Clinical trial NCT02661061
Conditions: Depression Relapse Recurrent Depressive Disorder Major Depressive Disorder
Keywords: ketamine glutamate relapse prevention
Sponsor: St Patrick's Hospital, Ireland
Start date: 2015-12-01; Completion date: 2018-05-23
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. midazolam for depression relapse prevention in persons at high risk. The main purpose of the pilot study is to assess trial processes to help inform a future definitive trial.

Detailed description:
Participants will be recruited at admission to St Patrick's University Hospital for treatment of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)-diagnosed recurrent unipolar depression and followed-up weekly to assess recovery according to standard criteria. Blood samples for epigenetic studies will be taken at baseline. Treatment-as-usual will continue throughout the entire trial. Participants who meet standardised response criteria will then be invited to be randomised to course of four two-weekly ketamine or midazolam (active comparator) infusions. Block randomisation will be independently performed. Physical, psychotomimetic and cognitive outcomes will be monitored before, during and after infusions. Blood samples will be taken at four time-points in the first infusion session and before the final infusion for neuroplasticity biomarker studies.Trial Interventions: participants will receive four two-weekly infusions of either ketamine at 0.05mg/kg or midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Repeated infusions of ketamine have been shown to be safe and well-tolerated by patients with mental illness. Minor haemodynamic changes and psychotomimetic side-effects can occur and will be assessed regularly during infusions and for 200 minutes afterwards.

Participants will be followed up over six months to assess for relapse according to standardised criteria. This is the highest-risk period for relapse and investigators hypothesize that ketamine will provide additional neurotrophic support (assessed by the laboratory biomarker project) which will result in lower relapse rates when compared to midazolam.

Arms: arm 1: Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. arm 2: Trial Interventions: participants will receive four two-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist.
Interventions: intervention 1: Ketamine intervention 2: Midazolam
Intervention descriptions: intervention 1: A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart. intervention 2: A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.

Protocol documents:
Prot_SAP_000.pdf: 
 
Clinical Trial Protocol  
 
 
1 
INFORMATION ON CLINICAL TRIAL PROTOCOL  
 
This protocol has been designed for a clinical trial subject to the European Communities (Clinical 
trials on Medicinal Products for Human Use) Regulations, 2004 (S.I. No 190 of 2004), as 
amended.  
 
 
2 
STUDY TITLE 
 
Ketamine for relapse prevention IN recurrent DepREssive Disorder: a randomised, 
controlled pilot trial with blood biomarker evaluation: The KINDRED Trial  
 
3 
STUDY SPONSOR 
 
St Patrick’s Mental Health Services as represented by the Medical Director, Prof. James Lucey 
 
 
4 
APPLICATION DETAILS 
 
4.1 Study title 
Ketamine for relapse prevention in recurrent depressive disorder: a randomised, 
controlled pilot trial 
4.2 Reference numbers 
Protocol identification (code or reference number): SPMHS Ref: 20/15 
 
EudraCT number: 2015-002020-37 
 
 
 
 
 
Date and version number: Version 3.0, as approved by the Research Ethics Committee of the 
Mater Misericordiae Hospitals on 15.9.16 
 
 
4.3 Applicant details 
4.4  
Principal Investigator  
Name(s)/ titles: Professor Declan McLoughlin, Research Professor of Psychiatry 
 
Contact details: 
Dept of Psychiatry, St Patrick’s University Hospital, James’ Street, Dublin 8 
T: 01 2493385  
E: d.mcloughlin@tcd.ie 
 
Sponsor 
Name:  St Patrick’s Mental Health Services as represented by the Medical Director, Prof. James 
Lucey 
 
Contact details: 
Office of the Medical Director, St Patrick’s University Hospital, James’ Street, Dublin 8 
E: jbraddock@stpatsmail.com 


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Clinical Trial Protocol | KINDRED Trial | Version 3.0 
 
Funder : Medical Research Charities Group - Health Research Board Joint Funding Scheme 
2016 "HRB-MRCG Joint Funding Scheme 2016 Contracts_MRCG-2016-23"   
Name: Ailbhe Lamont, Health Research Board  
Contact details: alamont@hrb.ie 
4.5 Signatures 
 
PRINCIPAL INVESTIGATOR, PROF. DECLAN MCLOUGHLIN 
Research Professor of Psychiatry 
 
 
 
Date:  
 
SPONSOR’S REPRESENTATIVE , PROF JAMES LUCEY 
Medical Director, St Patrick’s Mental Health Services  
 
 
 
 
Date: 
4.6 Other relevant information 
 
Contact details, Centre for Support and Training in Analysis and Research  
The School of Public Health, Physiotherapy and Population Science,  
Woodview House, University College Dublin, Belfield, Dublin 4. 
T: +353 (0)1 716 2076 
F: +353 (0)1 716 3421 
E: cstar@ucd.ie 
 
 
 
5 
CONFIDENTIALITY STATEMENT 
 
This document contains confidential information that must not be disclosed to anyone other 
than the sponsor, the investigative team, regulatory authorities, and members of the Research 
Ethics Committee. 
 
