street ready’ by an 
anaesthetist, all signs of acute intoxication 
are absent and they will be advised to be 
collected by a responsible adult or 
transportation will be arranged for them. At 
discharge patients will be given a 24 hour 
contact card for emergencies. 
Patients with uncontrolled hypertension, 
eclampsia or pre-eclampsia, severe 
coronary or myocardial disease, 
cerebrovascular accident or cerebral trauma 
will be excluded from the study (see section 
5.2). 
Concomitant use of antihypertensive agents 
increases risk of hypotension and therefore, 
patients on antihypertensive agents will be 
excluded from the study (see section 5.2). 
Anaphylactic 
reaction 
Rare  
Ketamine will be administered by an 
anaesthetic registrar or consultant in the 
Clinical Research Facility at sites with 
access to resuscitative equipment. Patients 
will not leave the site until they are judged 
‘street ready’ by an anaesthetist, all signs of 
acute intoxication are absent and they will 
be advised to be collected by a responsible 
adult or transportation will be arranged for 
them. At discharge patients will be given a 
24 hour contact card for emergencies. 
Patients with a known allergy to the IMP, 
placebo or any of its excipients will be 
excluded from the study (see section 5.2). 
Patients on trial treatment phase who have 
an allergic reaction to ketamine will be 
withdrawn from further IMP treatment.  
Elevated 
Intraocular 
pressure  
Not known  
Patients with glaucoma or globe injuries 
will be excluded from the study (see 
section 5.2). 
Diplopia 
Common 
Patients will agree not to drive or operate 
heavy machinery on the day of the 
infusions. They will not leave the site until 
they are judged ‘street ready’ by an 
anaesthetist, all signs of acute intoxication 
are absent and they will be advised to be 
collected by a responsible adult or 


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transportation will be arranged for them. At 
discharge patients will be given a 24 hour 
contact card for emergencies. 
Nystagmus, 
Hypertonia, 
Tonic clonic 
movements 
Common 
These effects are reported with anaesthetic 
doses but the dose we are using in this trial 
is much lower than anaesthetic doses and 
over a much longer period. Whilst in 
previous studies we have observed 
nystagmus, we have not observed tonic 
clonic movements. To mitigate this unlikely 
risk patients will agree not to drive or 
operate heavy machinery on the day of the 
infusions. Patients will not leave the site 
until they are judged ‘street ready’ by an 
anaesthetist, all signs of acute intoxication 
are absent and they will be advised to be 
collected by a responsible adult or 
transportation will be arranged for them. At 
discharge patients will be given a 24 hour 
contact card for emergencies. 
Prolonged 
acute effects, 
impaired 
hepatic 
clearance, 
drug-induced 
liver damage  
Not known 
Use of ketamine is indicated with caution in 
the chronic alcoholic and the acutely 
alcohol-intoxicated patient. This is because 
ketamine is metabolised in the liver and 
hepatic clearance is required for termination 
of clinical effects. A prolonged duration of 
action may occur in patients with cirrhosis or 
other types of liver impairment. 
Ketamine will be used at a lower dose than 
anaesthetic levels and will only be given in 3 
isolated low doses, spaced at weekly 
intervals. Ketamine has a very short half-life 
and so will be quickly eliminated from the 
system.  
Long term ketamine abuse can result in liver 
damage. However, we are giving just three, 
small doses. So liver damage is not an 
expected outcome. 
Patients with liver function tests (LFTs, 
specifically bilirubin, ALT, AST) 3 times > 
the upper limit of normal will be excluded 
from the study (see section 5.2). 
Emergence 
reactions: 
Hallucinations, 
abnormal 
dreams, 
Common 
Psychotomimetic symptoms or ‘emergence 
reactions’ are a key feature of ketamine 
administration. The psychological effects of 
anaesthetic doses vary between pleasant 
dream like states and vivid imagery to out of 


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nightmare, 
confusion, 
agitation, 
abnormal 
behaviour 
body experiences and hallucinations. A 
review examining these phenomena across 
450 volunteers given similar doses to those 
to be given in this study found only 6 
incidences of such mental states that were 
unpleasant enough to require the infusion to 
be stopped, all of which remitted completely 
in the hours following the cessation of the 
infusion [20]. Patients with schizophrenia 
given doses of ketamine similar to those 
administered in this study have been known 
to have longer lasting psychotomimetic 
states [38] and for that reason psychosis in 
the patient and schizophrenia in the patient 
or a first degree relative are an exclusion 
criteria for the study (see section 5.2). 
Emergence phenomena can be reduced in 
anaesthesia with the co-administration of a 
benzodiazepine; midazolam can be 
administered by the anaesthetist if the 
emergence phenomena are intolerable to 
the patient. Alternatively the infusion can be 
stopped and, due to short half-life of 
ketamine, these effects should remit very 
rapidly. 
Delirium, 
Flashback, 
dysphoria, 
insomnia, 
disorientation 
Rare 
This dose is lower than an anaesthetic dose, 
where risks are rare. A review examining 
these phenomena across 450 volunteers 
given similar doses to those to be given in 
this study found only 6 incidences of such 
mental states that were unpleasant enough 
to require the infusion to be stopped, all of 
which remitted completely in the hours 
following the cessation of the infusion [20]. 
Patients with schizophrenia given doses of 
ketamine similar to those administered in 
this study have been known to have longer 
lasting psychotomimetic states [38] and for 
that reason psychosis in the patient and 
schizophrenia in the patient or a first degree 
relative are an exclusion criteria for the 
study (see section 5.2). Emergence 
phenomena can be reduced in anaesthesia 
with the co-administration of a 
benzodiazepine; midazolam can be 
administered by the anaesthetist any 
symptoms are intolerable to the patient. 
Alternatively the infusion can be stopped 
and, due to short half-life of ketamine, these 


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effects should remit very rapidly.  
IMP will be administered at site. Patients will 
not leave the site until they are judged 
‘street ready’ by an anaesthetist, all signs of 
acute intoxication are absent and they will 
be advised to be collected by a responsible 
adult or transportation will be arranged for 
them. At discharge patients will be given a 
24 hour contact card for emergencies. 
Anxiety 
Uncommon 
If patients find any symptoms intolerable, a 
benzopdazepine can be co-administered 
which should reduce anxiety. Alternatively 
the infusion can be stopped and, due to 
short half-life of ketamine, these effects 
should remit very rapidly. 
Nausea, 
Vomiting 
Common 
Patients will fast for 6 hours before the 
infusion to reduce the risk of vomiting and 
pulmonary aspiration. In the case of 
vomiting, or if nausea is intolerable to the 
patient then the infusion will be stopped, 
whereupon these symptoms should remit 
very quickly.  
Ketamine 
abuse 
Not known 
Patients with a significant history of 
substance misuse other than alcohol will be 
excluded. No previous studies giving 
ketamine to this patient group found 
evidence that they subsequently went on to 
abuse the drug [4; 5].  
Respiratory 
depression, 
laryngospasm, 
obstructive 
airway 
disorder or 
apnoea
Rare 
These effects occur only with large doses 
and rapid infusions. Ketamine will be 
administered at a sub-anaesthetic dose and 
infused over 40 minutes, in the numerous 
previous studies using this dosing regimen 
this adverse effect has never been reported. 
Salivary 
hypersecretion 
Rare 
Participants will be warned of this potential 
side effect, which would not be prolonged 
and for the duration of the infusion only. 
Increased salivation in this context should 
not be associated with any further risks. We 
have not observed this adverse event with 
our previous sub-anaesthetic ketamine 
studies, therefore it may be confined to 
anaesthetic doses, but should there be any 
increased salivation this will be for the 
duration of the infusion only. 
Erythema, 
Common
Mild rash and redness of the skin have been 


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Rash 
morbilliform 
observed following ketamine, which remit 
upon cessation of administration of the drug, 
however these might concern participants if 
unexpected, therefore we will fully inform 
participants of this possibility in the 
information sheet.    
Cystitis, 
Haemorrhagic 
cystitis 
Rare 
Ketamine-induced ulcerative cystitis is now 
a clinical condition observed after prolonged 
daily or more than daily use of ketamine in 
abusers. Only one case has been reported 
in the medical literature following the 
repeated daily administration of ketamine for 
chronic pain. As patients in this study will 
only receive 3 doses of ketamine, spaced at 
a week apart, we do not anticipate cystitis to 
be a risk from ketamine administration in the 
current study, however this will be carefully 
monitored and we shall ask questions 
pertaining to cystitis in our recording of 
adverse events. 
Injection site 
pain, injection 
site rash 
Uncommon 
If participants experience this uncommon 
side effect, local anaesthetic may be given. 
They will be informed of the potential of a 
rash and this will be carefully monitored.  
Assessment of 
psychiatric 
conditions  
Inclusion of 
a 
participant 
with a 
comorbid 
psychiatric 
disorder 
The SPC for ketamine advises caution in 
patients with a history of psychosis therefore 
all participants will be assessed for 
psychosis using the SCID. For other 
comorbid psychiatric disorders the research 
team will ask the participant’s medical 
health professional to notify us. Hence 
anyone with a current psychiatric disorder 
apart from depression and anxiety will be 
excluded. 
Urine drug 
screen 
Allowing a 
cannabis 
dependent 
participant 
to take part 
in the trial.   
People with a previous or current cannabis 
dependence/severe use disorder diagnosis 
will be excluded from the trial, as will people 
with any other substance 
dependence/severe use disorder diagnosis 
(apart from alcohol). Therefore, the risk of 
including a cannabis dependent participant 
will be minimal. However, occasional 
cannabis use is comorbid with alcohol use. 
Cannabis use, like other substance use, will 
be monitored throughout the trial using a 
urine drug screen. Cannabis consumption 
leads to THC remaining in urine for 
approximately 28 days. Therefore, 


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occasional use of cannabis may result in a 
positive THC urine screen. However, 
occasional cannabis use is not grounds for 
exclusion. Therefore, people who are not 
dependent on cannabis (and do not have a 
history of it), but do have a positive THC 
urine drug screen, may be included. 
Urine drug 
screen 
Allowing a 
benzodiaze
pine 
dependent 
participant 
to take part 
in the trial. 
People with a diagnosis of previous or 
current benzodiazepine dependence/severe 
use disorder will be excluded from the trial, 
as will people with a diagnosis of any other 
substance dependence/severe use disorder 
(apart from alcohol). Therefore, the risk of 
including a benzodiazepine dependent 
participant is minimal. However, 
benzodiazepines are used in community 
and inpatient alcohol detox and for sleep 
problems. Benzodiazepine use, like other 
substance use, will be monitored throughout 
the trial using a urine drug screen. 
Benzodiazepine use has a relatively long 
detection window (up to 7 days for long-
acting). Therefore, benzodiazepine use in 
detox may result in a positive 
benzodiazepine urine screen. However use 
of benzodiazepines in detox is not grounds 
for exclusion. Therefore, people who are not 
dependent on benzodiazepines (and do not 
have a history of it), but do have a positive 
benzodiazepine urine drug screen, may be 
included.  
* From SPC of anaesthetic use of ketamine (Appendix E)  
 
RISK OF IMP 
Ketamine has a very wide margin of safety: several instances of 
unintentional anaesthetic administraion of overdoses up to 10 times that 
required have been followed by prolonged but complete recovery (see 
SPC).  
Use with caution is indicated in patients with acute intermittent porphyria, 
increased cerebrospinal fluid pressure (as assessed by questionnaire), 
hyperthyroidism, pulmonary and upper respiratory infection as well a 
pregnancy therefore to further mitigate risk these are all exclusion criteria 
for the study (see section 5.2). Several drugs may interact with ketamine 
(e.g. barbituates, narcotics, CNS depressants) therefore currently daily 
use of these medications will be an exclusion criteria (see section 5.2). 
Psychotomimetic symptoms or ‘emergence reactions’ are a key feature of 
ketamine administration. The psychological effects of anaesthetic doses 
vary between pleasant dream like states, vivid imagery to out of body 


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experiences and hallucinations. A review examining these phenomena 
across 450 volunteers given similar doses to those to be given in this 
study found only 6 incidences of such mental states that were unpleasant 
enough to require the infusion to be stopped, all of which remitted 
completely in the hours following the cessation of the infusion [20]. 
Patients with schizophrenia given doses of ketamine similar to those 
administered in this study have been known to have longer lasting 
psychotomimetic states [38] and for that reason psychosis in the patient 
and schizophrenia in the patient or a first degree relative are an exclusion 
criteria for the study (section 5.2). Emergence phenomena can be reduced 
in anaesthesia with the co-administration of a benzodiazepine; midazolam 
can be administered by the anaesthetist if the emergence phenomena are 
intolerable to the patient.  
 
WOCBP will be included in this clinical trial as per the ICH M3 (R2) which 
suggests WOCBP can be included in clinical trials without developmental 
toxicity in studies where there is intensive control for pregnancy. Any risks 
will be mitigated by the use of contraceptives and pregnancy testing. 
Ketamine is indicated for use in caesarean section. A recent Cochrane 
Review [37] compared ketamine for forceps delivery to other analgesics 
and found no difference in maternal or neonatal outcomes. However, 
preclinical data from rats given extremely high doses indicate some 
neurotoxicity in rats. The current trial will use methods of birth control 
which result in low failure rates of less than 1% per year (See Inclusion 
criteria section 5.1), if pregnancy is detected then participants will be 
immediately excluded.  
 
The summary of product characteristics advises caution in patients with 
neurotic traits or psychiatric illness (e.g. schizophrenia and acute 
psychosis). To mitigate risks against this risk and risk of potential suicide 
the protocol will exclude patients with these conditions as well as those 
who have suicidal ideation. At screening, the Columbia Suicide Severity 
Rating Scale will be used to assess suicide ideation. As patients at risk of 
suicide will be excluded, this tool will not need to be done at every 
assessment point as we have mitigated this risk from the outset. 
Additionally we will be monitoring depressive symptoms throughout the 
trial (Beck Depression Inventory and Hamilton Depression Rating Scale). 
The population group being studied are alcohol dependent individuals 
where alcohol use will be the primary disorder and not depression.  The 
IMP (Ketamine) is an anti-depressant drug and has indeed been shown to 
have efficacy at reducing suicidal ideation in individuals with treatment 
resistant depression thus we feel the risk of increased suicidal ideation 
from ketamine is minimal.   
 
 
All other risks related to trial design and methods 
 
i) Risks from study procedures 
 
The table below summarises the risks and mitigations of all tests above 
standard care that are being performed: 


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Intervention  
Potential risk 
Risk Management 
Cannulation and 
Venepuncture 
Cannulation is required 
for administration of 
IMP and placebo. 
Plasma samples will be 
taken 13 times during 
the course of this study. 
Both are accompanied 
with a risk of 
discomfort, bruising, 
excessive bleeding, 
fainting or feeling 
lightheaded, hematoma 
& infection  
Cannulation will be 
performed by an experienced 
anaesthetist and staff trained 
in venepuncture. 
Venepuncture risks will be 
managed using standard 
clinical care precautions 
which include wearing 
protective clothing, hand and 
surface hygiene. Risks to 
participants from 
venepuncture will be 
managed using standard 
clinical care. Non clinical staff 
performing venepuncture will 
receive appropriate training. 
Furthermore, in an effort to 
mitigate these risks, the 
participant information sheet 
(PIS) will make reference to 
these risks and inform people 
who have previously suffered 
complications during 
venepuncture or who have a 
fear of needles that they 
should not take part. Every 
effort will be made to make 
participants feel comfortable 
before, during and after 
cannulation and 
venepuncture by 
encouraging participants to 
relax and talking through any 
concerns they have about the 
procedure. 
Trust incident reporting will 
apply and be followed in the 
event of patient/staff needle 
stick injury. 
SCRAM-X bracelet 
Participants will have 
their alcohol use over 
active treatment 
monitored via the 
SCRAM-X bracelet 
worn on the ankle.  The 
wearer may not soak in 
the bath or swim. 
Inclusion criteria require 
patients to be willing to wear 
the bracelet for active 
treatment. 
The researchers who fit the 
bracelet will be extensively 
trained in fitting the bracelet 


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Wearing the bracelet 
carries with it a risk of 
discomfort. It can cause 
bruising, pain and scars 
from it rubbing against 
the skin. 
by colleagues at the health 
monitoring company Alere. 
Patients will be fully 
informed of the potential 
discomfort and the 
implications of wearing the 
bracelet in the participant 
information sheet. . 
Participants will be trained in 
how to clean under the 
bracelet to ensure that the 
risk of any skin problems is 
mitigated.  
Psychological therapy 
Psychological therapy 
may cause transient 
distress as the 
participant discusses 
sensitive and upsetting 
material 
Participants will be informed 
that they do not have to 
discuss material they are not 
comfortable discussing. 
Trained psychologists with 
experience of psychological 
therapies will administer the 
therapy and be supervised 
by a consultant clinical 
psychologist with over 20 
years experience in the field 
of treatment of alcohol use 
disorders.  
 
 
ii) Data risks 
Potential data risks include breach of participant confidentiality through 
inappropriate collection or storing of data. In order to minimise these risks, 
all researchers are GCP trained. Confidentiality will be ensured using 
standard procedures (e.g. password protected computers and data 
storage, all electronic data coded numerically so that individual 
participants cannot be identified; consent forms will be kept in secure 
locked cupboards in locked rooms). Any publications will similarly use 
anonymised data. The trial is occurring at two sites which facilitates data 
security. We appreciate that data about illicit drug use is sensitive and our 
security measures are appropriate to this. 
 
The investigator will ensure quality of the study data with respect to 
inclusion/exclusion criteria, protocol adherence, data collection and 
storage, and all physical data collected as part of this trial will be entered 
into a Red Pill database designed by sealedenvelope.com with quality 
control checks. 
 
The trial will be monitored by an appointed external monitor according to a 
monitoring plan developed by the sponsor and risk assessment of the trial. 
These risks will be further minimized by the use of a short trial duration 


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and finite follow up. Agreements are in place with the laboratories (ABS 
Laboratories, SCRAM-X and Alere) who will handle data from the study 
externally to ensure they agree to comply with confidentiality and relevant 
data protection acts.  
 