 
 
 


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Clinical Trial Protocol | KINDRED Trial | Version 3.0 
6 
TABLE OF CONTENTS 
 
7 
DOCUMENT HISTORY 
4 
8 
SYNOPSIS 
4 
9 
ABBREVIATIONS 
6 
10 
INTRODUCTION 
8 
11 
STUDY OBJECTIVE 
12 
12 
TRIAL DESIGN 
13 
13 
TREATMENT OF TRIAL SUBJECTS 
25 
14 
SAFETY REPORTING 
28 
15 
STATISTICS 
32 
16 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
35 
17 
DATA HANDLING AND RECORD KEEPING 
35 
18 
RETENTION OF ESSENTIAL DOCUMENTS 
36 
19 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
36 
20 
AUDITS AND INSPECTIONS 
37 
21 
ETHICS 
37 
22 
FINANCING AND INSURANCE/INDEMNITY 
39 
23 
CLINICAL STUDY REPORT AND PUBLICATION POLICY 
39 
24 
REFERENCES 
39 
 
 
 
 


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Clinical Trial Protocol | KINDRED Trial | Version 3.0 
7 
DOCUMENT HISTORY 
 
Document 
Date of Issue 
Summary of Change 
Original protocol 
Version 2.0 
Version 2.1  
 
 
Version 3.0 
19.5.15 
18.7.15 
24.8.15 
 
 
Approved by REC on 15.9.16 
Not applicable 
Addition of information 
regarding traffic law 
Addition of Childhood 
Trauma Questionnaire 
Change in eligibility criterion:  
“Meet DSM-V criteria for 
recurrent depressive disorder 
(RDD): ≥2 previous 
depressive episodes with at 
least 2-months(consecutive) 
subthreshold or no 
symptoms in between PLUS 
must also have experienced 
≥3 major depressive 
episodes (including index 
episode) within the previous 
2 years.” 
  
to   
“Meet DSM-V criteria for 
recurrent depressive disorder 
(RDD): ≥2 previous 
depressive episodes with at 
least 2-months (consecutive) 
subthreshold or no 
symptoms in between.” 
 
 
 
8 
SYNOPSIS 
 
Title of study 
Ketamine for relapse prevention in recurrent depressive disorder: a 
randomised, 
controlled pilot trial 
Name of 
sponsor/company 
St Patrick’s Mental Health Services as represented by the Medical 
Director, Prof. James Lucey 
Phase of 
development 
Feasibility study for Phase II Trial  
Objectives 
The overall aim is to assess ketamine for depression relapse prevention. 
Objective 1: To conduct a randomised controlled patient- and rater-
blinded pilot trial of two-weekly ketamine vs. midazolam over eight-
weeks for reducing relapse during the six-months following successful 
treatment of depression in people with RDD. 
Objective 2: To assess safety and tolerability of repeated (x4) infusions 
of ketamine vs. midazolam in this RDD population. 


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Objective 3: To explore the role of ketamine-induced changes in 
peripheral blood neuroplasticity molecules for: (i) monitoring biological 
response to ketamine during the first infusion and (ii) for evaluating this 
biological response in predicting lower relapse rates over six-months. 
Objective 4: To investigate epigenetic modulation of depression/stress-
related genes in patients with recurrent depression receiving inpatient 
treatment 
Trial design 
Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. 
midazolam for depression relapse prevention in persons at high risk. The 
main purpose of the pilot study is to assess trial processes to help inform 
a future definitive trial. 
Participants will be recruited at admission to St Patrick’s University 
Hospital for treatment of DSM-IV-diagnosed recurrent unipolar 
depression and followed-up weekly to assess recovery according to 
standard criteria. Blood samples for epigenetic studies will be taken at 
baseline. Treatment-as-usual will continue throughout the entire trial. 
Participants who meet standardised response criteria will then be invited 
to be randomised to course of four two-weekly ketamine or midazolam 
(active comparator) infusions. Block randomisation will be independently 
performed. Physical, psychotomimetic and cognitive outcomes will be 
monitored before, during and after infusions. Blood samples will be 
taken at four time-points in the first infusion session and before the final 
infusion for neuroplasticity biomarker studies. 
Trial Interventions: participants will receive four two-weekly infusions of 
either ketamine at 0.05mg/Kg or midazolam at 0.045mg/Kg. All infusions 
will be administered by a consultant anaesthetist. Repeated infusions of 
ketamine have been shown to be safe and well-tolerated by patients 
with mental illness. Minor haemodynamic changes and psychotomimetic 
side-effects can occur and will be assessed regularly during infusions and 
for 200 minutes afterwards. 
Participants will be followed up over six months to assess for relapse 
according to standardised criteria. This is the highest-risk period for 
relapse and I hypothesise that ketamine will provide additional 
neurotrophic support (assessed by the laboratory biomarker project) 
which will result in lower relapse rates when compared to midazolam. 
Key inclusion 
criteria 
 
≥18 years old 
 
HRSD-24 score of ≥21 
 
Voluntary admission for treatment of acute depressive episode 
 
Meet DSM-V criteria for recurrent depressive disorder (RDD): ≥2 
previous depressive episodes with at least 2-
months(consecutive) subthreshold or no symptoms in between 
 
For the randomised pilot trial, RDD patients must have: 
 
received antidepressant treatment for the acute depressive 
episode(pharmacological, psychotherapeutic or 
multidisciplinary) 
 
≥60% decrease from baseline HRSD-24 score and score ≤16 
 
Mini-Mental State Examination (MMSE) score of ≥24 
 
(v) able to provide informed consent 


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Clinical Trial Protocol | KINDRED Trial | Version 3.0 
Key exclusion 
criteria 
 
Current involuntary admission 
 
Medical condition rendering unfit for ketamine/midazolam 
 
Active suicidal intention 
 
Dementia 
 
History of Axis 1 diagnosis other than RDD 
 
ECT for treatment of index depressive episode 
 
Alcohol/substance abuse in previous six-months 
 
Pregnancy or inability to confirm use of adequate contraception 
during the trial 
Number of 
subjects 
N=98 to be recruited upon admission, expecting that at least n=51 will 
meet response criteria and that n=40 will consent to be randomised. This 
provides a sample size of n=20 per group 
Test product, 
dose and mode of 
administration 
Investigational Medicinal Product: Ketamine: Ketalar 10mg/ml 
Solution for Injection/Infusion, Pfizer Ireland 
Active comparator: Midazolam: Hypnovel 10mg/5ml solution for 
injection, Roche Pharmaceuticals Ireland 
 
Both made up as 50 ml colourless saline solutions and administered over 
40-minutes using a syringe driver pump, in an eight-week course of four 
infusions 
Duration of 
treatment 
Eight weeks  
Statistical 
methods 
Data analyses will be performed blinded to allocation by Prof Daly in the 
Centre for Support and Training in Analysis and Research (CSTAR). Pilot 
trial data will be analysed on an intention-to-treat basis for all patients 
who completed at least one infusion. Descriptive statistics will be used to 
report process outcomes. Relapse-free survival times will be compared 
between groups using Kaplan-Meier survival curves and log-rank test. 
Cox proportional hazard regression analysis will provide a 95% 
confidence interval for a hazard ratio for ketamine versus midazolam 
groups. These data will inform a future definitive trial 
Sample size 
We wish to recruit 20 patients per group, a total of 40, an acceptable 
number for the purposes of a pilot trial. A formal sample size calculation 
is not appropriate as per the Medical Research Council Guidelines. 
Response rates to inpatient depression treatment are approximately 
80%. However, as this is a heterogeneous sample with RDD, we expect 
response rates to be lower at 50-60%. Allowing for a 15% drop-out rate, 
We seek to recruit 98 patients upon admission, expecting that at least 
n=51 will meet response criteria and that n=40 will consent to be 
randomised. Prof McLoughlin’s team recently finished recruiting severely 
depressed inpatients (n=140) to an RCT of ECT at St Patrick’s University 
Hospital (see http://www.controlled-trials.com/isrctn/pf/23577151 ). 60 
patients were recruited in the first 16 months. As the proposed study is 
less intensive, with the attraction of an additional therapy and a wider 
cohort to recruit from, I expect the recruitment rate to be higher and to 
be able to recruit 98 participants to the pilot trial within 16 months. 
 