Anonymised data collected from the SCRAM-X will be transferred to the 
UK study centre (Alere) and transferred to the US via a secure firewalled 
server for collation and then returned to Alere where it will be transferred 
securely to the study team. The patient information sheet will explain this 
to the patient and specific consent for anonymised data to go to the US 
will be sought.  
 
Data collection using the SCRAM-X and of biological samples will be done 
in accordance with relevant UK confidentiality and data protection acts. 
Data collected with the bracelet will be entered anonymously into the 
Microsoft Access database. The patient information sheet will explain the 
measures taken to protect the patients’ identity and collected data. 
 
Biological samples will be labelled using anonymous patient IDs and will 
be sent by secure courier within the UK to the head analyst at our central 
laboratory (ABS Laboratories) who have reliably analysed biological 
samples for many of our previous research projects and is both regulated 
and accredited. 
 
Consent: Standard procedures will be used whereby participants have a 
minimum of 24 hours after reading the patient information sheet before 
deciding whether to take part and giving consent. They will be encouraged 
to discuss their participation with significant others. All researchers 
appointed with this project have previous experience taking consent from 
patients.  
 
Treatment  
The participant information sheet will state that the trial design does not 
allow for switching of participants in the placebo arm to the active arm at 
the end of the trial. This is because neuropsychological measures are 
subject to repeated practice effects. However if the active treatment is 
successful, participants would be informed if a large scale clinical trial is 
subsequently initiated. 
 
Patient Group 
Although we have excluded patients with suicidal ideation or any other 
current psychiatric diagnosis apart from depression or anxiety, as this is 
an alcohol dependent population it is possible that they may experience 
worsening of their mental state during the study duration. If we observe or 
if patients report any changes in mental state at any of the study visits 
which we would deem as putting themselves or others at risk then we will 
refer them back to their medical care provider (e.g. Consultant Addiction 
Psychiatrist if referred from substance misuse services or GP if self-
referral). 


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Objectives 
Primary objectives: 
 
1) To obtain preliminary data on whether ketamine is effective in promoting 
and prolonging abstinence in alcohol dependent patients following 
detoxification. 
2) To assess safety and tolerability of ketamine in alcohol dependence 
 
Secondary objectives: 
1) To make an early assessment on likely compliance to a combined 
ketamine and relapse prevention based cognitive behavioural therapy 
(CBT) 
2) To obtain preliminary data as to whether ketamine alone is as effective 
as a combined ketamine and psychotherapy treatment.  
 
Trial design 
 
Overall design 
This non-commerical parallel group, placebo-controlled double blind design 
aims to make a preliminary assessment of the effectiveness of ketamine in 
promoting and prolonging abstinence in alcohol dependent patients (Fig. 1). 
Why this design was chosen: A parallel group design is chosen as a 
crossover would not be feasible with the long time-scales of the study, and 
given marked carry-over effects that occur in substance-use reduction 
studies. Three weekly doses of ketamine were chosen as this protocol 
showed effectiveness in the preliminary studies [33]. This approach has 
been chosen, rather than a full-scale trial as it is important to confirm the 
preliminary findings in alcohol dependence. We have chosen to assess 
outcomes at 3 months  and 6 months as from examining other 
pharmacological and non-pharmacological trials, the largest change in 
drinking behaviour occurs in the first 3 months and then tails off [40]. 
However we will follow up again at 6 months to index maintenance of the 
treatment effect (balancing against the issues of retention of patients in the 
trial). 
 
For the purpose of this study, Relapse: 5 drinks (drink=13g) in men 
(8.1units) and 4 drinks (6.5 units) in women on any single occasion and 
Lapse is defined as ‘any other episode of alcohol consumption’. 
 
Blinding to the IMP: The trial design will be double blinded. This has been 
chosen so as to reduce any bias from the power of suggestion of which 
treatment the patient is received by both the researchers and the patient. 
The pharmacy or delegated unblinded personnel at both sites will prepare 


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the syringe for infusion in a blinded fashion so that the administering 
anaesthetist, psychological researcher and patient are all blind to treatment 
allocation.   
 
 
 


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Figure 1: Schematic of overall trial design from recruitment to end of follow up 
 
 
 
 


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Selection of Subjects 
 
Inclusion criteria 
1. 18 – 65 years old 
2. Meet either a) DSM-5 criteria for moderate/severe alcohol use disorder 
or b) DSM-IV criteria for alcohol abuse/dependence (see Appendix A) 
within the last 12 months 
3. Currently abstinent from alcohol (breathlyser BAC level 0.00) and 
negative urine drug screen (participants testing positive for THC who 
do not have a history or current cannabis dependency may be 
included; participants testing positive for benzodiazepines who  do not 
have 
a 
previous 
or 
current 
diagnosis 
of 
benzodiazepine 
dependence/severe use disorder may be included) 
4. Capacity to give informed consent as defined by GCP guidelines 
5. Willing to wear SCRAM-X bracelet for active treatment  
6. Females of childbearing potential and males must be willing to use an 
effective method of contraception (hormonal or barrier method of birth 
control; True abstinence) from the time consent is signed until 6 weeks 
after treatment discontinuation and inform the trial if pregnancy occurs. 
For the purpose of clarity, True abstinence is when this is in line with 
the preferred and usual lifestyle of the subject. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence, withdrawal, spermicides only or lactational 
amenorrhoea method for the duration of a trial, are not acceptable 
methods of contraception. 
7. Females of childbearing potential must have a negative pregnancy test 
within 7 days prior to being registered for trial treatment and on day of 
first treatment.  
 
Exclusion criteria 
1. Currently taking any other relapse prevention medication or anti-
depressants  
2. Current uncontrolled hypertension, systolic 140mm Hg or greater 
and diastolic 90mm Hg or greater 
3.  Currently has BMI outside normal limits <16 or > 35   
4. Any relevant mental or physical health issues as determined by 
medically qualified personnel, which may include: 
a. Current or history of psychosis as identified by DSM-5 or DSM-
IV SCID  
b. Current or historical diagnosis of schizophrenia in a first degree 
relative 


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c. Co-morbid current psychiatric diagnosis excluding depression 
and anxiety. 
d. Previous or current diagnosis of a susbtance dependence /  
severe substance misuse disorder as confirmed by the 
participant’s GP or if the participant has sought professional 
help for their dependence 
e. Clinically relevant history of neuropsychological difficulties 
f. One or more previous medically confirmed seizures including 
seizures witnessed by an appropriate clinician, documented 
evidence from an EEG or a history consistent with a diagnosis 
of an epileptiform illness 
g. Current suicidal ideation, as judged clinically  
 
5.  Any medication deemed, by the trial medical professionals, to pose 
risk combined with ketamine which may include daily prescribed 
use of: 
a. Barbiturates and/or narcotics 
b. Atracurium and tubocurarine 
c. Central 
nervous 
system 
(CNS) 
depressants 
(e.g. 
phenothiazines, sedating H1 – blockers or skeletal muscle 
relaxants) 
d.  Thiopental  
e. Thyroid hormones  
f. Antihypertensive agents 
g. Theophylline and methylxanthine  
 
6. Liver function tests that assess chronic liver damage (namely 
bilirubin, ALT, AST) > 3 times normal levels  
7. Where there are “Special warnings and precautions for use” 
according to the SPC and where risk vs benefit ratio is not in favour 
of giving ketamine, with assessment made by physical examination 
by medically qualified trial personnel, self-report or inspection of the 
medical notes. Current diagnosis of: 
a. Acute intermittent porphyria 
b. Dehydration or hypovolemia 
c.  Hyperthyroidism 
d. Pulmonary or upper respitatory tract infection 
e. Severe Coronary artery diesase, Cerebrovascular accident or 
cerebral trauma 
f.  Known glaucoma or globe injuries 


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g. Cirrhosis 
h. Epilepsy 
i. Intracranial mass lesions, hydrocephalus, or presence of head 
injury (i.e. evidence of lasting impact of head injury that is 
affecting everyday functioning) 
8. Not willing to use effective contraception or (females) take 
pregnancy test 
9.  Allergic reaction to ketamine  
10.  >10 previous inpatient detoxifications from alcohol 
11.  Pregnant or Breastfeeding  
12.  Allergies to excipients of IMP and placebo  
13. Use of another experimental investigational medicinal product that 
is likely to interfere with the study medication within 3 months of 
study enrolment. 
 
Recruitment 
The patients will be primarily recruited through Participant Identification 
Centres. These centres will be the substance misuse and addiction 
psychiatry services in Central, North West, South London as well as 
Devon, Dorset, Wiltshire, Somerset and Bristol who will refer potential 
participants to the research team. Avon and Wiltshire PIC will also 
distribute their “Everyone Included” letter, a research opportunity letter, to 
potentially eligible participants. The principal and co -investigators will 
work to raise awareness and educate all addiction service providers about 
the study. Based on previous experience, we expect that recruitment of 
suitable patients will primarily occur by being identified by their Doctor, 
nurse or other professional in the clinic or service they are attending. 
Patients will also be recruited from primary care (GP practices) with the 
aid of Clinical Commissioning Groups (CCGs) in the South West and 
London. PICs will be provided with a recruitment flyer that can be 
distributed amongst staff that are advertising the trial to potential 
participants to help them remember the key aspects of the trial, e.g. basic 
inclusion/exclusion criteria, and facilitate discussion. If interested, the 
patient/user will be given a REC approved invitation to participate letter, 
giving a brief description of the study and the contact details of the study 
team. Patients may contact the study team themselves, or complete the 
return slip and agree that their name and contact number can be given to 
the research fellows. The research team will then ensure the patient 
receives the Patient Information Sheet, via post, email or via the study 
team and follow up the patient with a telephone call to further discuss the 
study and conduct a pre-screening assessment (see section 7.4). 
 
The research fellow / assistant psychologist will then contact the individual 
interested in participating via phone and discuss the trial and answer any 
queries they may have. If they would like to participate, the researcher will 


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then go through the prescreening questionnaire to establish whether the 
patient appears eligible to attend for a full screening appointment. If the 
patient appears eligible, the researcher will arrange to see them at the 
clinical research facility. If a potentially eligible patient is identified prior to 
detoxification from alcohol, an appointment will be made for after their 
detoxification. At the initial visit with the researcher and a medical doctor, 
the trial will be explained, written informed consent obtained,  their 
eligibility assessed and baseline assessments completed. The site will 
take a full medical history at screening but will write to the GP to inform 
them of participation in the trial and the GP will be requested to inform us if 
they have any concerns about the patient participating in the trial. Once 
eligibility is confirmed, a date will be made for them to attend the study 
centre for their first treatment visit. 
 
We will also set up a study website to accompany the study, where 
patients can register their interest and we will publicise the trial through 
forums and social networking, relevant charities such as Foundation 66, 
Alcohol Concern, newspaper, radio and TV, in advice centres, via word of 
mouth and face to face contact. All trial publicity advertisement as 
described here will be submitted and approved by the Research Ethics 
Committee. 
 
Study procedures and schedule of assessments 
 
Informed consent procedure 
It is the responsibility of the Investigator, or a person delegated by the 
Investigator to obtain written informed consent from each subject prior to 
participation in the trial, following provision of the trial participant’s 
information sheet (PIS) and an adequate explanation of the aims, 
methods, anticipated benefits and potential hazards of the study. The 
person taking consent will be GCP and protocol trained, suitably qualified 
and experienced, and will have been delegated this duty by the CI/PI on 
the delegation log. 
 
At least 24 hours will be given for consideration by the patient before 
taking part. The PI or delegate will record when the patient information 
sheet (PIS) has been given to the patient.  The Investigator or designee 
will explain the patients are under no obligation to enter the trial and that 
they can withdraw at any time during the trial, without having to give a 
reason. No clinical trial procedures will be conducted prior to taking 
consent from the participant. Consent will not denote enrolment into trial. A 
second signed Informed Consent form will be given to the participant.  The 
other original signed form will be retained at the study site in the site file 
and a copy placed in the medical notes. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form will be 
reviewed and updated if necessary and subjects will be re-consented as 
appropriate. Re-consenting can be delegated to trial psychologists who 
have completed GCP training, protocol training and informed consent 


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training. All trial psychologists including research assistants and 
postdoctoral research associates can be delegated this task. 
 
Randomisation procedures 
A blocked design for randomisation will be used to allocate patients using 
a 1:1:1:1 ratio for the 4 respective groups. Randomisation will be 
performed by a specialist company (www.sealedenevelope.com) who will 
hold the randomisation list and provide 24/7 internet access for unblinding 
services. Early drop-outs (during screening and the baseline week up until 
randomisation) will be replaced. Once patients have been randomised at 
week 0 they will not be replaced regardless of compliance or dropout 
status and will be analysed as part of the intention to treat analysis. After 
randomisation, the site research team will be given a unique trial 
randomisation code via email from sealedenvelope.com. This code 
corresponds to an envelope at the site which contains the treatment 
allocation. These envelopes will be provided by the trial statistician at the 
start of the trial and are kept in a secure location by allocated partially 
unblinded staff. The trial statistician will be provided the treatment 
allocation codes prior to the start of the trial to prepare the envelopes. 
Separate envelopes will be provided for the delegated staff preparing the 
IMP (containing the IMP treatment allocation) and the psychology staff 
(containing the psychological treatment allocation). To protect the blind, 
pharmacy or delegated unblinded staff preparing the IMP at site will be 
notified separately via email of the randomisation code. An additional e-
mail is sent to the psychology team at site who can refer to the correct 
envelope 
to 
determine 
the 
psychological 
treatment 
allocation. 
Randomisation details of patients will be entered on a trial Subject Log 
and will follow the instructions set out in a Standard Operating Procedure 
(SOP) on randomisation. Data review will take place when half the target 
samples have been randomised. Upon randomisation, patients will be 
given a study specific patient card which will have study title, IMP details, 
patient ID and contact details of the out of hours contact in cases of 
emergency.  
 
Unblinding 
Emergency Unblinding  
The study code should only be broken for valid medical or safety reasons 
e.g. in the case of a severe adverse event where it is necessary for the 
investigator or treating health care professional to know which treatment 
the patient is receiving before the participant can be treated. Subject 
always to clinical need, where possible, members of the research team 
should remain blinded. 
 
The code breaks for the trial are held at www.sealedenevelope.com  
 


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Authorised members of the research team will have administrative rights 
to the unblinding system and a nominated individual will be available 24 
hours a day. 
 
In the event a code is required to be unblinded a formal request for 
unblinding will be made by the Investigator/treating health care 
professional to the authorised individual. 
 
If the person requiring the unblinding is a member of the Investigating 
team then a formal request to the authorised individual will be made who 
will then log in to the sealed envelope web-based system to obtain the 
unblinded information.  
 
If the person requiring the unblinding is not the CI then that health care 
professional will notify the Investigating team (via the 24 hour telephone 
number on the patient contact card) that an unblinding is required for a 
trial subject and an assessment to unblind should be made in consultation 
with the clinical and research teams. Unblinding will take place if in the 
opinion of a treating physician a patient’s health is compromised or an 
SAE has occurred that requires unblinding.  The treating physician has the 
ultimate decision and right to unblind the patient. 
 
Authorised individuals will break the blind by logging into the 
sealedenvelope.com, a web-based system for the trial and entering the 
unique randomisation number (the identifier used for the trial medication). 
The system will immediately notify the authorised individual of the 
unblinded treatment allocation. 
 
On receipt of the treatment allocation details the CI or treating health care 
professional will deal with the participant’s medical emergency as 
appropriate.  
 
The CI/PI will document the breaking of the code and the reasons for 
doing so on the CRF/data collection tool, in the site file and medical notes. 
It will also be documented at the end of the study in any final study report 
and/or statistical report. 
 
The CI/Investigating team will notify the JRO (acting on behalf of the 
Sponsor) in writing as soon as possible following the code break detailing 
the necessity of the code break.  
 
Trial Committees, where required within their charters will also be notified 
in writing. 
 
Subject always to clinical need, and where possible, other members of the 
research team will remain blinded. 
 
The CI (or appointed clinical cover team, consisting of a group of 
anaesthetists and psychiatrists) will be contactable via telephone / text / 


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email for out of hours procedures and unblinding. Please refer to 
‘Unblinding SOP’ for further details.   
 
Unblinding for the submission of SUSAR reports:  
The following procedure will be used to unblind for the submission of a 
SUSAR report to the regulatory agencies. 
 An authorised member of the JRO sponsor’s office will unblind in the 
event of a SUSAR report and will therefore, hold administration rights 
to the unblinding system.  
 The Sponsor will follow the SOP on unblinding. 
 The Sponsor will provide the unblinded information on the e-SUSAR 
website form.  
 Unblinded information in the SUSAR reports will not be forwarded to 
the trial team and kept in the JRO sponsor file. 
 SUSAR reports will be disseminated to Investigators at site, but the 
report will remain blinded. 
 
Screening Period 
Identification and Pre-screening (within 12 weeks of Screening visit): 
Pre-screening assessment will be carried out by delegated members of 
the research team. Initial approaches to participants will be made only by 
the members of the appropriate clinical teams and referred to the research 
team (see section 5). A telephone assessment by the research team will 
be made to conduct the following: 
 Discuss the trial. 
 Further confirm initial eligibility using the inclusion and exclusion 
criteria in section 5, and whether the patient will be called for a full 
screening visit. 
 Complete REC approved pre-screening questionnaire on medical 
history and dependency history to further assess initial eligibility.   
 Book screening visit to those who pass the initial eligibility and still 
express interest in participating. 
 
Screening Visit (Visit 1 Day 28 to 1 days before visit 2 (baseline) 
visit):  
Formal screening will take place at this screening visit as set out in 
Appendix B and listed below. The methods of the assessments are 
explained in section 7.9. Consent will be taken from the patient prior to the 
assessments at this visit (see section 7.1).  
 


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Following screening and eligibility determination, those still meeting criteria 
for inclusion in the study can be fitted with the SCRAM-X bracelet anytime 
between the screening visit and visit 2. A date for visit 2 will be arranged, 
within 28 days of the screening date.  
 