 
9 
ABBREVIATIONS 


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ACE-R  Addenbrooke’s Cognitive Examination, Revised 
AE  
Adverse event 
Akt  
Ak-Thyoma/Protein Kinase B 
AR  
Adverse reaction 
BDNF 
 Brain Derived Neurotrophic Factor 
BPRS  Brief Psychiatric Rating Scale 
CA  
Competent authority 
CADSS  Clinician-Administered Dissociative States Scale 
CRA  
Clinical research associate 
CRF  
Case report form 
CRO  
Contract research organisation 
CSTAR  Centre for Support and Training in Analysis and Research, University College Dublin 
CT  
Clinical trial 
CTA  
Clinical trial authorisation 
CXR  
Chest x-ray 
DNA  
Deoxyribonucleic Acid 
DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG  
Electrocardiogram 
ECT  
Electroconvulsive therapy 
eEF-2  Eukaryotic elongation factor 2 
EHQ  
Edinburgh Handedness Questionnaire 
EU  
European Union 
e-CRF  Electronic case report form 
FBDS  Forward and Backward Digit Spans 
GCP  
Good Clinical Practice 
GP  
General Practitioner 
GSK-3  Glycogen Synthase Kinase 3 
HRSD-24 Hamilton Depression Rating Scale, 24-item version 
HPRA  Health Products Regulatory Authority  
HSE  
Health Service Executive 
IB  
Investigator’s brochure 
ICF  
Informed consent form 
ICH  
International Conference on Harmonisation 
IMP  
Investigational medicinal products 
IMPD  Investigational medicinal product dossier 
LMP  
(Date of) Last Menstrual Period 
MDD  Major depressive disorder 
MMSE  Mini Mental State Exam 
MSTRD Maudsley Staging for Treatment-Resistant Depression 
mTOR  Mammalian target of Rapamycin 
NART 
National Adult Reading Test 
NMDA  N-methyl-D-aspartate 
NOK  
Next of kin 
PBMC  Peripheral Blood Mononuclear Cells 
PBS 
 Phosphate Buffered Saline 
PI  
Principal Investigator (Refers to Prof. Declan McLoughlin) 
PIL  
Patient/subject information leaflet 
PRISE  Patient-Rated Inventory of Side Effects 


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QIDS-SR 16 Quick Inventory of Depressive Symptoms, Self-Report, 16-item 
RA  
Nominated Responsible Adult 
RDD 
Recurrent Depressive Disorder 
REC  
Research ethics committee 
ROI  
Republic of Ireland 
SAE  
Serious adverse event 
SAR  
Serious adverse reaction 
SCID  
Structured Clinical Interview for DSM-IV Axis I Disorders 
SmPC  Summary of product characteristics 
SOP  
Standard operating procedure 
SPUH  St. Patrick’s University Hospital 
SUSAR Suspected unexpected serious adverse reaction 
TCIN  
Trinity College Institute of Neuroscience   
YMRS  Young Mania Rating Scale 
 
10 INTRODUCTION 
 
10.1 
Background information 
 
DEPRESSION AND RELAPSE  
Depression is projected to become the second greatest cause of disability worldwide by 2020. 
According to the Irish mental health charity Aware, over 300,000 people in Ireland experience 
depression at any time (http://www.aware.ie/help/information/information-on-depression ). It is 
the most costly brain disorder in Europe, accounting for 1% (€118 billion annually) of the total 
European economy2. Indeed, depression is currently the second largest cause globally for years 
lived with disability1. It is thus a public health priority, additionally so in Ireland with worryingly 
high suicide rates (see http://nsrf.ie/wp-content/uploads/reports/SSISReport2013.pdf ). 
One of the major reasons for the social and economic costs of depression is that it can be a 
chronic disorder. Over 50% of people who experience one depressive episode will have further 
episodes, with on average 5-9 episodes in their lifetime3. Even following successful 
antidepressant therapy for an acute episode, relapse rates are high, ranging 40-70%4. The first 
six months after remission represent the highest-risk period, with an average time to relapse of 
3.5 months 3. Much of the burden of depression is therefore contributed to by its relapsing 
nature.  
 
RELAPSE PREVENTION 
It is well established that continuation treatment with antidepressants reduces the odds of 
relapse by 70%, independent of the underlying risk of relapse.5 Nonetheless, relapse rates within 
six months are still too high at 40-70%.6 A major challenge now is how best to prevent relapse 
after successful treatment of depression. However, remarkably, the evidence base for relapse 
prevention is small.  For example, the National Institute for Health and care Excellence (NICE) in 
the UK have identified that evidence on relapse prevention in depression is limited and 
recommended research in this area8 (and https://www.nice.org.uk/guidance/cg90/chapter/4-
research-recommendations  ). To date, the reported randomised controlled trials for relapse 
prevention following successful antidepressant therapy have focused on the effect of 12 
months’ tricyclic or SSRI antidepressant therapy, showing consistent but limited reduction in 
relapse rates as above.7 
 
Ongoing registered trials of relapse prevention in depression (http://www.controlled-
trials.com/isrctn  and http://clinicaltrials.gov ) focus on psychological or internet-based 


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Clinical Trial Protocol | KINDRED Trial | Version 3.0 
interventions.  Interestingly, there are no currently registered trials of pharmacological 
treatments for relapse prevention. This possibly reflects a lack of industrial interest in this 
important, but difficult, area. There is clearly a need for other, potentially better, methods for 
relapse prevention.  One such possibility is the anaesthetic/analgesic ketamine. 
 
KETAMINE AND DEPRESSION  
Ketamine is a competitive glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist with a 
half-life of 2-3 hours.  Ketamine has a remarkably rapid antidepressant effect,9,10 targeting core 
symptoms in treatment-resistant depression when given as single sub-anaesthetic doses 
(usually a 40 minute 0.5 mg/kg intravenous infusion). 11 It is psychotomimetic (with abuse 
potential) but at low dosage it is safe.9;10;11;12 Only 1.45% of sub-anaesthetic infusions in patients 
and healthy controls have been reported to cause mild dissociative and psychotic symptoms 
that resolve soon after finishing infusions.13,14 To control for these effects, and also avoid “carry-
over” effects in crossover studies while improving blinding, midazolam is now being used as an 
active control in parallel-group design trials rather than inactive placebo saline.11 Thereafter 
robust antidepressant effects (average four-hour response rate of 77%) 9 occur and can persist 
for a few days, i.e. beyond immediate NMDAR blockade. Chronic, mostly recreational, high-dose 
ketamine use can cause uropathy and dependency15. However, repeated (e.g. 2-3/week for two 
weeks) infusions of sub-anaesthetic ketamine are safe with more sustained antidepressant 
effects in both antidepressant-free and ongoing-treated patients.9 
Together, these findings have led to the most exciting development in treating and 
understanding depression in over 50 years and represent a paradigm shift away from 
conventional slow-acting monaminergic antidepressants.10 Preclinical studies have shown that 
within just two hours ketamine increases synaptogenesis and spine formation in rodent 
prefrontal cortex and rapidly reverses chronic stress-induced depressive behaviours and 
prefrontal neuronal atrophy.16 These effects are mediated, at least in part, via Akt/GSK-
3/mammalian target of rapamycin (mTOR) signalling and increased dendritic translation of 
synaptic proteins 17as well as deactivation of eukaryotic elongation factor 2 (eEF2) kinase, 
resulting in de-suppression of brain-derived neurotrophic factor (BDNF) translation.18 BDNF 
mediates synaptic plasticity and is implicated in mechanisms of antidepressants.18,19 
Interestingly, a lesser response to ketamine was found in low-activity Met BDNF Val66Met 
polymorphism carriers while increased plasma BDNF was detectable in responders compared to 
non-responders four hours post-infusion18 though this hasn’t been found in all studies.   
Changes in blood mononuclear cell levels of phosphorylated mTOR, eEF2 and GSK-3β have also 
been associated with response to ketamine 20;21 suggesting potential as biomarkers for 
response. 
The PI and team has started a HRB-funded pilot trial of ketamine for depression relapse 
prevention following electroconvulsive therapy (EudraCT number 2014-004262-14; and 
NCT02414932 at www.clinicaltrials.gov ). However, no other trials are currently registered or 
reported using ketamine as an adjunctive treatment to reduce relapse rates following successful 
depression treatment - an important potential use of ketamine that this proposal addresses.   
 
KETAMINE-ASSOCIATED BIOMARKERS 
Ketamine causes acute neurotrophic effects which may result in more sustained positive clinical 
effects. Potential biomarkers to investigate ketamine in the novel role of relapse prevention are 
therefore molecules that have been associated with both neuroplasticity and ketamine’s 
antidepressant effects. Based upon the above findings, the most appropriate biomarkers for 
initial evaluation include neuroplasticity markers, i.e. BDNF as well as phosphorylated species of 
mTOR, eEF2 and GSK-3β. Additionally, several meta–analyses have established that both serum 


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and plasma BDNF are reduced in major depression and rise to normal levels with effective 
antidepressant treatment. 
 