The visit schedule is set out below and as a chart in Appendix B: 
I. 
Trial Discussion 
II. 
Informed Consent 
III. 
Medical history   
IV. 
Physical Examination (repeat screens of height and weight may be 
conducted if initial results do not fall within boundaries described in 
5.2 but patient meets other criteria for eligibility) 
V. 
SCID 
VI. 
Vital Signs (repeat screens of blood pressure may be conducted if 
initial results do not fall within boundaries described in 5.2 but 
patient meets other criteria for eligibility) 
VII. 
Bloods to assess eligibility (U&Es, LFTs, FBC; repeat screens may 
be conducted every 7days if initial results do not fall within 
boundaries described in 5.2 but patient meets other criteria for 
eligibility, see Appendix B and section 7.9.2 for details of the tests 
that will be used).  
VIII. 
Eligibility Determination 
IX. 
Urine Drug Screen (repeat screens may be conducted if initial 
results do not fall within boundaries described in 5.2 but patient 
meets other criteria for eligibility, see Appendix B and section 7.9.2 
for details of the tests that will be used) 
X. 
Pregnancy test in WOCBP (urine test) 
XI. 
Breathalyser (repeat breathalyser screens may be conducted if 
initial result does not fall within boundaries described in 5.1 but 
patient wishes to continue with detoxification and return once they 
are abstinent) 
XII. 
Routine SCRAM-X fitting  (unless study team deem this not 
possible) 
XIII. 
Concomitant medication review 
XIV. 
Alcohol and Drug Use History 
XV. 
BDI 
XVI. 
HAM-D 
XVII. 
Columbia Suicide Severity Rating Scale 
XVIII. 
Reasons for drinking questionnaire 
XIX. 
STAI 
XX. 
ACQ-NOW 


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XXI. 
BPRS 
XXII. 
PSI 
XXIII. 
Alcohol Timeline Follow Back 
 
If more than 28 days pass between the screening visit and visit 2 a 
refresher screening visit can be run to update the data collected at the 
initial screening visit to ensure eligibility is still reliable before attending 
visit 2. Such a refresher session would involve re-running assessments for 
measures which could have changed over the course of time between the 
two visits. The visit schedule is set out below and in Appendix B. 
 
I. 
Refresher Trial Discussion 
II. 
Updated Medical history   
III. 
Physical Examination 
IV. 
SCID 
V. 
Vital Signs 
VI. 
Bloods to assess eligibility (U&Es, LFTs, FBC; repeat screens may 
be conducted every 7days if initial results do not fall within 
boundaries described in 5.2 but patient meets other criteria for 
eligibility, see Appendix B and section 7.9.2 for details of the tests 
that will be used.)  
VII. 
Eligibility Determination 
VIII. 
Urine Drug Screen (see Appendix B and section 7.9.2 for details of 
the tests that will be used) 
IX. 
Pregnancy test in WOCBP (urine test) 
X. 
Breathalyser 
XI. 
Concomitant medication review 
XII. 
Updating Alcohol and Drug Use History 
XIII. 
BDI 
XIV. 
HAM-D 
XV. 
Columbia Suicide Severity Rating Scale 
XVI. 
BPRS 
XVII. 
PSI 
XVIII. 
Alcohol Timeline Follow Back 
XIX. 
SCRAM-X checks (if already attached) / alternative SCRAM-X 
fitting (unless study team deem this not possible) 
 


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If participants are deemed ineligible at any point prior to randomisation, 
solely based on one of the following variable physical measures then 
participants can be invited back to the research facility to repeat one or 
more such tests to determine whether these are genuinely outside of 
protocol eligibility boundaries: 
I. Breathalyser (If the initial breathalyser reading is >0, patients who 
wish to continue with detoxification and return once they are 
abstinent will be re-consented appropriately), 
II. Inflated 
blood 
pressure 
with 
no 
evidence 
of 
uncontrolled 
hypertension, e.g. due to situational anxiety or recent alcohol 
withdrawal,  
III. Elevated LFTs,  
IV. BMI outside of trial limits,  
V. Positive urine drug screen due to recreational drug use, when there is 
no evidence of a current substance dependence.  
 
 
Baseline assessments (Visit 2, 1 to 28 days after screening): 
The methods of the assessments are described in detail in section 7.9.  
I. 
Vital Signs (see Appendix B and section 7.9.2 for details of the tests 
that will be used). Vital signs will be continuously monitored 
throughout the infusion until the participant has recovered. This 
monitoring will be recorded on a standard observation chart, stored 
as source data. The eCRF will record 3 sets of readings, one prior 
to the infusion, another after the infusion terminates, and then 
finally after the participants recovery.   
II. 
Bloods, blood samples for BDNF and ketamine will be obtained pre-
IMP/placebo administration and post IMP administration (see 
Appendix B and section 7.9.2 for details of the tests that will be 
used.)  
III. 
Full eligibility determination 
IV. 
Urine Drug Screen (see Appendix B and section 7.9.2 for details of 
the tests that will be used.) 
V. 
Pregnancy test in WOCBP (urine test) 
VI. 
Breathalyser 
VII. 
Randomisation 
VIII. 
IMP/placebo Administration (see section 7.6) 
IX. 
SCRAM-X checks (if already fitted) / alternative SCRAM-X fitting 
(where routine fitting at screening not completed) 
X. 
Relapse Prevention Based Cognitive Behavioural Therapy 
XI. 
Adverse Events Review 


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XII. 
Concomitant medication review 
XIII. 
BDI  
XIV. 
HAM-D 
XV. 
POMS 
XVI. 
STAI 
XVII. 
ACQ-NOW 
XVIII. 
BPRS 
XIX. 
PSI 
XX. 
Alcohol Timeline Follow Back 
XXI. 
Fagerstrom Nicotine Dependence  
XXII. 
Craving VAS 
XXIII. 
SF-12 
XXIV. 
Prose Recall 
XXV. 
Delay Discounting (monetary choice questionnaire) 
XXVI. 
Stop Signal Reaction time 
XXVII. 
Working memory (digit span WAIS-IV) 
XXVIII. 
Adverse Effect VAS( e.g. nausea, intoxication, anxiety, memory : 20 
mins before infusion and every 20 mins for next 2 hours) 
XXIX. 
Pattern Recognition Memory Test 
 
Treatment procedures (visits 2 (i.e. baseline; 1 to 28 days 
after screening), visit 4 (4 to 21 days after visit 2) and 6 (4 to 
21 days after visit 4)) 
IMP Dosing Patients will receive 3 x weekly infusions of ketamine 
(Ketalar®) (0.8mg/kg made up to 50ml with saline over 40 minutes) or 3 x 
weekly infusion of placebo (0.9% saline over 40 minutes). The drug/ 
placebo will be prepared in a blinded fashion by pharmacy (who are 
unblinded) or delegated unblinded site staff on the ward at site and will be 
administered by the research anaesthetist at the Clinical Research Facility 
at sites who will remain blinded.  
S+ Ketamine hydrochloride packaged as: Ketalar ® for Injection. The total 
amount to be delivered will be calculated on the basis of the patient’s 
weight (0.8 mg/kg). Site pharmacy will order ketamine and dispense per 
patient, added to saline (0.9%) to make up to 50ml in syringes for the 
infusion pump. For patients allocated the placebo, site pharmacy will 
prepare a 50ml saline (0.9%) solution in syringes for the infusion pump.  
Doses will be administered using a computer controlled infusion pump. 
Participants will be given the option of whether they’d like to listen to non-
vocal instrumental music during the infusion to block out environmental 
noise.  
 


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Relapse Prevention Based Psychological Therapy:  A seven session 
manualised intervention and accompanying workbook developed with 
alcohol specialist clinical psychologists (the supporting documents will give 
the details for manual and workbook). The aim of these 7 sessions is to 
help to develop an enjoyable and meaningful life without alcohol. It 
focuses around two broad themes. The first theme relates to relapse 
prevention, i.e. skills and strategies to reduce the likelihood of relapse and 
maintain abstinence. The second theme focuses on promoting well-being 
and deals with issues such as purpose, meaning and life enjoyment, along 
with skills for coping with life’s day-to-day problems and stresses. 
Session 1: This session focusses on introducing the concepts of high risk 
situations and triggers as well as on planning your activities.  
Session 2:  This session focusses on recognising high risk situations and 
planning effective coping responses. In addition we identify essential 
resources for sobriety. 
Session 3: The aim of this session is to develop further understanding of 
the role of thinking in drinking and how thinking biases can lead to 
unhelpful feelings and behaviour. In this session we also work on 
developing effective problem solving skills. 
Session 4: The aim of this session is to develop general skills to recognise 
urges and craving and to plan an effective response. In this session we 
also introduce relaxation techniques and the concept of mindfulness.  
Session 5:  The aim of this session is to identify early warning signs of 
possible relapse. We also introduce the Demand Control Support model of 
stress to enhance insight into stress and ways of managing stress. 
Session 6:  This session focusses on lapse management and developing 
emergency plans aimed at preventing full relapse and we work on 
enhancing life enjoyment and satisfaction. 
Session 7:  In the final session we look at roles and identities and 
introduce another mindfulness practice. We then develop a plan for the 
next three months 
 
Education control will be a 7 session educational programme educating 
patients about the risks of alcohol use and the effects of alcohol on the 
body (the supporting documents will also provide more detail).  
 
Subsequent assessments 
Visit 3 (1 to 5 days after visit 2), visit 5 (1 to 5 days after visit 4), 7 (1 
to 5 days after visit 6)  
I. 
Vital Signs  
II. 
Bloods (see Appendix B and section 7.9.2 for details of the tests 
that will be used.) 


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III. 
Urine Drug Screen (See Appendix B and section 7.9.2 for details of 
the tests that will be used.) 
IV. 
Breathalyser 
V. 
SCRAM-X checks 
VI. 
Relapse Prevention Based Cognitive Behavioural Therapy 
VII. 
Adverse Events Review 
VIII. 
Concomitant medication review 
IX. 
HAM-D 
X. 
POMS 
XI. 
ACQ-NOW 
XII. 
BPRS 
XIII. 
Craving VAS 
XIV. 
Prose Recall Task 
XV. 
Adverse Effects VAS 
 
Visit 4 (4 to 21 days after visit 2) & visit 6 (4 to 21 days after visit 4) 
(Infusion Days) 
I. 
Vital Signs, vital signs will be continuously monitored throughout 
the infusion and until the participant has recovered. This monitoring 
will be recorded on a standard observation chart and will be stored 
as source data. The eCRF will record 3 sets of readings, one prior 
to the infusion, another after the infusion terminates, and then 
finally after the participants recovery. Bloods, blood samples for 
BDNF 
and 
ketamine 
will 
be 
obtained 
pre-IMP/placebo 
administration and post IMP administration (see Appendix B and 
section 7.9.2 for details of the tests that will be used.) 
II. 
Urine Drug Screen (See Appendix B and section 7.9.2 for details of 
the tests that will be used.) 
III. 
Pregnancy test in WOCBP (urine test) 
IV. 
Breathalyser 
V. 
IMP/ placebo Administration 
VI. 
SCRAM-X checks 
VII. 
Relapse Prevention Based Cognitive Behavioural Therapy 
VIII. 
Adverse Events Review 
IX. 
Concomitant medication review 
X. 
BDI 
XI. 
HAM-D 
XII. 
POMS 


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XIII. 
STAI 
XIV. 
ACQ-NOW 
XV. 
BPRS 
XVI. 
PSI 
XVII. 
Alcohol Timeline Follow Back 
XVIII. 
Craving VAS 
XIX. 
Prose Recall 
XX. 
Adverse Effects VAS ( e.g. nausea, intoxication, anxiety, memory : 
20 mins before infusion and every 20 mins for next 2 hours) 
XXI. 
Pattern Recognition Memory Test 
 
Telephone reminders (Week 3; Week 11; Week 23) 
1. In between the last three visits, the patients will be telephoned to remind 
them of their appointment and confirm attendance.  
 
Visit 8 (4 to 21 days after visit 6), 9 (11 to 13 weeks after visit 2), 10 
(23 to 25 weeks after visit 2)  
I. 
SCID for visits 9 and 10 only 
II. 
Vital Signs for visit 8 only 
III. 
Bloods (see Appendix B and section 7.9.2 for details of the tests 
that will be used),  
IV. 
Urine Drug Screen (See Appendix B and section 7.9.2 for details of 
the tests that will be used.) 
V. 
Breathalyser 
VI. 
SCRAM-X removal (visit 8 only) 
VII. 
Relapse Prevention Based Cognitive Behavioural Therapy for visit 
8 only 
VIII. 
Adverse Events Review 
IX. 
Concomitant medication review 
X. 
Alcohol and Drug use History 
XI. 
BDI 
XII. 
HAM-D 
XIII. 
POMS 
XIV. 
STAI 
XV. 
ACQ-NOW 
XVI. 
BPRS 
XVII. 
PSI 


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XVIII. 
Alcohol Timeline Follow Back 
XIX. 
Drink diary 
XX. 
Fagerstrom Nicotine Dependence 
XXI. 
Craving VAS 
XXII. 
SF-12 
XXIII. 
Prose Recall 
XXIV. 
Delay Discounting (monetary choice questionnaire) 
XXV. 
Stop Signal Reaction time 
XXVI. 
Working Memory (digit span WAIS-IV) 
XXVII. 
Adverse Effects VAS 
XXVIII. 
Pattern Recognition Test 
 
 
Table of study assessments 
Appendix B has a table listing all the study assessment per visit..  
 
Methods 
 
Non laboratory procedures 
Medical History: The medical history will be taken by the researcher from 
the patient and by referring to medical notes to measure eligibility.  
 
The assessment days at which questionnaire and neurocognitive 
measures will be administered can be found in section 7. Below is a list of 
questionnaire and neurocognitive measures and their state of validation: 
 
Validated Interviews and Questionnaires:  
 The Structured Clinical Interview for DSM-IV/DSM-5 Disorders 
(SCID) is used to confirm a diagnosis of alcohol dependence and 
the absence of current psychiatric diagnoses which are listed as 
exclusion criteria (e.g. schizophrenia). This diagnostic schedule is 
widely used. It lasts 20-30 minutes.  
 The Beck Depression inventory (BDI) is a 21 item self-rated 
questionnaire which will be given at varying time points to measure 
depressive symptoms. 
 The Hamilton Depression Inventory (HAM-D) is a 21 item clinician 
rated depression scale.  
 The Columbia Suicide Severity Rating Scale is a 6 item interview 
used to assess suicidal ideation and behaviour and will be used to 
verify the exclusion criteria of subjects with suicide ideation.   


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 The State form of the Spielberger Trait Anxiety inventory (STAI) 
questionnaire (20 items) will be used to measure anxiety throughout 
the study.   
 The Profile of Mood States 2 (POMS 2) Short Form will be used for 
the 
quick 
assessment 
of 
affective 
states 
(Anger-Hostility; 
Confusion-Bewilderment; 
Depression-Dejection; 
Fatigue-Inertia; 
Tension-Anxiety; Vigour-Activity; Friendliness).  
 The Fagerstrom Test of Nicotine Dependence (FTND) – A five item 
scale to index nicotine dependence.  
 The Brief Psychiatric Rating Scale (BPRS) is a clinician rated 
assessment of current psychotic symptoms based on a short 
interview. 
 The Psychotomimetic States Inventory (PSI) is a self-rated scale of 
transient psychotic symptoms.  
 SF-12 is a short scale that measures social functioning.  
 A semi-structured interview detailing the patient’s alcohol and drug 
use history will also be used.  
 The Alcohol TimeLine Follow Back (TLFB) is a drinking assessment 
method that obtains estimates of daily drinking and has been 
evaluated with clinical and nonclinical populations. Using a 
calendar, people provide retrospective estimates of their daily 
drinking over a specified time period. Several memory aids can be 
used to enhance recall (e.g., calendar; key dates serve as anchors 
for reporting drinking; standard drink conversion). The Alcohol 
TLFB has been shown to have good psychometric characteristics 
with a variety of drinker groups, and can generate variables that 
provide a wide range of information about an individual’s drinking 
(e.g., pattern, variability, and magnitude of drinking). 
 A drink diary will be given to each participant to take home in 
between Visits 8, 9 and 10. Participants will be asked to record their 
alcohol consumption every day in between study visits. Drink 
diaries are regularly used in alcohol research to record subjective 
alcohol consumption.  
 Alcohol Craving Questionnaire - short-form (ACQ-NOW) is a 12-
item scale that assesses current alcohol craving. 
Validated Neurocognitive measures: 
 Delay discounting (e.g. monetary choice questionnaire): this is a 
task that measures an individual’s preference for immediate small 
award over a long term bigger gain. 
 Prose recall task: this looks at episodic memory by testing 
participants recall of a short news broadcast. 


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 Stop signal task: Stop signal reaction time examines response 
inhibition, participants have to inhibit prepotent responses to stimuli 
on the screen when they see a cue or ‘stop signal’. 
 Working memory task (e.g. digit span WAIS-IV): Working memory 
measures an individual’s ability to maintain and manipulate small 
amounts of information.  
 Pattern recognition memory task (BPS-O Task) is a memory task 
that taps hippocampal functioning and requires participants to 
distinguish between perceptually similar items that they have seen 
before and those they have not. 
Questionnaires that are not validated:  
 The Pre-Screening questionnaire has been developed to assess 
suitability for inclusion into the trial. 
 Adverse Effects Visual Analgoue Scale (VAS) has been developed 
to measure adverse events during the ketamine infusion and 
treatment.  
 Craving VAS: a one item visual analogue scale will be used to 
assess craving for alcohol anchored at one end with ‘No desire to 
drink alcohol’ and the other ‘Very strong desire to drink alcohol’. 
 
Breathalyser tests will be used at each visit for the following reasons:  
 Screening & re-screening – To assess eligibility 
 Baseline visit (1st infusion) – To assess eligibility/ensure safety of 
IMP administration/ensure patient is able to complete cognitive 
tasks and questionnaires, as well as engage with therapy/education 
 Visit 3, 5, 7 & 8 – To ensure patient is able to complete cognitive 
tasks and questionnaires, as well as engage with therapy/education 
 Visit 4 & 6 (2nd & 3rd infusion) – To ensure safety of IMP 
administration/ensure patient is able to complete cognitive tasks 
and questionnaires, as well as engage with therapy/education 
 Visit 9 & 10 - To ensure patient is able to complete cognitive tasks 
and questionnaires 
Once randomised, if a patient attends for any visit and does not blow 0 on 
the breathalyser the visit will be terminated (either for the primary purpose 
of safety on infusion visits or of data integrity on non-infusion visits) and 
the patient invited to re-attend to complete the visit within the allocated 
visit window. 
 
Concomitant Medication: All prescription medication, over-the-counter 
medication, vitamins, and/or herbal supplements will be recorded on case 
report forms (CRFs). 
 
Vital Signs: Resting pulse, pulse oximetry and blood pressure (BP) 
measurements will be measured at each visit phase for safety monitoring. 
Vital signs will be continuously monitored throughout the infusion until the 
participant has recovered. This monitoring will be recorded on a standard 


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observation chart, stored as source data. The eCRF will record 3 sets of 
readings, one prior to the infusion, another after the infusion terminates, 
and then finally after the participants recovery.  
 
Physical Examination: Height, weight and oral/tympanic temperature will 
be recorded. 
At screening a physician will perform a physical examination of the 
cardiovascular, respiratory, GI and neurological system to a level of detail 
that would be expected for a patient due to receive anaesthesia. 
 
Laboratory procedures 
In order to assist the identification of pathology and confirm physical health 
and eligibility for inclusion in the study the following blood tests will be 
performed: biochemistry (urea, sodium, potassium, glucose, calcium, 
thyroid stimulating hormone) haematology (haemoglobin, white cell count, 
platelets, mean red cell volume); liver function (Bilirubin, ALT, AST, Total 
Protein, Alkaline Phos, Albumin, Globulin, Gamma-GT). The following liver 
function tests will be used to assess eligibility: bilirubin, ALT, AST. The 
following urine drug screen will be performed [extended panel: 
methamphetamine, 
cocaine, 
THC, 
benzodiazepines, 
tricyclic 
antidepressants, barbituates, phencyclidine,, amphetamines, morphine, 
methadone]  (urine test cup/dip test). An additional urine drug screen test 
for ketamine will be done on the screening visit and on visits 2, 4, 6, 8, 9 
and 10. Urine pregnancy tests (urine test) will be done on the screening 
visit and on infusion visits.  
 
The laboratory results will be reviewed and reports signed by the 
Investigator who will record in the CRF whether they are normal, abnormal 
but not clinically significant or abnormal AND clinically significant. In the 
latter case the eligibility of participants will be reviewed. 
 
The following samples will be processed at Local Labs for screening:  
 Biochemistry (urea, sodium, potassium, glucose, calcium, thyroid 
stimulating hormone)  
 Haematology (haemoglobin, white cell count, platelets, mean red 
cell volume);  
 Liver function (Bilirubin, ALT, AST, Total Protein, Alkaline Phos 
(ALP), Albumin, Globulin, Gamma-GT) 
The following urine tests will be performed at site using provided kits with 
results recorded in the medical notes/source data (urine test cup/ dip stick 
test) at screening visit and on Visits 2, 4 and 6: 
 Urine Drug Screen (extended panel: methamphetamine, cocaine, 
THC, benzodiazepines, tricyclic antidepressants, barbituates, 
phencyclidine, ketamine, amphetamines, morphine, methadone)  
(urine test cup/dip test)  
 Pregnancy test (urine test) 


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The following urine drug screens will be performed at site using provided 
kits with results recorded in the medical notes/source data (urine test cup/ 
dip stick test) at Visits 3, 5 and 7: 
 Urine Drug Screen (extended panel: methamphetamine, cocaine, 
THC, benzodiazepines, tricyclic antidepressants, barbituates, 
phencyclidine, amphetamines, morphine, methadone)  (urine test 
cup)  
The following urine drug screens will be performed at site using provided 
kits with results recorded in the medical notes/source data (urine test cup/ 
dip stick test) at Visits 8, 9 and 10: 
 Urine Drug Screen (extended panel: methamphetamine, cocaine, 
THC, benzodiazepines, tricyclic antidepressants, barbituates, 
phencyclidine, ketamine, amphetamines, morphine, methadone)  
(urine test cup)  
 
The following samples will be processed and analysed at local labs for all 
subsequent follow up visits: 
 Liver function (Bilirubin, ALT, AST, Total Protein, Alkaline Phos 
(ALP), Albumin, Globulin, Gamma-GT) 
 
The following samples will be processed and analysed for subsequent 
visits according to the study specific SOP at an HTA licensed, accredited 
Central Laboratory:  
 BDNF 
 Ketamine,  
 
The Laboratory SOP provides the details on sample handling, processing, 
storage and shipment for those samples going to the central laboratory. 
On infusion days (visits 2, 4 and 6) blood samples will be taken to pre- and 
post-infusion to assess changes in BDNF and ketamine levels. Blood 
samples taken after the infusion will be collected after the participant has 
recovered from the infusion.  
 
Definition of end of trial 
The end of the trial will be the last follow-up visit of the participant at 23 to 
25 weeks post visit 2.  


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Discontinuation/withdrawal of participants and ‘stopping 
rules’ 
All efforts will be made to maintain participants in the study where 
possible and to continue assessments as intended. However, there are 
circumstances under which treatment may be discontinued and/or 
participants withdrawn from the trial. 
 Discontinuation from treatment  
The investigator may discontinue a patient from treatment if it is 
considered necessary for any reason including: 
 Ineligibility (either arising during the study or retrospective) 
 Significant protocol deviation e.g. if treatment is stopped for longer 
than 21 days (All protocol deviations and violations will be recorded 
and reported to the sponsor) 
 Significant non-compliance with treatment or study requirements 
e.g. If the participant misses 2 consecutive infusions, as detailed in 
section 9.12 
 An adverse event which requires discontinuation of the study 
medication or results in inability to continue to comply with study 
procedures 
 Disease progression which requires discontinuation of the study 
medication  
 Pregnancy 
 In the case of an overdose (see section 10.5.5) 
 
Where treatment is discontinued, participants will be invited to attend 
follow up visits 9 & 10 on the basis of our planned intention to treat 
analysis which assumes (and formally tests: see section 13.3.4) that data 
are missing at random.  
 
The reason for participant treatment discontinuation will be recorded in the 
case report form (CRF). 
 Withdrawal from the trial 
Participants have the right to withdraw at any time. Participants who 
formally withdraw from the study at any point will not receive any further 
contact from the study team. Participants who withdraw before Visit 2 
(Baseline) will be replaced by assigning successive screening IDs to 
eligible subjects, but after completing randomisation on visit 2 participants 
will not be replaced due to the planned intention to treat analysis. 
 


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In addition the investigator may withdraw a participant from the study at 
any time if it is considered necessary for any reason including: 
 Ineligibility (either arising during the study or retrospective) 
 Significant protocol deviation 
 Significant non-compliance with treatment or study requirements  
 An adverse event which results in inability to continue to comply 
with study procedures 
 Disease progression which results in inability to comply with study 
procedures 
 Consent withdrawn, loss of capacity or detention under Mental 
Health Act 
 Failure to respond to contact attempts from the study team  
 Pregnancy 
The reason for participant withdrawal will be recorded in the case report 
form (CRF). 
 Stopping rules 
The trial may be stopped before completion for the following reasons: 
 
If the CI and/or sponsor decide to suspend the trial pending safety 
review of an emergent issue 
 
The CI and /or sponsor decide to stop the trial for safety, 
administrative or other reasons 
 
 
Name and description of all drugs used in the trial 
 
Treatment of subjects 
Investigational product/treatment 
Participants will receive the following: 
1. 3 x weekly infusions of IV ketamine hydrochloride (Ketalar®) at a 
dose of 0.8mg/kg over 40 mins, or 
2. 3 x weekly infusion of placebo (50ml Saline 0.9%) over 40 mins.  
3. Ketamine is packaged as: Ketalar® glass vial with rubber closure 
and aluminium flip-off cap containing. Exipients with known effects: 
Each 1 ml contains 2.6 mg of sodium. The total amount to be 
delivered will be calculated on the basis of the patient’s weight (0.8 
mg/kg). Site pharmacy will order ketamine and dispense per 
patient, added to saline (0.9%) to make up to 50ml solution in 
syringes for the infusion pump to infuse intravenously.  Doses will 
be administered using a computer controlled infusion pump. 


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Placebo will be 50 ml saline (NaCl) 0.9% in syringes for the 
infusion pump.    
 
 
Concomitant medication 
Ketamine interacts with the following substances and therefore their 
concomitant use will not be permitted during active treatment days: 
barbiturates and/or narcotics, atracurium and tubocurarine, central nervous 
system (CNS) depressants (e.g. phenothiazines, sedating H1 – blockers or 
skeletal muscle relaxants) , thiopental, thyroid hormones, antihypertensive 
agents, theophylline and other methylxanthines.  
 
Due to potential impacts on the primary outcomes taking any other relapse 
prevention medication or anti-depressants will not be permitted during the 
period of study (Visit 2 - Visit 8). 
Other concomitant medication use will be recorded in the CRF. 
 
  Investigational Medicinal Product  
 
Name and description of investigational medicinal 
product(s) 
The product under test will be three weekly doses of ketamine 
hydrocholoride (Ketalar®) at a dose of 0.8mg/kg I.V. over 40 minutes. 
Ketalar® 10mg/ml or 50mg/mL Injection vials will be used. Ketamine is a 
Controlled Drug (Schedule 4, Part 1). Placebo will be saline (0.9%) given 
I.V. over 40 mins.   
 
Doses will be made up from Ketalar® neutral glass vial with rubber closure 
and aluminium flip-off cap containing ketamine hydrochloride. The 
Marketing License holder is Pfizer.  
 
Name and description of each NIMP 
N/A No NIMPs to be used in this trial 
 
Summary of findings from non-clinical studies 
 
Please refer to the Summary of Product Characteristics (SPC) and Section 
2.1. 
 
 
Summary of findings from clinical studies 
Please refer to the Summary of Product Characteristics (SPC) and Section 
2.3. 


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Summary of known and potential risks and benefits 
              See Section 2.4 and 2.5 and Summary of Product Characteristics. 
 
Description and justification of route of administration and 
dosage 
Ketamine will be administered at a dose of 0.8mg/kg IV over 40 mins 
using an infusion pump. The original study of ketamine for relapse 
prevention in alcoholics used a high IM bolus dose (2.5mg/kg), however 
our collaborator Evgeny Krupitsky suggested the use of a lower dose in 
alcohol dependence (1.2mg/kg IM) which data from a small sample (n=15) 
suggests was also effective. The lowest dose of ketamine that is likely to 
be effective is clearly preferable to minimise psychotomimetic effects 
which may reduce treatment tolerability and increase risk of drop-out. The 
proposed dose is higher than that routinely used in patients with treatment 
refractory depression (usually 0.5mg/kg IV see 43 for a review) but well 
within the range of doses that increase synaptogenesis in preclinical 
studies (up to 30 mg/kg IP).  Similar doses have also been used 
successfully in treatment resistant depression (1.0mg/kg IM: 95). The 
reasons for use of this higher dose is that, given the better bioavailability 
of ketamine IV, this dose roughly equates to the lowest effective IM bolus 
dose in alcohol dependent patients used by our collaborator EK. The 
conversion of IM to IV dose was based on extrapolation of 
pharmacokinetic (PK) data [96; 97] as well as consultation with Professor 
Anthony Absalom (Cambridge / Groningen) who has investigated the PK 
profile of ketamine. We have opted for an IV route of administration as the 
effects are more easily controlled by the clinician, i.e. the duration of 
effects are shorter, and there is less variability in Cmax [99]. Placebo will 
be 50ml saline (0.9%) given IV over 40 mins using an infusion pump.  
 
 
Dosages, 
dosage 
modifications 
and 
method 
of 
administration 
Patients will be administered three doses of 0.8 mg/kg ketamine IV or 
three doses of the placebo (50ml Saline 0.9%) given IV over 40 mins 
through computer controlled infusion pump. As dose will be tailored to 
weight of participants, the site pharmacy or delegated unblinded site staff 
on the ward will prepare individualised doses according to the 
randomisation and patient individual weight.  
 
 
Preparation and labelling of Investigational Medicinal 
Product 
Preparation and labelling of the investigational medicinal products should 
be completed in accordance with Annex 13 of Good Manufacturing 
Practice (GMP) guidelines. Labelling exemption will apply and a 
dispensing labelling (as defined in the SoDA) will be used.  
 


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The prepared IMP and Placebo will be labelled with the approved 
templates provided by the sponsor.  
 
Drug accountability 
Routine hospital stocks of ketamine and saline will be used for this trial. A 
drug inventory/dispensing record will be maintained and updated by the 
authorised unblinded personnel at pharmacy or delegated unblinded site 
staff on the ward for all drugs provided and dispensed at each study site. 
At the end of the study, one copy of the drug inventory/dispensing record 
should be sent to the sponsor, one kept in the central study file and one in 
the site files. An unblinded person at each study site is responsible for all 
drug supplies. Written documentation is mandatory. 
 
The unblinded persons at the sites will keep adequate records of the 
receipt, preparation, administration and return or destruction of the study 
medication. They will conceal the accountability forms to blinded 
personnel and ensure these logs are maintained and kept in the pharmacy 
file at site. All data regarding the study medication must be recorded on 
the relevant forms provided by the sponsor or local pharmacy 
accountability forms. Any dispensed but completely unused infusions 
(where the infusion bag has not been opened) at the London site will be 
returned to pharmacy and destroyed in line with site pharmacy 
procedures. Partially unused infusions at the London site cannot be 
accepted by pharmacy. Therefore the local controlled drug policy will be 
followed at the Clinical Research Facility to ensure that materials are 
appropriately destroyed. Completely unused or partially unused infusions 
at the Exeter site cannot be accepted by pharmacy and are therefore 
destroyed at the Clinical Research Facility. In all instances a record of this 
destruction will be kept in accordance with relevant SOPs, to document 
the return and/or destruction of materials at site. 
9.10 Source of IMPs including placebo 
The IMP will be sourced from routine hospital stock and their handling and 
management will be subject to standard procedures of the pharmacy. 
Sourcing of IMP is also discussed in the Summary of Drug Arrangements.  
The following IMPs and placebo can be used from routine hospital stock 
and their handling and management will be subject to standard 
procedures of the Pharmacy: 
 IMP (Ketamine): Ketalar® 
 Placebo (Saline 0.9 %) hospital stocks and any brand can be used 
as long as they are licensed for use within the UK.  


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Dose modifications 
No dose modification will be permitted. If intolerable side effects are 
experienced, the subject will be withdrawn from IMP treatment (see also 
section 7.11). 
 
Assessment of compliance 
Compliance includes both adherences to IMP and Protocol study 
procedures. The trial medication will be administered by the research 
anaesthetist only in the context of the patient attending the Clinical 
Research Facility. Patients will not be responsible for any trial medication. 
A member of the research team will ensure that the arrangements for each 
treatment visit are agreed with the participant and their carer. Where 
necessary, the researcher will assist in transportation. If a participant fails 
to attend a clinic visit for the infusion then the researcher will endeavour to 
contact the patient to identify the reason. Where possible an alternate 
appointment will be made within the infusion visit window (see Appendix 
B). If the participant fails to attend a clinic visit for the follow-up day the 
researcher will endeavour to contact the patient to identify the reason and 
where possible arrange an alternative visit within the follow up visit window 
(see Appendix B). All episodes of failure to attend will be recorded in the 
medical notes, CRF and protocol deviation log. If the participant misses 2 
consecutive infusions, then they will be withdrawn from treatment and will 
be invited to attend follow up visits 9 and 10 as part of our intention to treat 
protocol. Noncompliance to the Protocol study procedures will be 
documented by the investigator and reported to the Sponsor as agreed. 
Persistent noncompliance (<80%) may lead the patient to be withdrawn 
from the study. 
 
Post-trial IMP arrangements 
There is no plan to allow continued treatment with ketamine.  
 
 


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Recording and reporting of adverse events and reactions 
 
Definitions 
Term
Definition
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical 
trial subject administered a medicinal product and which 
does not necessarily have a causal relationship with this 
treatment.
Adverse Reaction 
(AR) 
Any untoward and unintended response in a subject to 
an investigational medicinal product which is related to 
any dose administered to that subject.  
This includes medication errors, uses outside of protocol 
(including misuse and abuse of product)
Serious adverse 
event (SAE), serious 
adverse reaction 
(SAR) or unexpected 
serious adverse 
reaction  
Any adverse event, adverse reaction or unexpected 
adverse reaction, respectively, that: 
 
results in death, 
 
is life-threatening, 
 
requires hospitalisation or prolongation of 
existing hospitalisation, 
 
results in persistent or significant disability or 
incapacity, or 
 
consists of a congenital anomaly or birth 
defect
Important Medical 
Event 
These events may jeopardise the subject or may require 
an 
intervention 
to 
prevent 
one 
of 
the 
above 
characteristics/consequences. Such events should also 
be considered ‘serious’.
Unexpected adverse 
reaction 
An adverse reaction the nature and severity of which is 
not consistent with the information about the medicinal 
product in question set out: 
 (a) in the case of a product with a marketing 
authorization, in the summary of product 
characteristics 
for 
that 
product, 
(b) in the case of any other investigational 
medicinal product, in the investigator's brochure 
relating to the trial in question.
SUSAR
Suspected Unexpected Serious Adverse Reaction
 
Recording adverse events 
All adverse events will be recorded in the medical records and CRF only 
following consent.  
 
If the investigator suspects that the subjects’ disease has progressed 
faster due to the administration of the IMP, then he will record and report 


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this as an unexpected adverse event. Adverse events that are known to 
the IMP when used in its licensed indication (listed in Appendix C, or 
events that are disease related or related to procedures as listed in section 
10.3.3) will only be recorded in the medical notes, however serious AEs 
will be recorded in the CRF and SAE log.  
 
Clinically significant abnormalities in the results of objective tests (e.g. liver 
function, biochemistry) will also be recorded as adverse events. If the 
results are not expected as part of disease or IMP, these will also be 
recorded as unexpected. All adverse events will be recorded with clinical 
symptoms and accompanied with a simple, brief description of the event, 
including dates as appropriate. All adverse events will be recorded until 6 
months post-treatment. All Serious Adverse Events will be reportable to 
the Sponsor from IMP administration up to 30 days post last IMP 
administration.  