EPIGENETICS AND DEPRESSION 
Epigenetics refers to control mechanisms that work alongside DNA sequences, altering their 
activity without changing the sequence itself. Recent research shows that depressed patients 
have a different epigenetic profile compared with control subjects. 39,40 We will examine 
epigenetic modulation of depression/stress-related genes (e.g. BDNF, FKBP5) in our sample of 
inpatients with recurrent depressive disorder. Epigenetic modifications that will be examined 
may include DNA methylation, which involves the addition of a methyl group at the promoter 
region of a gene’s DNA sequence. This modification usually suppresses gene expression and 
may be measured by pyrosequencing41 a DNA sequencing technique that identifies methylated 
DNA nucleotide bases. A second type of epigenetic modification that may be measured is 
chromatin activation status. To allow the storage of condensed information within the nucleus, 
DNA is stored in the form of chromatin. Active, open chromatin promotes gene expression while 
chromatin in its closed state suppresses gene expression. Chromatin activation status can be 
analysed using a technique called chromatin immunoprecipition42 whereby genomic DNA 
associated with chromatin in its open or closed state can be precipitated with targeted 
antibodies and analysed by quantitative PCR. Small non-protein coding RNA molecules known 
as microRNAs (miRNA)that also act as epigenetic modulators of gene expression, by 
suppressing messenger RNA translation to protein, may be measured using reverse transcription 
PCR. The downstream changes modulated by these epigenetic changes can be examined by 
measuring messenger RNA (mRNA) and protein products of the genes involved. Examining such 
epigenetic modulations may provide insight into the pathogenesis of depression. 
 
OUTCOMES, OUTPUTS AND TIMESCALE 
 
The purpose of this research programme is to conduct a randomised pilot trial of 
ketamine for relapse prevention in depression and refine molecular biomarkers for ketamine 
response. Outcomes of the proposed study will include: knowledge gained from the pilot trial to 
inform a future randomised controlled trial; safety and tolerability data on ketamine in this novel 
treatment group; and the utility of neuroplasticity biomarkers in the relapse-prevention 
response to ketamine. This proposal addresses the Irish Government’s 2012 Research 
Prioritisation exercise regarding the Platform Science and Technology Area “Basic Biomedical 
Science”, with relevance to the "Diagnostics" Priority Area 
(http://www.forfas.ie/media/ffs20120301-Research_Prioritisation_Exercise_Report.pdf ).  
Additionally, the proposal fits in well with Trinity College Dublin’s major research theme of 
“Neuroscience” as identified in its most recent Strategic Plan 2014-2019 
(https://www.tcd.ie/strategy/ ). 
 
This study has the potential to directly impact on clinical practice by testing a novel 
therapeutic strategy in a unique population with a major unmet clinical need. Developing a truly 
new therapy for depression relapse prevention will improve quality of life for patients and their 
families, inform health services’ treatment guidelines, raise public awareness of mental health, 
and could have a positive socioeconomic impact in Ireland and abroad. 
 
10.2 
Rationale for the study 
 
INVESTIGATIONAL MEDICINAL PRODUCTS 
 


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Ketamine (ketamine hydrochloride 0.5 mg/kg; Pfizer Healthcare Ireland) and midazolam (0.045 
mg/kg; Roche Products Ireland Ltd) will be made up as 50 ml colourless saline solutions and 
administered over 40-minutes using a syringe driver pump, in an eight-week course of four 
infusions. The optimal dosing regimen for a study such as this has not been established, 
however it is known that repeated sub-anaesthetic doses of ketamine are well-tolerated by a 
psychiatric population. The dosing schedule of four two-weekly infusions over a total of eight 
weeks was chosen as there is evidence that ketamine’s effects last up to 14 days. It is 
hypothesised that a course of ketamine infusions over this schedule may provide additional 
neurotrophic support which would reduce relapse rates when compared with the active 
comparator, midazolam.  Midazolam was chosen as an active comparator based on other 
studies as it results in similar acute effects as ketamine at sub anaesthetic doses 27,28.  
 
RISKS AND BENEFITS 
 
Physical:  
 
(i) Phlebotomy-Related Risks and Hazards:  
Serious adverse effects of phlebotomy are rare, but may include loss of consciousness with 
seizures. Injury to adjacent anatomical structures is rare and vasovagal attacks may occur 
occasionally. Bruising and haematoma may occur in up to 12.3% of subjects (WHO, 2010).In this 
study, phlebotomy will only be performed by experienced doctors and St Patrick’s University 
Hospital protocol on phlebotomy will be strictly adhered to. All efforts will be made to reduce 
the likelihood of any adverse events due to phlebotomy; however, discomfort during the 
procedure is common.  
Classification: Transient to serious.  
Probability: Serious adverse effect=Rare, Transient adverse effect=Common.  
 