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Assessments of Adverse Events 
Each adverse event will be assessed for the following criteria: 
10.3.1 Severity 
Category
Definition
Mild 
The adverse event does not interfere with 
the volunteer’s daily routine, and does not 
require 
intervention; 
it 
causes 
slight 
discomfort.
Moderate 
The adverse event interferes with some 
aspects of the volunteer’s routine, or 
requires intervention, but is not damaging to 
health; it causes moderate discomfort.
Severe 
The adverse event results in alteration, 
discomfort or disability which is clearly 
damaging to health.
 
10.3.2   Causality 
The assessment of relationship of adverse events to the administration of 
IMP is a clinical decision based on all available information at the time of 
the completion of the case report form. The following categories will be 
used to define the causality of the adverse event: 
 
Category
Definition
Definitely 
There is clear evidence to suggest a causal 
relationship, and other possible contributing 
factors can be ruled out.
Probably 
There is evidence to suggest a causal 
relationship, and the influence of other factors 
is unlikely.
Possibly 
There is some evidence to suggest a causal 
relationship (e.g. the event occurred within a 
reasonable time after administration of the 
trial medication). However, the influence of 
other factors may have contributed to the 
event (e.g. the patient’s clinical condition, 
other concomitant events).
Unlikely 
There is little evidence to suggest there is a 
causal relationship (e.g. the event did not 
occur 
within 
a 
reasonable 
time 
after 
administration of the trial medication). There 
is another reasonable explanation for the 
event (e.g. the patient’s clinical condition, 
other concomitant treatments).
Not related 
There 
is 
no 
evidence 
of 
any 
causal 
relationship.


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Not 
Assessable
Unable to assess on information available. 
 
Expectedness 
Category
Definition
Expected 
 
An adverse event that is consistent with the 
information about the IMP listed in the SPC or 
clearly defined in this protocol.
Unexpected 
An adverse event that is classed in nature as 
serious and which is not consistent with the 
information about the IMP listed in the SPC.  
 
The reference document to be used to assess expectedness against the 
IMP and placebo is the SPC. The protocol and SCRAM-X bracelet 
brochure will be used as the reference document to assess disease 
related and/or procedural expected events.  
 
The following Adverse Events are expected disease related and/or 
procedural expected events: 
 Bruising caused by venepuncture 
 Dissociative and psychotomimetic effects, analgesia, dizziness, 
lack of co-ordination, unsteadiness, impaired memory and impaired 
concentration following ketamine infusion 
 Skin rash caused by the SCRAM-X bracelet 
 Drinking relapse 
 
10.3.4  Seriousness 
Seriousness as defined for an SAE in section 10.1.  
 
Collection, recording and reporting of adverse events (including serious 
and non-serious events and reactions) to the sponsor will be completed 
according to the sponsor’s SOP (INV/S05). 
 
Procedures for recording and reporting Serious Adverse 
Events 
All serious adverse events will be recorded in the hospital medical notes 
and the CRF, and the sponsor’s AE log.  The AE log will be reported to the 
sponsor at least once per year. The Chief or Principal Investigator will 
complete the sponsor’s serious adverse event form and the form will be 
faxed to the sponsor on 020 3108 2312 or preferably emailed on 
sae@ucl.ac.uk, within 24 hours of his / her becoming aware of the event. 
The Chief or Principal Investigator will respond to any SAE queries raised 
by the sponsor as soon as possible. All SUSARs must be notified to the 


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sponsor immediately (within 24 hours) according to the sponsor’s written 
SOP. Reporting to the sponsor will be completed as per the sponsor’s 
SOP and using the UCL SAE form (INV/S05).   
 
Notification of deaths 
All deaths, including deaths deemed unrelated to the IMP, if they occur 
earlier than expected will be reported to the sponsor within 24 hours of site 
being made aware of the event.  
 Reporting SUSARs 
The sponsor will notify the main REC and MHRA of all SUSARs.  SUSARs 
that are fatal or life-threatening must be notified to the MHRA and REC 
within 7 days after the sponsor has learned of them. Other SUSARs must 
be reported to the REC and MHRA within 15 days after the sponsor has 
learned of them. The procedure for unblinding in the event of a SUSAR is 
documented in section 7.3. 
 Development Safety Update Reports 
The sponsor will provide the main REC and the MHRA with Development 
Safety Update Reports (DSUR) which will be written in conjunction with 
the trial team and the Sponsor’s office. The report will be submitted within 
60 days of the Developmental International Birth Date (DIBD) of the trial 
each year until the trial is declared ended. This will be done in accordance 
with the sponsor’s SOP (SPON/S17). 
 Annual progress reports 
An annual progress report (APR) will be submitted to the REC within 30 
days of the anniversary date on which the favourable opinion was given, 
and annually until the trial is declared ended. The chief investigator will 
prepare the APR. 
 Pregnancy (If applicable) 
We intend to record and notify pregnancies to the sponsor (using the 
sponsor’s SOP). Any pregnancy that occurs during the treatment weeks will 
result in exclusion from treatment. 
  
In the event of a pregnancy occurring during the study, this must be 
reported using a sponsor pregnancy reporting form. 
 
To ensure subject’s safety, each pregnancy must be reported to the 
sponsor within 24 hours of learning of its occurrence. The pregnancy must 
be followed to determine the outcome (including premature termination) and 
status of mother and child. 


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Pregnancy complications and elective terminations for medical reasons 
must be reported as an AE or SAE. Spontaneous abortion must be reported 
as an SAE to the CI and Sponsor within 24 hours of learning of its 
occurrence.  
 
Any SAE occurring in association with a pregnancy brought to the 
investigator’s attention after the subject has completed the study and 
considered by the investigator as possibly related to the investigational 
product, must be promptly reported to sponsor.   
 Overdose  
We do not envisage an overdose as drugs are prepared by pharmacy and 
then administered by the anaesthetist at the Clinical Research Facility. 
Accidental administration of 50 times the protocol dose constitutes an 
overdose. In the event of an overdose and protocol deviation then the 
sponsor will be notified (and this information will be placed in the deviation 
log) and trust policy on incident reporting will be followed. Overdoses will 
be observed from drug charts, or an anaesthetic response in the patient. If 
an SAE is associated with the overdose then this will be fully described in 
the SAE report form. We will use intention to treat analysis in the case of 
an overdose. In the case of an overdose, the patient will be withdrawn 
from treatment and will be invited to attend follow up visits 9 and 10 as 
part of our intention to treat protocol. 
 Reporting Urgent Safety Measures  
If any urgent safety measures are taken the PI/Sponsor shall immediately 
and in any event no later than 3 days from the date the measures are 
taken, give written notice to the MHRA and the relevant REC of the 
measures taken and the circumstances giving rise to those measures. The 
guidance on the MHRA website will be used for details on clinical trials 
safety reporting. 
 
The type and duration of the follow-up of subjects after 
adverse events. 
If a patient has an adverse reaction during infusion they will be monitored 
in the Clinical Research Facility until a resolution or stabilisation is 
reached. If an SAE happens while the subject is not in the research facility 
they will be given the number of an on-call anaesthetist and told to present 
to A&E at site (preferably) or the nearest hospital. Any SUSAR related to 
the IMP will need to be reported to the Sponsor irrespective of how long 
after IMP administration the reaction has occurred. 


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 Notification of Serious Breaches to GCP and/or the 
protocol (SPON/S15)  
 A “serious breach” is a breach which is likely to effect to a significant 
degree:  
(a) the safety or physical or mental integrity of the subjects of the 
trial;  
or 
(b) the scientific value of the trial. 
 
The sponsor of a clinical trial shall notify the licensing authority in writing of 
any serious breach of: 
(a) the conditions and principles of GCP in connection with that trial;  
or  
(b) the protocol relating to that trial, as amended from time to time, within 7 
days of becoming aware of that breach. 
 
The sponsor will be notified immediately of any case where the above 
definition applies during the trial conduct phase.  The sponsor’s SOP on 
the ‘Notification of violations, urgent safety measures and serious 
breaches’ will be followed.  
 
Data management and quality assurance 
 
Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 
1998. The Case Report Forms (CRFs) will not bear the subject’s name or 
other personal identifiable data. The subject’s initials, date of birth and 
patient ID, will be used for identification. 
 
Data collection tools and source document identification 
Data to be collected can be found in sections 7.5 and 7.7. Every effort will 
be made to maximise completeness of data. Trial data will be collected in 
an Electronic Case Report Form hosted on sealedenvelope.com, prepared 
using their “Red Pill” service (www.sealedenvelope.com/redpill). Source 
data documents will be defined at site prior to the start of the trial.  
 
Full details of source data and documentation will be identified in a 
separate source document identification list but in summary will comprise 
of the following:  
 
Patient Clinical Record (medical notes) 
 
Trial specific source data worksheets  and trial specific logs  


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 
Laboratory test print outs 
 
Questionnaires and measurement scales  
 
Encrypted memory stick containing computer tasks data files and 
SCRAM-X data 
 
Data to be recorded in the source data first and then transcribed into the 
CRF: 
 
Patient demographics; age, date of birth and initials 
 
Medical history including drug use, alcohol use, smoking 
 
Physical examination  
 
Patient eligibility assessment 
 
Allergies 
 
Concomitant medication 
 
Study IMP treatment 
 
Therapies: Psychoeducation Therapy, Relapse-prevention based 
CBT 
 
Clinical Assessment measurements: Vital signs, Blood and urine 
screen. On infusion visits (visits 2, 4 and 6) continuous monitoring of 
vital signs will occur through the infusion until the participant has 
recovered. This monitoring will be recorded on a standard 
observation chart and will be stored as source data. The eCRF will 
record 3 sets of readings, one prior to the infusion, another after the 
infusion terminates, and then finally after the participants recovery.  
 
Adverse Events (refer to section 10) 
 
Assessment tools:  
 Pattern Recognition Test  
 Stop Signal Reaction Time  
 Delay Discounting (monetary choice questionnaire) 
 Working Memory (digit span WAIS-IV) 
 Prose Recall 
 SCRAM-X checks 
 BPRS   
 PSI 
 Adverse events VAS  
 Craving VAS 
 Fagerstrom smoking  
 Timeline follow Back  
 Drink diary 
 Reasons for drinking questionnaire 
 Columbia Suicide Severity Rating Scale 
 BDI  
 HAM-D 
 POMS  


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 STAI  
 SF-12 
 ACQ-NOW 
 
The following data to be collected in the source documents but will not be 
collected in the CRF: 
 
Adverse events that are expected for the IMP and which are not 
serious and listed in section 10  
 
Questionnaires and measurements scales to determine adverse 
effects/treatment adherence will be delivered in clinics by fully trained staff 
to ensure completeness. In cases where there are some missing data, the 
patient will be asked those questions on the telephone (a member of the 
Investigator Team will call him/her). 
 
It will be the responsibility of the Lead Researcher to ensure the accuracy 
of all data entered into the CRF. The delegation log will identify all those 
personnel with responsibilities for data collection and handling, including 
those who have access to the trial database.  
 
Data handling and analysis 
A bespoke password protected “Red Pill” database designed by 
sealedenvelope.com (limited to nominated staff recorded on the 
delegation log by the CI) will be used for data entry and storage of 
anonymised patient records and CRF data. This database will be hosted 
on a secure server at sealedenvelope. All source data (other than data 
collected from the SCRAM-X bracelet) will be securely stored at site with 
access limited to only authorised staff. Data from the SCRAM-X bracelet 
will be stored on a secure drive at the Psychopharmacology and Addiction 
Research Centre, Washington Singer Laboratories. Automated data 
(SCRAM-X, pattern recognition task, stop signal task) will be kept on an 
encrypted  memory stick with the source data.  
 
The CRF and trial specific documents held by the researcher will be stored 
securely with access restricted and limited to nominated research staff 
recorded on the delegation log and in accordance with the data protection 
act 1998, UCL Information Security Policy and Trust Information 
Governance Policy. Electronic and questionnaire source data will be 
stored in a password protected Microsoft Access database. The Red Pill 
database will keep a record of all changes to and access of the database. 
All data and audit log files from the Red Pill eCRF are backed up daily to 
tape within the data-centre with a two week retention period. Since the 
databases and log files are cumulative (no deletion), it is not necessary to 
keep backups beyond this retention period. In addition all data and log 
files are replicated immediately and continuously to a remote server for 
off-site storage. 
 


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The CRF will be accessible by the research team through access codes 
on the password protective electronic database site (the detailed 
arrangements will be in the data management SOP). The data will be 
available for download by the trial statistician and nominated members of 
the study team over a CTPS encrypted protocol. Once downloaded, data 
will be stored on a password protected networked drive at the University of 
Exeter. At the end of the study, sites will file copies of the eCRFs for their 
patients on an encrypted  memory stick for archiving purposes.  
 
The CI will be ultimately responsible for data entry and quality. Trial staff 
as identified on the delegation log will also be responsible for data entry 
and quality. Single data entry with quality control checks will be used in the 
eCRF. Once data has been entered a visual check between what has 
been entered and the CRF/source data will be made by another member 
of the research team. Validity checks will be made using dates of testing 
days against each patient ID. Data stored within the Access database will 
be entered using Teleform software and then verified by the data 
manager.  
 
Data analysis will be performed independently of data entry by the trial 
statistician. 
 
Data will be stored and backed up daily by through the Red Pill service. 
The drives will be backed up frequently, allowing for data retrieval in the 
event of data loss. Data transfer and storage will be in accordance with the 
UK Data Protection Act 1998 as well as UCL Information Security Policy 
and Trust Information governance policy.  Once all data checks and data 
are completed, the database will be locked and read only. Users can still 
view the contents of the database and produce reports. The database will 
also be accessed centrally by the study statistician (on a read only basis) 
for data analysis and access of the database will be logged in the data 
transfer log kept in the TMF or the database will be sent by Professor 
Celia Morgan to the statistician electronically as read only through a 
secure process of password protected encryption and this will be 
documented in the data transfer log kept in the TMF. 
 
Record keeping and archiving 
Archiving will be authorised by the Sponsor following submission of the 
end of study report. The Chief Investigator will be responsible for the 
secure archiving of essential trial documents and the trial database as per 
their trust/university policy. All essential documents will be archived for a 
minimum of 25 years after completion of trial. The investigator or a 
delegate at site is responsible for the secure archiving of essential site trial 
documents as per local trust policy arrangements.  Destruction of essential 
documents will require authorisation from the Sponsor.   


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Statistical Considerations  
Dr Fiona Warren is the trial statistician who will be responsible for all 
statistical aspects of the trial from design through to analysis and 
dissemination.     
13.1 Outcomes 
13.1.1 Primary outcomes 
Relapse rates at 6 months  
Percentage Days Abstinent at 6 months  
13.1.2  Secondary outcomes 
 Number of days of continuous abstinence at 3 months ( Time-line follow 
back) 
 Percentage days abstinent at 3 months (timeline follow-back) 
 State mood (Profile of Mood states) 
 Depression (Beck Depression Inventory; Hamilton Depression Scale) 
 Anxiety (Speilberger Trait Anxiety Inventory) 
 Psychotic symptoms (Brief Psychiatric Rating Scale; Psychotomimetic 
States Inventory) 
 Cigarette smoking (Fagerstrom Smoking) 
 Craving (Visual Aanalogue Scales) 
 Quality of Life (SF-12) 
 Episodic Memory (Prose Recall) 
 Delay Discounting (monetary choice questionnaire) 
 Response Inhibition (Stop Signal Reaction time) 
 Working Memory (digit span WAIS-IV) 
 Hippocampal Functioning (Pattern Recognition Test) 
 Adverse Effects (Adverse Effects VAS) 
 Alcohol Craving Questionnaire - short-form (ACQ-NOW) 
13.2 Sample size and recruitment 
13.2.1 Sample size calculation 
As this is a proof of concept study we wish to include the minimum number 
of subjects, and must balance considerations of feasibility, including 


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recruitment, whilst providing a reliable early indicator of efficacy that would 
warrant continuing to a larger trial.  
 
Our justification of sample size of n=96: 
 
Following randomisation the patient allocation will be n=24 per cell. Drop-
out rates will be minimised with incremental payment schedules as we 
have used in previous studies where we have achieved high retention 
rates in difficult populations (e.g. [93]). It is anticipated that wearing the 
SCRAM-X bracelets may also reduce drop-out rates as they are designed 
to increase compliance with treatment programmes in offending 
populations (Compliance Monitoring Systems, LLP). However, we have 
adopted a very conservative estimated 50% drop-out. If this level of drop-
out is observed, that will leave n=12 in each individual cell, with a total of 
n=24 patients having been administered ketamine and n=24 placebo.  
 
With n=24 people in each drug arm we will be able to estimate a decrease 
in the relapse rate from 50% in patients given placebo to 25% (90% CI: 
3% to 47%) in patients given ketamine. 
 