(ii) Risks and Hazards associated with Ketamine: for more detail please see Appendix: 
investigator’s brochure. Ketamine is psychotomimetic (with abuse potential) but is safe at low 
dosage, with patients and healthy controls experiencing mild dissociative and psychotic 
symptoms (which can be unpleasant) that resolve soon after finishing infusions. In sub 
anaesthetic doses, ketamine is a safe drug but can cause transient rises in pulse and blood 
pressure during infusion and for up to 80 minutes afterward. Thus monitoring procedures will be 
followed as per “interventions” in this trial protocol. A recent review of ketamine in depression 
concluded that outside recreational usage, there have been no reports of persistent adverse 
effects with sub anaesthetic uses of ketamine.  
 
(iv) Risks and Hazards associated with Midazolam: for more detail please see Appendix: 
investigator’s brochure. Midazolam has recently been used as an active comparator to ketamine 
in parallel-group design trials as it mimics some of the effects of ketamine and may improve 
blinding over inactive placebo saline. At sub anaesthetic doses there have been no reported 
serious adverse events. However transient physical symptoms can occur during infusions, 
including minor lowering of blood pressure. The monitoring procedures detailed in 
“interventions” have been put in place to ensure possible harm is minimised. Infusions will be 
administered by an experienced consultant anaesthetist with assistance from researchers in a 
facility equipped for general anaesthesia and resuscitation.  
Classification: Transient to serious.  
Probability: Serious adverse effect=Rare. Non-serious adverse effect=Unlikely.  
Transient adverse effect=Common.  


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(v) Risks and hazards associated with peripheral venous cannulation and intravenous 
administration of investigative medicinal products: 
Complications that can arise following the procedure of cannulation include infiltration, 
extravasation, venous spasm, phlebitis, thrombophlebitis, haematoma, nerve injury, arterial 
puncture, embolism and needle stick injury (HSE, 2013). In this study, peripheral venous 
cannulation will be performed by a consultant anaesthetist using aseptic technique and in 
accordance with the local venous cannulation policy. Cannulae will be used for a 40-minute 
infusion and removed 30 minutes prior to discharge from the infusion clinic. The cannulation 
site will be monitored during the infusion and regularly for 200 minutes thereafter. Discomfort is 
common during the insertion of a peripheral venous cannula, however every effort will be made 
to minimise pain or discomfort, including the use of topical anaesthetics where indicated.  
Classification: Transient to serious.  
Probability: Serious adverse effect=Rare, Transient adverse effect=Common.  
 
2. Psychological:  
 
(i) Distress: Some participants may find questionnaires distressing or anxiety-provoking, or the 
experience may change the way they view or manage their illness. This is difficult to predict, 
however researchers will be vigilant for possible negative psychological effects and seek to 
minimise these wherever possible. In the case of patients, where distress is noted, this will be 
brought to the attention of the treating team.  
Classification: Transient.  Probability: Unknown 
 
3. Psychosocial:  
 
(i) Inconvenience: Attending for assessments or interventions may cause inconvenience to 
participants. We will seek to minimise lifestyle inconvenience by keeping assessments concise, 
accommodating participants on return visits to the hospital for non-trial-related appointments 
where possible, or telephone/home assessments as necessary and reimbursing participants for 
travel and meal expenses where applicable.  
Classification: Transient. Probability: Common. 
  
11 STUDY OBJECTIVE 
 
The overall aim is to assess the feasibility of this study of ketamine for depression relapse 
prevention, to inform a future definitive trial. 
  
11.1 
Primary objective 
 
Objective 1: To conduct a randomised controlled patient- and rater-blinded pilot trial of two-
weekly ketamine vs. midazolam over eight-weeks for reducing relapse during the six-months 
following successful treatment of depression in people with RDD. 
 
11.2 
Secondary objective 
 
Objective 2: To assess safety and tolerability of repeated (x4) infusions of ketamine vs. 
midazolam in this RDD population. 
 


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11.3 
Exploratory objectives 
 
Objective 3: To explore the role of ketamine-induced changes in peripheral blood 
neuroplasticity molecules for: (i) monitoring biological response to ketamine during the first 
infusion and (ii) for evaluating this biological response in predicting lower relapse rates over six-
months. 
 