A decrease of 25% in relapse would be clinically important, and lower than 
that observed in the preliminary work ([33]: 42%); it would clearly suggest 
that further investigation is warranted. Our confidence intervals are 
relatively broad as this is a proof of concept study and we wish to minimize 
the numbers of subjects involved.   
13.2.2  Planned recruitment rate 
The recruitment period will be 4 years. Approximately 540 patients every 
12 months pass through the detoxification services in the NHS trusts we 
will recruit from, therefore we consider the recruitment of these 96 
individuals over 24 months to be achievable. 
13.3 Statistical analysis plan 
13.3.1 Summary of baseline data and flow of patients 
We will assess the comparability of the randomised groups including each 
factor including demographics and the baseline assessments described in 
section 7. We plan to produce a consort flow diagram (http://www.consort-
statement.org/). 
13.3.2  Primary outcome analysis 
There are two primary outcomes: (i) proportion relapsed (recommenced 
using alcohol) at 6-month follow-up; and (ii) percentage of days abstinent 
at 6-month follow-up (the denominator being 175 days) .The proportion of 
relapsed participants at 6-month follow-up will be reported as a 
percentage for each arm, as well as for the ketamine arms combined and 


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the psychotherapy arms combined. Although no formal power calculations 
for a between-group analysis have been performed, the proportion of 
relapsed participants at 6-month follow-up will be expressed as a relative 
risk (RR) with a 95% confidence interval for the following comparisons: (i) 
all ketamine participants versus all non-ketamine participants; (ii) ketamine 
+ psychotherapy participants versus ketamine + non-psychotherapy 
participants; and (iii) ketamine + psychotherapy participants vs. placebo + 
no psychotherapy participants. These analyses are purely exploratory and 
should be viewed with caution both in the light of lack of power and 
multiple testing. Percentage of days abstinent at 6-month follow-up will be 
reported descriptively in the same way by arm and combination of arms; 
additionally, the between-group mean differences and 95% confidence 
intervals will be reported for the comparisons set out above; again, these 
analyses should be regarded as exploratory. The primary analysis will be 
an intention-to-treat (ITT) complete case analysis including all randomised 
participants. A secondary analysis will be conducted including only those 
participants deemed to have completed to a sufficient degree their 
allocated interventions, that is, a per protocol analysis. All analyses will be 
performed by a statistician who is blinded to the treatment allocations and 
will be performed using Stata v.13.  
 
13.3.3 Secondary outcome analysis 
There are 15 secondary outcomes (section 13.1.2); all of these outcomes 
will be reported descriptively on an ITT complete case basis; additionally, 
the between-group mean differences and 95% confidence intervals will be 
reported on an exploratory basis for the primary comparison (all ketamine 
participants versus all non-ketamine participants). Also, as a feasibility 
outcome, attrition will be reported as a proportion (with 95% confidence 
interval) overall and by arm.  
13.3.4  Sensitivity and other planned analyses 
All participants will be in a state of detoxification at recruitment, hence in 
the event of loss to follow-up, it is not appropriate to make an assumption 
that the participant had or had not relapsed at 6 months. To address the 
issue of missing data due to loss to follow-up, a sensitivity analysis will be 
performed using multiple imputation methods, for relapse at 6-month 
follow-up only, making the assumption that all missing data were missing 
at random. 
13.4 Randomisation methods 
See Section 7.2 for a full description of randomisation methods, block 
design will be used.  


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13.5 Interim analysis 
As an interim analysis with regards to trial continuation, attrition among 
participants receiving ketamine only will be determined; the trial will be 
discontinued if more than 21/24 (88%) of participants who were 
randomised to ketamine are lost to follow-up at 3 months. Only aggregate 
data will be provided to the statistician at 3-month follow-up to ensure that 
treatment arm allocation will remain concealed. Due to the short duration 
of follow-up, no interim analyses for the primary or secondary outcomes 
are planned. From a safety perspective, adverse events will be monitored 
by the trial team and any concerns will be addressed. 
13.6 Other statistical considerations 
A full statistical analysis plan (SAP) will be presented to the TMG prior to 
commencing the analyses. Any amendments to the SAP will be recorded, 
with the nature of the amendment, the date of amendment and date 
approved by the TMG. 
14 
Name of Committees involved in trial 
A trial management group (TMG) will be put in place for this trial which 
consists of the Project Manager, CI, Lead Researcher, Co-Investigators, 
Trial Anaesthetist, Trial Statistician, Research Associate and Research 
Assistant. The terms of reference and current members of this committee 
will be held in the Trial Master File and can be provided upon request. 
15 
Direct Access to Source Data/Documents 
The investigator(s)/ institution(s) will permit trial-related monitoring, audits, 
REC review, and regulatory inspection(s), providing direct access to 
source data/documents. Trial participants are informed of this during the 
informed consent discussion. Participants will consent to provide access to 
their medical notes. 
16 
Ethics and regulatory requirements 
The sponsor will ensure that the trial protocol, patient information sheet, 
consent form, GP letter and submitted supporting documents have been 
approved by the appropriate regulatory body (MHRA in UK) and a main 
research ethics committee, prior to any patient recruitment.  
 
Any changes in research activity and documentation, except those 
necessary to remove an apparent, immediate hazard to the participant in 
the case of an urgent safety measure, must in the first instance be 
reviewed by the Chief Investigator. All amendments, will be submitted by 
the CI to the sponsor who will assess if the amendment is substantial or 
non-substantial. Substantial amendments to the protocol and other trial 


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related essential documents as assessed by the sponsor will be submitted 
in writing to the appropriate REC, Regulatory Authority and Trust 
Research & Development (R&D) for approval prior to implementation of 
amended documents. 
 
Before 
the 
site 
can 
enrol 
patients 
into 
the 
trial, 
the 
Chief 
Investigator/Principal Investigator or designee must apply for NHS 
permission from their Trust Research & Development (R&D) and be 
granted written permission.  It is the responsibility of the Chief Investigator/ 
Principal Investigator or designee at each site to ensure that all 
subsequent amendments gain the necessary approval.  This does not 
affect the individual clinician’s responsibility to take immediate action if 
thought necessary to protect the health and interest of individual patients 
(see section 10.5.6 for reporting urgent safety measures). 
 
Within 90 days after the end of the trial, the CI/Sponsor will ensure that the 
main REC and the MHRA are notified that the trial has finished.  If the trial 
is terminated prematurely, those reports will be made within 15 days after 
the end of the trial. The CI will supply the Sponsor with a summary report 
of the clinical trial, which will then be submitted to the MHRA and main 
REC within 1 year after the end of the trial.  
17 
Monitoring requirement for the trial 
A trial specific monitoring plan will be established for studies. The trial will 
be monitored with the agreed plan. 
18 
Finance 
This trial is being funded by the Medical Research Council. 
19 
Insurance 
University College London holds insurance against claims from 
participants for injury caused by their participation in the clinical trial. 
Participants may be able to claim compensation if they can prove that UCL 
has been negligent. However, as this clinical trial is being carried out in a 
hospital, the hospital continues to have a duty of care to the participant of 
the clinical trial. University College London does not accept liability for any 
breach in the hospital’s duty of care, or any negligence on the part of 
hospital employees. This applies whether the hospital is an NHS Trust or 
otherwise.   
 
Participants may also be able to claim compensation for injury caused by 
participation in this clinical trial without the need to prove negligence on 
the part of University College London or another party.  Participants who 
sustain injury and wish to make a claim for compensation should do so in 
writing in the first instance to the Chief Investigator, who will pass the 
claim to the Sponsor’s Insurers, via the Sponsor’s office. 


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Hospitals selected to participate in this clinical trial shall provide clinical 
negligence insurance cover for harm caused by their employees and a 
copy of the relevant insurance policy or summary shall be provided to 
University College London, upon request. 
20 
Publication policy 
All proposed publications will be discussed with Sponsor prior to 
publishing other than those presented at scientific forums/meetings. 
Please refer to UCL publication policy. 
21 
Statement of compliance 
The trial will be conducted in compliance with the approved protocol, the 
UK Regulations, EU GCP and the applicable regulatory requirement(s). 
22 
References 
1. 
Health and Social Care Information Centre Statistics on Alcohol: 
England 2011;2012.   2012  [Available from: 
http://www.hscic.gov.uk/pubs/alcohol11]. 
2. 
World Health Organisation, Global Status Report on Alcohol and 
Health 2011, 2011. 
3. 
McLellan, A.T., et al., . JAMA, 2000. 284(13): p. 1689-95. 
4. 
Zarate, C.A., Jr., et al Arch Gen Psychiatry, 2006. 63(8): p. 856-64. 
5. 
Krupitsky, E.M. and A.Y. Grinenko,. J Psychoactive Drugs, 1997. 
29(2): p. 165-83. 
6. 
Curran, G.M., et al.,. J Subst Abuse Treat, 2000. 19(3): p. 259-65. 
7.  
Martin, D. and Lodge, D., Neuropharmacology, 1985(24): p. 999-
1003.  
8.  Goodman & Gillman, Pharmacology and Therapeutics 2003  
9.  Linderfors, N, et al., Brain Res 1997  759: 205-12 
10.  Krystal, J.H., Sanacora, G., Duman, R.S., Biol. Psychiatry, 2013 
(73): p. 1133– 1141. 
11.  Burgdorf J, Zhang XL, Nicholson KL, et al. 
Neuropsychopharmacology. 2013(38): p. 729–742. 
12.  Koike, H., Iijima, M., and Chaki, S. Pharmacol. Biochem. Behav. 
2013 (107): p. 20–23. 
13. Yang, C et al Front, Med 2012 6: 411-5 
14. Browne CA & Lucki, I Front Pharmacol 2013 4:161 


Short title: KARE: Ketamine for reduction of Alcoholic Relapse Sponsor code:  13/0253      Page 79 of 89 
 UCL Protocol template V2, 27/01/2012                              Final Version 12.0 20 January 2020 
Page 79 of 89 
15.  Iijima M, Fukumoto K, Chaki S. Behav Brain Res 2012(235): p. 287-
92. 
16.  Carrier, N., and Kabbaj, M.Neuropharmacology 2013(70): p, 27–34.  
17.  Li N, et al. Science. 2010(329): p. 59–964. 
18.  Koike H, Iijima M, Chaki S. Behav Brain Res. 201(224): p. 107–111. 
 
 
19.  Bechtholt-Gompf AJ, Smith KL, John CS, Kang HH, Carlezon WA Jr, 
Cohen BM, Ongür D. Psychopharmacology (Berl). 2011(215): p. 
689–95. 
20. Perry, EB et al., Psychopharmacology 2007 192: 253-260  
21. ReD-Kite ISRCTN 89575054  
22.  Diamond PR., Farmery AD., Atkinson S., Haldar J., Williams N., 
Cowen PJ., Gedder JR., McShane R. J Psychopharmacol 2014(6): 
p. 536–544 
23.  Zarate C Jr,Machado-Vieira R, Henter I,et al. Harv Rev Psychiatry 
2010(18): p. 293-303 
24. DiazGranados, N., Ibrahim, L., Brutsche, NE, Newberg, A, Kronstein, 
P., Khalife, S, et al., Arch Gen Psychiatry 2010 67: 793-802  
25. Price RB, Nock MK, Charney DS, Mathew SJ. Biol Psychiatry. 
2009;(66(5)): p. 522–526. 
26. Kranaster L, Kammerer-Ciernioch J, Hoyer C, Sartorius A. Eur Arch 
Psychiatry Clin Neurosci. 2011(261): p. 575–582. 
27. Erdill, F., Ozgul, U., Clak, C., Cumurcu, B., Durmus, M. J ECT 2015 
Feb 25 (PMID 25719444)  
28.  Kerr CL, Windeyer C, Boure LP et al. Am J Vet Res 2007(68): p, 
1287–1293 
29.  Irwin SA, Iglewicz A. J Palliat Med 2010(13): p. 903–8. 
30. Kolp, E., Krupitsky, E., Young, M.S., Jansen, K., Friedman, H., 
O’Connor, LA, International Journal of Transpersonal Studies 2007 26: 1-
17  
31. Clinical trials.gov identifier: NCT01551329 
32. Petrakis, personal communication  
33.  Krupitsky, E. M., & Grinenko, A. Y. Journal of Psychoactive Drugs, 
1997(29): p, 165–183. 
34. Morgan CJ & Curran HV, Addiction 2012 107: 27-38  
35.  Krupitsky EM, Burakov AM, Dunaevsky IV, Romanova TN, Slavina 
TY, Grinenko AY. J Psychoactive Drugs. 2007(39): p. 13–19.  
36.  Petrakis IL. Journal of Clinical Psychopharmacology 2006(26, Suppl. 
1): p. 3–12.  
37. Nikpoor, P. & Bain, E., Cochrane Database Syst Rev 2013 9: 
CD008878 


Short title: KARE: Ketamine for reduction of Alcoholic Relapse Sponsor code:  13/0253      Page 80 of 89 
 UCL Protocol template V2, 27/01/2012                              Final Version 12.0 20 January 2020 
Page 80 of 89 
38.  Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga 
CA. 2001(25): p. 455–467 
39. Herrera, D.G., et al. Proc Natl Acad Sci U S A, 2003. 100(13): p. 
7919-24. 
40. Chick, J., et al.,. Alcohol Alcohol, 2000. 35(2): p. 176-87. 
41. Health and Social Care Information Centre, Statistics on Alcohol: 
England, 2013.  
42. Harris, A.H., et al., Psychol Serv, 2013. 
43. Aan Het Rot, M., et al., Biol Psychiatry, 2012. 72(7): p. 537-47. 
44. Duman, R.S. and G.K. Aghajanian,. Science, 2012. 338(6103): p. 
68-72. 
45. Sabino, V., et al., Behav Brain Res, 2013. 247: p. 9-16. 
46. Clinicaltrials.gov. 2013. 
47. Hasin, D.S., et al.,. Arch Gen Psychiatry, 2005. 62(10): p. 1097-106. 
48. Pettinati, H.M.,. Biol Psychiatry, 2004. 56(10): p. 785-92. 
49. Mason, B.J., et al. JAMA, 1996. 275(10): p. 761-7. 
50. Luckenbaugh, D.A., et al.,. Bipolar Disord, 2012. 14(8): p. 880-7. 
51. Krystal, J.H., et al.,. Arch Gen Psychiatry, 1998. 55(4): p. 354-60. 
52. Chambers, R.A., Drug Alcohol Depend, 2013. 130(1-3): p. 1-12. 
53. Li, N., et al., Science, 2010. 329(5994): p. 959-64. 
54. Denk, M.C., et al.,. Am J Psychiatry, 2011. 168(7): p. 751-2. 
55. Mandyam, C.D. and G.F. Koob, Trends Neurosci, 2012. 35(4): p. 
250-60. 
56. Helfer, J.L., et al.,. Brain Res, 2009. 1294: p. 1-11. 
57. Hernandez-Rabaza, V., et al.,. Addict Biol, 2010. 15(4): p. 413-23. 
58. Nixon, K., et al.. Neurobiol Dis, 2008. 31(2): p. 218-29. 
59. Stevenson, J.R., et al. Neuropsychopharmacology, 2009. 34(5): p. 
1209-22. 
60. Nixon, K. and F.T. Crews. J Neurosci, 2004. 24(43): p. 9714-22. 
61. Crews, F.T., K. Nixon, and M.E. Wilkie. Alcohol, 2004. 33(1): p. 63-
71. 
62. Zanardini, R., et al., Alcohol Clin Exp Res, 2011. 35(8): p. 1529-33. 
63. Grosjean, B. Am J Psychother, 2005. 59(3): p. 181-97. 


Short title: KARE: Ketamine for reduction of Alcoholic Relapse Sponsor code:  13/0253      Page 81 of 89 
 UCL Protocol template V2, 27/01/2012                              Final Version 12.0 20 January 2020 
Page 81 of 89 
64. Bates, M.E., J.F. Buckman, and T.T. Nguyen. Neuropsychol Rev, 
2013. 23(1): p. 27-47. 
65. Birch, A.M., N.B. McGarry, and A.M. Kelly, Hippocampus, 2013. 
23(6): p. 437-50. 
66. Krystal, J.H., et al., Pharmacol Ther, 2003. 99(1): p. 79-94. 
67. Hashimoto, K., E. Shimizu, and M. Iyo, Brain Res Brain Res Rev, 
2004. 45(2): p. 104-14. 
68. Morgan, C.J., et al., Psychopharmacology (Berl), 2004. 172(3): p. 
298-308. 
69. Krupitsky, E.M., et al., Neuropsychopharmacology, 2001. 25(6): p. 
936-47. 
70. Perry, E.B., Jr., et al., Psychopharmacology (Berl), 2007. 192(2): p. 
253-60. 
71. aan het Rot, M., et al., Biol Psychiatry, 2010. 67(2): p. 139-45. 
72. Hunt, W.A., L.W. Barnett, and L.G. Branch, J Clin Psychol, 1971. 
27(4): p. 455-6. 
73. Vaillant, G.E., Addiction, 2003. 98(8): p. 1043-51. 
74. Groot, Y.C., et al., J Int Neuropsychol Soc, 2002. 8(5): p. 645-54. 
75. Shallice, T., Philos Trans R Soc Lond B Biol Sci, 1982. 298(1089): p. 
199-209. 
76. Verbruggen, F., G.D. Logan, and M.A. Stevens,. Behav Res 
Methods, 2008. 40(2): p.  
           479-83. 
77. Gandek, B., et al., J Clin Epidemiol, 1998. 51(11): p. 1171-8. 
78. Spielberger, C.D. and P.R. Vagg, J Pers Assess, 1984. 48(1): p. 95-
79. Bohn, M.J., D.D. Krahn, and B.A. Staehler, Clin Exp Res, 1995. 
19(3): p. 600-6. 
80. Chick, J., et al., Alcohol Alcohol, 2000. 35(6): p. 587-93. 
81. Griffiths, A., et al Addiction, 2012. 107(10): p. 1809-16. 
82. Gueorguieva, R. and J.H. Krystal, Arch Gen Psychiatry, 2004. 61(3): 
p. 310-7. 
83. Krupitsky, E., et al., J Subst Abuse Treat, 2002. 23(4): p. 273-83. 
84. Collaborating Centre for Mental Health (2011); The NICE guideline 
on diagnosis,  


Short title: KARE: Ketamine for reduction of Alcoholic Relapse Sponsor code:  13/0253      Page 82 of 89 
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Page 82 of 89 
          assessment and management of harmful drinking and alcohol 
dependence.  
85.    Morgan, CJA, Muetzelfeldt, L., Curran HV, Addiction 2010 105:121-
133 
86.    Morgan, CJA, Schafer, G, Freeman, T, Curran HV,  2011   
         Neuropsychopharmacology 35 (9), 1879-1885 
87.    Wilson B., Cockburn J.,& Baddeley A. (1985) The Rivermead 
Behavioural Memory Test.  
         Bury St Edmunds: Thames Valley Test Company 
88.    Beck A. T., Steer R. A.,& Brown G. K. (1996) Manual for the Beck 
Depression  
        Inventory–II. San Antonio, TX: Psychological Corporation. 
89.   Cocks, K & Torgerson, D.J. 2013  J Clin Epidemiology 66:197-201 
90.   Harmer, C. Cowen, P. 2013 Phil Trans  R. Soc: B Phil. Trans. R. Soc. 
B 368: 20120407 
91.   Krebs, T. & Johansen, 2012 Y. J Psychopharm 26:994-1002 
92.  Kolp, E. et al., 2006 Human Psychol 34: 399-422 
93.  Morgan, CJA et al., 2010 Addiction 105: 121-133 
94.  Zarate CA, Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, 
Diazgranados N,     Cravchik A, et al. Biol Psychiatry. 2012(71): p. 
939–946 
95. Zanicotti, CG, Perez, D., Glue, P  J Palliat Med 2012 15:400-3 
96. Clements JA, Nimmo WS, Grant, IS. J Pharm Sci 1982 71:539-542 
97. Clements JA, Nimmo WS. Br J Anaesth 1981 53: 27-30 
98. Murrough, JW et al. Biol Psychiat 2013 74: 250-256 
99. Grant, IS, Nimmo, WS, Clements JA Br J Anaesth 1981 53: 805-810 
 
 
 
 
 


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Appendix A: DSM IV and 5 criteria for alcohol abuse/dependence and 
moderate/severe alcohol use disorder 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B:  Schedule of Study Procedures 
 
Pre-
Screening 
Screening 
Refreshe
r 
Screenin
g
Baseline 
Treatment Phase  
 
Follow Up  
Visit # 
-1 
1 
1 
2 
3 
4 
5 
6 
7 
8 
9 F-UP 
10 F-UP 
 
 
 
1 to 28 days 
before visit 2 
 
Only to be 
run if 28 
days 
elapses 
between 
screening 
and visit 2
 
1 to 28 
days after 
screening 
 
1 to 5 
days 
after 
visit 2 
4 to 21 
days 
after visit 
2 
1 to 5 
days 
after visit 
4 
 4 to 21 
days 
after visit 
4 
1 to 5 
days 
after visit 
6 
4 to 21 
days 
after visit 
6 
11 to 13 
weeks after 
visit 2 
23 to 25 
weeks after 
visit 2 
Trial discussion with 
Participant 
x 
x 
X 
 
 
 
 
 
 
 
 
 
Pre Screening Questionnaire 
x 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
X 
 
 
 
 
 
 
 
 
 
Physical a
 
X 
X 
 
 
 
 
 
 
 
 
 
SCID 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
Vital Signs b   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Bloods c, d 
 
X c 
X 
X d 
X d 
X d 
X d 
X d 
xd 
X d 
X d 
X d 
Eligibility determination 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Urine Drug screen  
 
Xe
X 
Xe
Xf
Xe
Xf
Xe
Xf
Xe
Xe
Xe
Pregnancy Test I WOCBP 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
Breathalyser 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomisation  
 
 
 
X 
 
 
 
 
 
 
 
 
SCRAM-X fitting 
 
Xg
Xg
Xg
 
 
 
 
 
 
 
 
IMP/Plac administration 
 
 
 
X 
 
X 
 
X 
 
 
 
 
SCRAM-X checks 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Relapse-prevention based 
CBT  
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events review 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol and Drug Use 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 


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History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-
Screening 
Screening 
Refresher 
screening 
Baseline  
Treatment Phase  
 
Follow Up  
Visit # 
-1 
1 
1 
2 
3 
4 
5 
6 
7 
8* 
9* 
F-UP 
10* 
F-UP 
 
 
 
 
1 to 28 days 
before visit 2 
 
Only to be 
run if 28 
days 
elapses 
between 
screening 
and visit 2
 
1 to 28 days 
after 
screening 
 
1 to 
5 
day
s 
after 
visit 
2
4 to 21 
days 
after visit 
2 
1 to 5 
days 
after visit 
4 
 4 to 21 
days 
after visit 
4 
1 to 5 
days 
after visit 
6 
4 to 21 
days 
after visit 
6 
11 to 13 
weeks after 
visit 2 
23 to 25 
weeks after 
visit 2 
BDI 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
HAM-D 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia Suicide Severity 
Rating Scale 
 
x 
X 
 
 
 
 
 
 
 
 
 
POMS 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reasons for Drinking 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
STAI 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
ACQ-NOW 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PSI 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Alcohol Timeline Follow 
Back 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Drink diary 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Fagerstrom Nicotine 
Dependence 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Craving VAS 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-12 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Prose Recall  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Performed by Research Fellow, Nurse or Assistant 
Performed by Anaesthetist 
* In the week prior to Visits 8, 9 and 10 patients will be telephoned to remind them of their attendance.  
 
a) Physical – Height, weight, An examination of cardiovascular, respiratory, GI and neurological function to a level of detail 
that would be expected for a patient due to receive anaesthesia.  
b) Vital signs:  oral/tympanic temperature, resting pulse, pulse oximetry and Blood Pressure. 
c) Bloods (Screening) – FBC (haemoglobin, white cell count, platelets, mean red cell volume); Liver function (Bilirubin, ALT, 
AST, Total Protein, Alkaline Phos (ALP), Albumin, Globulin, gamma-glutamyl transpeptidase (GGT)), Biochemistry (urea, 
sodium, potassium, glucose, calcium, thyroid stimulating hormone). 
d) Bloods (Study): BDNF; ketamine; Liver function (Bilirubin, ALT, AST, Total Protein, Alkaline Phos (ALP), Albumin, Globulin, 
gamma-glutamyl transpeptidase (GGT)).  
e) Urine Drug screen (Screening, infusion days and F-UP visits) -  (methamphetamine, cocaine, THC, benzodiazepines, 
tricyclic antidepressants, barbituates, phencyclidine,amphetamines, morphine, methadone, ketamine). 
f)  Urine Drug screen (Non-infusion days, treatment phase) – (methamphetamine, cocaine, THC, benzodiazepines, tricyclic 
Delay Discounting (monetary 
choice questionnaire) 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Stop Signal Reaction Time 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Working Memory (digit span 
WAIS-IV) 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Adverse effects VAS + 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pattern Recognition Memory 
Test 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 


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antidepressants, barbituates, phencyclidine, amphetamines, morphine, methadone).  
g)  SCRAM-X device can be fitted at any one of these visits.  
 
 


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Appendix C: Known Adverse Effects of Ketamine when used in an anaesthetic setting 
 
The following Adverse Events have been reported: 
 
MedDRA 
System Organ Class 
Frequency† 
Undesirable Effects 
Immune system disorders 
Rare 
Anaphylactic reaction* 
Metabolism and nutrition disorders 
Uncommon 
Anorexia 
Psychiatric disorders 
Common 
Hallucination, Abnormal dreams, Nightmare, Confusion, 
Agitation, Abnormal behaviour 
Uncommon 
Anxiety 
Rare 
Delirium* Flashback*, Dysphoria*, Insomnia, 
Disorientation* 
Nervous system disorders 
Common 
Nystagmus, Hypertonia, Tonic clonic movements 
Eye disorders 
Common 
Diplopia 
Not Known 
Intraocular pressure increased 
Cardiac disorders 
Common 
Blood pressure increased, Heart rate increased 
Uncommon 
Bradycardia, Arrhythmia 
Vascular disorders 
Uncommon 
Hypotension 
Respiratory, thoracic and 
mediastinal disorders 
Common 
Respiratory rate increased 
Uncommon 
Respiratory depression, Laryngospasm 
Rare 
Obstructive airway disorder*, Apnoea* 
Gastrointestinal disorders 
Common 
Nausea, Vomiting 
Rare 
Salivary hypersecretion* 
Hepatobiliary disorders 
Not known 
Liver function test abnormal, Drug-induced liver injury** 


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Skin and subcutaneous tissue 
disorders 
Common 
Erythema, Rash morbilliform 
Renal and urinary disorders 
Rare 
Cystitis*, Haemorrhagic cystitis* 
General disorders and administration 
site conditions 
Uncommon 
Injection site pain, Injection site rash 
† Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Not known (frequency 
cannot be estimated from the available data) 
* AE frequency estimated from post-marketing safety database 
** Extended period use (>3 days) or drug abuse 
 

SAP_001.pdf: 
KARE Statistical analysis plan v. 1.2, 11/03/2020 
1 
 
Statistical Analysis Plan: Ketamine for reduction of Alcoholic RElapse (KARE) 
 
 
Trial full title 
A phase II, randomised, double-blind, placebo- 
controlled, multi-site, parallel group clinical trial to 
examine ketamine as a pharmacological treatment 
for alcohol dependence in an alcohol dependent 
population 
 Trial short title 
Ketamine for reduction of Alcoholic RElapse (KARE) 
Trial registration number 
EudraCT no.: 2015-000222-11 
Trial chief investigator 
Dr Brigitta Brandner (UCL) 
Trial  Lead researcher 
Professor Celia Morgan (UoE) 
Trial project manager 
Dr Martin Anyim (UCL) 
Trial statistician 
Dr Fiona Warren (UoE) 
SAP author 
Dr Fiona Warren (UoE) 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
2 
 
Contents 
1. Abbreviations and definitions ............................................................................................................. 3 
2. Statistical guidelines............................................................................................................................ 3 
3. Trial background ................................................................................................................................. 3 
4. Trial information ................................................................................................................................. 3 
4.1 Interventions ................................................................................................................................. 3 
4.2 Phase of trial ................................................................................................................................. 4 
4.3 Randomisation level ...................................................................................................................... 4 
4.4 Study design .................................................................................................................................. 4 
4.5 Purpose of the analyses ................................................................................................................ 4 
4.6 Sample size calculation ................................................................................................................. 5 
4.7 Study populations ......................................................................................................................... 5 
5. Study objectives and endpoints .......................................................................................................... 5 
5.1 Study objectives ............................................................................................................................ 5 
5.2 Endpoints ...................................................................................................................................... 6 
5.3 Derived variables .......................................................................................................................... 6 
6 General analysis considerations........................................................................................................... 7 
6.1 Timing of analyses ......................................................................................................................... 7 
6.2 Types of analyses .......................................................................................................................... 8 
6.3 Covariates and subgroups ............................................................................................................. 8 
6.4 Presentation of inferential analyses ............................................................................................. 8 
6.5 Missing data .................................................................................................................................. 8 
6.6 Adverse events .............................................................................................................................. 8 
8 References ........................................................................................................................................... 9 
9 Appendix – example figures and tables ............................................................................................... 9 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
3 
 
1. Abbreviations and definitions 
 
Table 1 Abbreviations and definitions 
Abbreviation 
Full terminology/definition 
CONSORT 
CONsolidated Standards of Reporting Trials 
CTU 
Clinical Trials Unit 
eCRF 
Electronic Case Report Form 
EudraCT 
European Clinical Trials Database 
ITT 
Intention to treat 
KARE 
Ketamine for reduction of Alcoholic RElapse 
MRC 
Medical Research Council 
PI 
Principal Investigator 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
UCL 
University College London 
UCLH 
University College London Hospitals NHS Foundation 
Trust 
UoE 
University of Exeter 
 
 
2. Statistical guidelines 
 
Analyses are to be conducted in accordance with ICH-9 statistical guidelines for clinical trials and CONSORT 
reporting checklist for trials [1, 2]. The SAP for this trial has been developed in accordance with the Standard 
Operating Procedure (SOP): Statistical Principles (SOP number NIHRexe/207/GEN). 
 
3. Trial background  
 
The KARE trial is a phase-II randomised trial comparing an active drug intervention (ketamine) with a placebo 
(saline), and comparing psychotherapy with no psychotherapy (alcohol education). This trial is funded by the 
Medical Research Council (MRC), and sponsored by University College London (UCL), Sponsor number 
13/0253. The EudraCT reference number is 2015-000222-11. The trial has been approved by the South West – 
Central Bristol Research Ethics Committee (reference number: 15/SW/0312). 
 
This trial aims to gather data regarding the clinical effectiveness of intravenous ketamine (with and without a 
concurrent psychotherapy intervention) with regard to prevention of relapse (recommencing alcohol use) in 
participants who are currently abstinent, but who have a current diagnosis of alcohol dependence. The trial 
will also gather data regarding safety and tolerability of ketamine, and assess compliance with the drug and 
psychotherapy interventions. Full details of the trial are set out in the KARE trial protocol, Final Version 12, 
dated 20.01.2020. This statistical analysis plan (SAP) is written in relation to this protocol.  
 
Participants are randomised individually to their combination of ketamine/placebo and 
psychotherapy/psychoeducation control using a blocking design. Participants are aware of all available 
treatment options, and that they could potentially be allocated to any of these. The drug intervention is 
administered by an anaesthetist who is blinded to the drug intervention allocation and also to the therapy 
intervention. The psychotherapist cannot be blinded to the therapy intervention, but is blinded to the drug 
intervention. The patient is also blinded to the drug intervention, but is aware of whether they receive 
psychotherapy or control. 
 
4. Trial information 
 
4.1 Interventions 
 
KARE has two forms of intervention, a drug intervention and a psychotherapy intervention. The active drug 
intervention is ketamine, an anaesthetic/analgesic drug, to be administered intravenously. The placebo control 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
4 
 
is saline. As well as a drug intervention the participants will receive concurrently either a psychotherapy 
intervention, or a psychoeducation control intervention. Hence, there are four combinations: (i) ketamine + 
psychotherapy; (ii) ketamine + psychoeducation; (iiI) placebo + psychotherapy; (iv) placebo + psychoeducation. 
Participants will receive their allocated drug infusion in 3 doses over 3 weeks. Participants will concurrently 
receive either psychotherapy or psychoeducation control. The trial will be performed at two sites: Devon 
(Royal Devon & Exeter Foundation NHS Trust) and London (UCLH). 
 
4.2 Phase of trial 
 
KARE is a Phase II clinical trial (a proof of concept study/feasibility study). 
 
4.3 Randomisation level 
 
Randomisation will be performed by an independent organisation, Sealed Envelope, that specialises in 
randomisation and online databases for clinical trials (https://www.sealedenvelope.com/).  Participants are 
randomised individually. To aim for balance across the four treatment combinations, a block randomisation 
will be performed (block sizes are known only to the trial statistician and the designated staff at Sealed 
Envelope). Randomisation will be performed separately for each site. A list of randomisation allocation codes 
will be generated in advance by Sealed Envelope, with each code indicating the drug allocation (ketamine or 
placebo) and the psychotherapy intervention (psychotherapy or psychoeducation). These codes will be sent to 
the trial statistician, who will generate two envelopes for each participant, one indicating the drug allocation 
and the other indicating the psychotherapy intervention. These envelopes will be securely delivered to trial 
staff at each site. The trial unblinded research nurse will receive the drug allocation envelopes for the Devon 
site, and the hospital pharmacist at UCLH. The trial psychologists at each site will receive the psychotherapy 
allocation envelopes for the Devon and London sites. When recruited by trial researchers, the participant’s 
data will be entered to the online eCRF database. The participant will be allocated a trial ID number. The 
randomisation will be performed using the online eCRF database by the trial anaesthetist at each site. This trial 
ID number will be linked to the next available randomisation allocation code, and this information will be sent 
via email to the relevant member of the trial team so that they can open the participant’s envelope to discover 
their randomised allocation.  
 
4.4 Study design 
 
KARE has two interventions (drug therapy and psychological therapy), each with two possible forms, resulting 
in a two by two factorial intervention design, with a total of four possible interventions (Section 4.1).  
 
The drug intervention will be administered by the site anaesthetist, who will be blinded to drug allocation and 
psychotherapy allocation. Psychotherapy/psychoeducation will be administered by the trial psychologists at 
each site who will be blinded to the drug allocation. Participants will also be blinded to drug allocation. 
Participant outcome data will be collected by site investigators who are blinded to drug allocation. The trial 
statistician will be blinded to both drug allocation and psychotherapy allocation throughout the trial. 
 
Participants will be randomised to the trial after eligibility has been confirmed via prescreening and screening, 
and after having provided informed consent. The SCRAM-X ankle monitor (measuring alcohol levels in sweat) 
will be attached at screening. Treatment will commence as soon as possible after randomisation, and continue 
for a period of 3 weeks (one infusion session and two sessions of psychological therapy/psychoeducation per 
week). Follow-up data will be collected at 3 and 6 months after baseline. The last follow-up visit is scheduled 
for 24 weeks post baseline.  
 
4.5 Purpose of the analyses 
 
The purposes of the analyses are as follows: 
 
(i) 
to provide baseline descriptive data by trial arm; 
(ii) 
to assess the feasibility of data collection;  
(iii) 
to assess loss to follow-up at 3 and 6 months; 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
5 
 
(iv) 
to assess the proportion of missing data at 6 months; 
(v) 
to provide descriptive outcome data by trial arm (ketamine vs placebo, psychotherapy vs 
psychoeducation, and all four arms individually) at 6 months; 
(vi) 
to provide relative risks (with 95% confidence intervals) for relapse of alcohol consumption 
comparing (a) ketamine vs placebo; (b) ketamine plus psychotherapy vs ketamine plus 
psychoeducation; (c) ketamine plus psychotherapy vs placebo plus psychoeducation; 
(vii) 
to provide mean difference (with 95% confidence intervals) for percentage of days abstinent at 6-
month follow-up for the same combinations by arm as for (vi); and 
(viii) 
to descriptively report adverse events. 
 
All inferential analyses are to be regarded as exploratory and viewed with caution due to lack of statistical 
power and multiple testing. For the primary outcomes, the primary analyses will be performed on an intention 
to treat (ITT) basis using complete case data only (see Section 6.5 for approaches to missing primary outcome 
data). As a sensitivity analysis, the inferential analyses for the primary outcomes only (vi and vii above) will be 
performed using only those participants deemed to have a completed their allocated interventions to a 
specified degree (per protocol analysis). For the participants who receive ketamine, a per protocol treatment 
will be defined as receiving three or more infusions. No specification of a minimum treatment has been 
defined for psychotherapy/psychoeducation. Hence, all participants who receive placebo drug therapy will be 
considered as having been treated per protocol. For the secondary outcomes, only an ITT analysis using 
complete case data will be performed. All analyses will be performed by a statistician who is blinded to 
treatment allocation. All analyses will be performed using Stata v14.  
 
4.6 Sample size calculation 
 
As this is a proof of concept study, no inferential analyses are planned, therefore no formal power calculations 
have been performed. The sample size of 96 (24 participants per treatment combination) was selected for the 
following reasons. As a proof of concept study, feasibility of recruitment, and desire to minimise the number of 
subjects, were considerations. If a level of dropout of 50% is observed, this will leave 12 participants per arm, 
24 receiving ketamine and 24 receiving placebo. We anticipate a relapse rate of 50% in the placebo arm, and 
would be able to estimate a reduced relapse rate of 25% in the ketamine arm with a 95% CI width of 37 
percentage points (see Protocol Final Version 12, 20.01.2020 Section 13.2.1 for further details).  
 
4.7 Study populations 
 
Inclusion and exclusion criteria for participants are set out in the Protocol, Final Version 12, 20.01.2020   
Section 5. 
 
The primary analyses will be performed using the ITT population (participants analysed according to their 
randomised allocations). Further sensitivity analyses will be performed using the per protocol population 
(defined in Section 4.5). All analyses will be performed using complete case data only. Participants found to be 
ineligible after randomisation will be excluded from all analyses. 
 
5. Study objectives and endpoints 
 
5.1 Study objectives 
 
The objectives of the study are as follows (Protocol, Final Version 12, 20.01.2020 Section 3). 
 
Primary objectives 
 
1) To obtain preliminary data on whether ketamine is effective in promoting and prolonging abstinence in 
alcohol dependent patients following detoxification. 
2) To assess safety and tolerability of ketamine in alcohol dependence. 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
6 
 
Secondary objectives 
 
1) To make an early assessment on likely compliance to a combined ketamine and relapse prevention based 
cognitive behavioural therapy (CBT). 
2) To obtain preliminary data as to whether ketamine alone is as effective as a combined ketamine and 
psychotherapy treatment. 
 
5.2 Endpoints 
 
The primary and secondary outcome variables are set out in the Protocol, Final Version 12, 20.01.2020 , 
Section 13.1 (reproduced in Table 2). There are two primary outcomes: 
 
1) relapse (defined as 5 drinks (8.1 units alcohol) in men and 4 drinks (6.5 units alcohol) in women on a 
single occasion) at 6-month follow-up; binary outcome; and 
2) percentage days abstinent (not using alcohol at all) at 6-month follow-up; percentage, to be analysed 
as a continuous variable. 
 
The two primary outcomes are to be derived from timeline follow-back. 
 
There are 19 secondary variables, derived from 16 secondary outcomes (Protocol, Final Version 12, 
20.01.2020, Section 13.1.2; depression is measured by two variables, Beck Depression Inventory and Hamilton 
Depression Scale; Short Form Health Survey 12 (SF-12) produces a physical and a mental component scale; 
psychotic symptoms is measured by two variables, Brief Psychiatric Rating Scale and Psychotomimetic States 
Inventory). 
 
1) maximum number of days of continuous abstinence within the first 3 months (time-line follow back); 
continuous; 
2) percentage days abstinent at 3 months ( time-line follow back);  percentage, to be analysed as a 
continuous outcome; 
3) Profile of Mood states; continuous; 
4) Beck Depression Inventory; continuous;  
5) Hamilton Depression Scale; continuous; 
6) Speilberger Trait Anxiety Inventory; continuous; 
7) Brief Psychiatric Rating Scale; continuous; 
8) Psychotomimetic States Inventory; continuous; 
9) Fagerstrom Test of Nicotine Dependence (FTND; smokers only); continuous; 
10) Alcohol craving (visual analogue scale); continuous; 
11) Alcohol Craving Questionnaire - short-form (ACQ-NOW); 
12) Short Form Health Survey 12 (SF-12), physical component scale (PCS); continuous; 
13) Short Form Health Survey 12 (SF-12), mental component scale (MCS); continuous; 
14) episodic memory (Prose Recall); continuous; 
15) delay discounting; continuous; 
16) response inhibition (Stop Signal Reaction time); continuous; 
17) working memory; continuous; 
18) hippocampal functioning (Pattern Recognition Test); continuous; and 
19) adverse effects (visual analogue scale); continuous. 
 
 
5.3 Derived variables 
 
The only derived variables will the binary relapse variable and the number/percentage of days abstinent, to be 
derived from timeline follow-back data. Further details are to be confirmed. 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
7 
 
 
 
 
6 General analysis considerations 
 
6.1 Timing of analyses 
 
An analysis of loss to follow-up only (using count data only) for the ketamine arms will be performed at 3-
month follow-up. The trial will be discontinued if more than 42/48 (88%) participants allocated to ketamine 
are lost to follow-up at 3 months. No further interim analyses are planned (confirmed by funder, December 
2019). 
 
The final analyses will take place once all outcome data (after 6-month follow-up is complete) has been 
entered into the trial database and cleaned. The data manager will liaise with the trial statistician to make the 
outcome data available for analysis. 
 
Table 2 Outcome variables 
 
Outcome 
Variable type 
Timepoints 
measured 
Data source/measurement method 
Primary outcomes 
Relapse (defined as 5 
drinks (8.1 units alcohol) 
in men and 4 drinks (6.5 
units alcohol) in women 
on a single occasion) 
Binary 
6 months 
Timeline follow-back (participant report) 
 
Percentage days 
abstinent (not using 
alcohol at all) 
Percentage 
6 months 
Timeline follow-back (participant report) 
 
Secondary outcomes 
Number of days of 
continuous abstinence 
Continuous 
3 months 
Timeline follow-back (participant report) 
 
Percentage days 
abstinent 
Continuous 
3 months 
SCRAM-X 
Timeline follow-back (participant report) 
 
Profile of Mood states;  
Continuous 
6 months 
Questionnaire: participant  report 
Beck Depression 
Inventory 
Continuous
6 months
Questionnaire: participant report
Hamilton Depression 
Scale 
Continuous
6 months
Questionnaire: participant  report
Speilberger Trait Anxiety 
Inventory 
Continuous
6 months
Questionnaire: participant report
Brief Psychiatric Rating 
Scale 
Continuous
6 months
Questionnaire: participant report
Psychotomimetic States 
Inventory 
Continuous
6 months
Questionnaire: participant report
Fagerstrom Test of 
Nicotine Dependence 
(FTND) 
Continuous
6 months
Questionnaire: participant report
Alcohol Craving (visual 
analogue scale) 
Continuous 
6 months 
Questionnaire: participant report 
Alcohol Craving 
Questionnaire (ACQ); 
Continuous
6 months
Questionnaire: participant report
Short Form Health 
Survey 12 (SF-12), 
Continuous
6 months
Questionnaire: participant report


KARE Statistical analysis plan v. 1.2, 11/03/2020 
8 
 
physical component 
scale (PCS)  
Short Form Health 
Survey 12 (SF-12), 
mental component scale 
(MCS) 
Continuous
6 months
Questionnaire: participant report
Episodic memory (Prose 
Recall) 
Continuous
6 months
Computer task: participant completed 
Delay discounting 
Continuous
6 months
Questionnaire: participant report 
Response inhibition 
(Stop Signal Reaction 
time) 
Continuous
6 months
Computer task: participant completed
Working memory 
Continuous
6 months
Questionnaire: participant report
Hippocampal functioning 
(Pattern Recognition 
Test) 
Continuous
6 months
Computer task: participant completed
Adverse effects (visual 
analogue scale) 
Continuous
6 months
Questionnaire: participant report 
 
 
6.2 Types of analyses 
 
The primary analyses, for both primary and secondary outcomes, will be based on the ITT population, using 
complete case data only. The primary outcomes will be reported descriptively using ITT data.  Inferential 
analyses for the three two-arm comparisons (ketamine vs placebo; ketamine plus psychotherapy vs ketamine 
plus psychoeducation; and ketamine plus psychotherapy vs placebo plus psychoeducation) will be performed 
for the primary outcomes using ITT and per protocol data. The secondary outcomes will be reported 
descriptively by arm using ITT data, and inferential analyses will be performed using ITT data for the primary 
two-arm comparison only, ketamine vs placebo. 
 
6.3 Covariates and subgroups 
 
All inferential analyses will be adjusted by site. Due to the small number of participants, and the feasibility 
nature of the study, no subgroup investigations will be performed.  
 
6.4 Presentation of inferential analyses 
 
For the inferential analyses, the point estimate for the between arm comparison and 95% confidence interval 
will be reported. Due to the feasibility nature of the study, and the lack of formal power calculation, no p-
values will be reported.  
 
6.5 Missing data 
 
The primary analyses for primary and secondary outcomes will be based on complete case data only. For the 
primary outcomes only, we will use multiple imputation to impute any missing data, if data are missing for 
more than 5% of participants. Individual item missingness for questionnaire outcomes will be dealt with by 
using the average of reported items to substitute for missing items if no more than a certain number (to be 
determined for each questionnaire) of items are missing.    
 
6.6 Adverse events 
 
Data on adverse events will be set out descriptively by trial arm.  
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
9 
 
7 Audit trail 
 
Date of SAP 
SAP version 
number 
Date presented to 
Trial management 
group/Trial 
steering committee 
Significant 
amendments since 
previous version 
Date approved 
15 June 2016 
1.0 
15 June 2016 
N/A 
15 June 2016 
2 December 2019 
1.1 
5 December 2019 
1. Inferential 
analyses to be 
adjusted by site 
(Section 7.3) 
5 December 2019 
27 January 
1.1 (supersedes 
v1.1. 2/12/2019) 
27 January 2020 
1. Definition of 
primary outcome 
refined and data 
source for primary 
outcome 
confirmed (Section 
5.2). 
2. Protocol version 
amended in 
anticipation of 
submission 
(Version 12, 
20.01.2020) 
27 January 2020 
11 March 2020 
1.2 
12 March 2020 
1. Confirmation of 
use of Protocol 
Final Version 12, 
20.01.2020 
(throughout). 
 
12 March 2020 
 
8 References 
 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical Principles for Clinical Trials. Guideline E9. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guid
eline.pdf(last accessed 25 April 2016) 
2. Moher D, Schulz KF, Altman DG.  The CONSORT statement: revised recommendations for improving 
the quality of reports of parallel-group randomised trials. Lancet. 2001. 14;357:1191-4. 
 
9 Appendix – example figures and tables 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
10 
 
Figure 1 Participant flow diagram 
 
 
 
 
 
 
 
 
 
Prescreening n= X
Screening N= X
Ineligible n= X
Declined to participate 
n= X
Eligible and provided 
informed consent N= X 
Ineligible n= X
Declined to participate 
n= X 
Declined to wear 
SCRAM-X monitor n=X 
Ketamine + 
psychotherapy N= 
X 
Ketamine + 
psychoeducation 
N= X 
Placebo + 
psychotherapy N= 
X 
Ketamine + 
psychoeducation 
N= X 
3-month follow-
up data available 
n= X 
3-month follow-
up data available 
N= X 
3-month follow-
up data available 
N= X 
3-month follow-
up data available 
N= X 
6-month follow-
up data available 
n= X 
6-month follow-
up data available 
N= X 
6-month follow-
up data available 
N= X 
6-month follow-
up data available 
N= X 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
11 
 
Table 3 Participant characteristics at baseline  
Participant 
characteristic 
Ketamine + 
psychotherapy (N= 
) 
Ketamine + 
psychoeducation 
(N= ) 
Placebo + 
psychotherapy (N= 
) 
Placebo + 
psychoeducation 
(N= ) 
Gender; n (%) 
 
 
 
 
Male 
 
 
 
 
Female 
 
 
 
 
Age; mean (SD); 
[min, max] 
 
 
 
 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
12 
 
Table 4 Relapse of alcohol use and percentage of days abstinent at 6-month follow-up: intention to treat population using complete case data. 
Outcome 
Ketamine 
(n= ) 
Placebo  
(n= ) 
PT (n= ) 
PE (n =) 
Ketamine + 
PT (n ) 
Ketamine + 
PE (n ) 
Placebo + PT 
(n ) 
Placebo + PE 
(n ) 
Ketamine 
vs 
placebo 
RR (95% 
CI) 
Ketamine 
+ PT vs 
Ketamine 
+ PE 
RR (95% 
CI) 
Ketamine 
+ PT vs 
placebo 
+PE RR 
(95% CI) 
Relapse; n 
(%) 
Timeline 
follow-back 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ketamine 
vs 
placebo 
mean 
difference 
(95% CI) 
Ketamine 
+ PT vs 
Ketamine 
+ PE 
mean 
difference 
(95% CI) 
Ketamine 
+ PT vs 
placebo 
+PE mean 
difference 
(95% CI) 
Percentage 
days 
abstinent; 
mean (SD); 
median 
[IQR] 
Timeline 
follow-back 
 
 
 
 
 
 
 
 
 
 
 
 
PE: Psychoeducation 
PT: Psychotherapy 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
13 
 
Table 5 Relapse of alcohol use and percentage of days abstinent at 6-month follow-up: per protocola population using complete case data. 
Outcome 
Ketamine 
(n= ) 
Placebo  
(n= ) 
PT (n= ) 
PE (n =) 
Ketamine + 
PT (n ) 
Ketamine + 
PE (n ) 
Placebo + PT 
(n ) 
Placebo + PE 
(n ) 
Ketamine 
vs 
placebo 
RR (95% 
CI) 
Ketamine 
+ PT vs 
Ketamine 
+ PE 
RR (95% 
CI) 
Ketamine 
+ PT vs 
placebo 
+PE RR 
(95% CI) 
Relapse; n 
(%) 
Timeline 
follow back 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ketamine 
vs 
placebo 
mean 
difference 
(95% CI) 
Ketamine 
+ PT vs 
Ketamine 
+ PE 
mean 
difference 
(95% CI) 
Ketamine 
+ PT vs 
placebo 
+PE mean 
difference 
(95% CI) 
Percentage 
days 
abstinent; 
mean (SD); 
median 
[IQR] 
Timeline 
follow back 
 
 
 
 
 
 
 
 
 
 
 
 
aPer protocol population defined as receiving at least three ketamine infusions. No definition of per protocol for placebo, psychotherapy, or psychoeducation interventions. 
PE: Psychoeducation 
PT: Psychotherapy 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
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Table 6 Relapse of alcohol use and percentage of days abstinent at 6-month follow-up: intention to treat population using complete case and imputed data. 
Outcome 
Ketamine 
(n= ) 
Placebo  
(n= ) 
PT (n= ) 
PE (n =) 
Ketamine + 
PT (n ) 
Ketamine + 
PE (n ) 
Placebo + PT 
(n ) 
Placebo + PE 
(n ) 
Ketamine 
vs 
placebo 
RR (95% 
CI) 
Ketamine 
+ PT vs 
Ketamine 
+ PE 
RR (95% 
CI) 
Ketamine 
+ PT vs 
placebo 
+PE RR 
(95% CI) 
Relapse; n 
(%) 
Timeline 
follow back 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ketamine 
vs 
placebo 
mean 
difference 
(95% CI) 
Ketamine 
+ PT vs 
Ketamine 
+ PE 
mean 
difference 
(95% CI) 
Ketamine 
+ PT vs 
placebo 
+PE mean 
difference 
(95% CI) 
Percentage 
days 
abstinent; 
mean (SD); 
median 
[IQR] 
Timeline 
follow back 
 
 
 
 
 
 
 
 
 
 
 
 
PE: Psychoeducation 
PT: Psychotherapy 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
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Table 7 Secondary outcomes at 3-month follow-up 
Outcome 
Ketamine 
(n= ) 
Placebo  (n= 
) 
PT (n= ) 
PE (n =) 
Ketamine + 
PT (n ) 
Ketamine + PE 
(n ) 
Placebo + 
PT (n ) 
Placebo + PE (n ) 
Ketamine vs 
placebo  
mean difference 
(95% CI) 
Number of 
continuous 
days 
abstinenta,b; 
mean (SD), 
median [IQR] 
 
 
 
 
 
 
 
 
 
Percentage 
days 
abstinenta,b; 
mean (SD); 
median [IQR] 
 
 
 
 
 
 
 
 
 
PE: Psychoeducation 
PT: Psychotherapy 
aAbstinent means not using alcohol at all. 
bOutcomes measured using timeline follow-back. 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
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Table 8 Secondary outcomes at 6-month follow-up 
Outcome 
Ketamine 
(n= ) 
Placebo  (n= 
) 
PT (n= ) 
PE (n =) 
Ketamine + 
PT (n ) 
Ketamine + PE 
(n ) 
Placebo + 
PT (n ) 
Placebo + PE (n ) 
Ketamine vs 
placebo  
mean difference 
(95% CI) 
Profile of Mood 
states; mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Beck Depression 
Inventory; mean 
(SD) 
 
 
 
 
 
 
 
 
 
Hamilton 
Depression 
Scale; mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Speilberger Trait 
Anxiety 
Inventory; mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Brief Psychiatric 
Rating Scale; 
mean (SD), n 
 
 
 
 
 
 
 
 
 
Psychotomimetic 
States Inventory; 
mean (SD), n 
 
 
 
 
 
 
 
 
 
Fagerstrom Test 
of Nicotine 
Dependence 
(FTND); mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Alcohol Craving 
Questionnaire 
(ACQ); mean 
(SD), n 
 
 
 
 
 
 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
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Craving (visual 
analogue scale; 
mean (SD), n 
 
 
 
 
 
 
 
 
 
Short Form 
Health Survey 12 
(SF-12), physical 
component scale 
(PCS); mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Short Form 
Health Survey 12 
(SF-12), mental 
component scale 
(MCS); mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Episodic memory 
(Prose Recall); 
mean (SD), n 
 
 
 
 
 
 
 
 
 
Delay 
discounting; 
mean (SD), n 
 
 
 
 
 
 
 
 
 
Response 
inhibition (Stop 
Signal Reaction 
time); mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Working 
memory; mean 
(SD), n 
 
 
 
 
 
 
 
 
 
Hippocampal 
functioning 
(Pattern 
Recognition 
Test);  mean 
(SD), n 
 
 
 
 
 
 
 
 
 


KARE Statistical analysis plan v. 1.2, 11/03/2020 
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Adverse effects 
(visual analogue 
scale); mean 
(SD), n 
 
 
 
 
 
 
 
 
 
PE: Psychoeducation 
PT: Psychotherapy