Objective 4: To investigate epigenetic modulation of depression/stress-related genes in 
patients with recurrent depression receiving inpatient treatment 
 
 
11.4 
Primary and secondary outcome measures 
 
The primary outcomes for this pilot trial are process outcomes to inform a future definitive 
trial22, e.g. completion of assessments; success of blinding. Although some attrition can be 
expected during the six-month follow-up period, information collected on rates and reasons for 
drop-out will form a valuable feasibility outcome. Non-compliance is not expected due to 
intravenous administration of agents. 
 
Clinical outcomes are secondary. The primary clinical outcome is relapse rate at six months, 
measured using the objectively-rated 24-item Hamilton Rating Scale for Depression (HRSD-
24)25. Standard criteria for depression severity, treatment response, remission and relapse will be 
used (please see definitions in “assessments”) in a six-month follow-up schedule which involves 
the HRSD-24 and other instruments at weeks 12, 20 and 26 post-treatment-response. Safety 
and tolerability outcomes consist of psychotomimetic, dissociative, cognitive and physical health 
effects of repeated ketamine infusions, measured before, during and after infusions using a 
range of validated instruments. Outcomes in the biomarker study are changes in blood levels of 
molecules including total Shank3 and phosphorylated and total BDNF, pMTOR, pGSK3β and 
peEF2 in response to the first ketamine/midazolam infusion following immunoassays performed 
on blood samples collected at time points -60, +40, +120 and +240 minutes, and a final sample 
before the fourth infusion. Outcomes in the epigenetics study are e.g. DNA methylation and 
chromatin activation status.  
 
12 TRIAL DESIGN 
 
12.1 
General considerations 
 
This single-site, randomised, controlled, parallel-group pilot trial 23will take place at St Patrick’s 
University Hospital.  
 


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12.2 
Selection of study population 
 
12.2.1 Overall description of trial subjects 
 
Trial participants will be people who have been admitted to St Patrick’s University Hospital for 
treatment of depression and who have a history of recurrent depressive disorder.  
 
12.2.2 Inclusion criteria 
 
- ≥18 years old 
- HRSD-24 score of ≥21 
- Voluntary admission for treatment of acute depressive episode 
- Meet DSM-V criteria for recurrent depressive disorder (RDD): ≥2 previous depressive 
episodes with at least 2-months(consecutive) subthreshold or no symptoms in between 
 
For the randomised pilot trial, RDD patients must have: 
- received antidepressant treatment for the acute depressive episode(pharmacological, 
psychotherapeutic or multidisciplinary) 
- ≥60% decrease from baseline HRSD-24 score and score ≤16 
- Mini-Mental State Examination (MMSE) score of ≥24 
- able to provide informed consent 


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To be eligible for inclusion, each subject must meet each of the following criteria at Screening 
and must continue to fulfil these criteria at Baseline.   
 
12.2.3 Exclusion criteria 
All candidates meeting any of the exclusion criteria at screening/ baseline will be excluded from 
study participation.  
 
Subjects are excluded from the study if any of the following criteria are met at Screening or at 
Baseline: 
 
(i) 
Current involuntary admission 
(ii) 
Medical condition rendering unfit for ketamine/midazolam 
(iii) 
Active suicidal intention 
(iv) 
Dementia 
(v) 
History of Axis 1 diagnosis other than RDD 
(vi) 
ECT for treatment of index depressive episode 
(vii) 
Alcohol/substance abuse in previous six-months 
(viii) 
Pregnancy or inability to confirm use of adequate contraception during the trial 
 
12.3 
Study assessments and procedures 
 
 


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The following windows constitute a protocol violation:  


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(i) 
Recruitment more than four days after admission 
(ii) 
First infusion clinic more than two weeks after discharge 
(iii) 
Any more than four infusions 
(iv) 
Infusions taking place less than two weeks apart 
(v) 
Any more than five follow-up assessments  
(vi) 
Final follow-up assessment taking place more than seven months after discharge  
 
Informed consent will be obtained prior to any study-related procedures being undertaken . 
  
12.3.1 Description of Study Assessments 
 
Medical and Surgical History  
Details of current and previous diagnoses and treatments will be recorded.  
 
Demographics  
The date of birth, gender and race will be recorded.  
 
Vital Signs  
Vital signs will not be recorded for the purposes of the trial outside of infusion clinics.  
During infusion clinics participants’ heart rate, pulse oximetry and blood pressure will be 
monitored before and during infusions and for a further 200 minutes.  
 
ECG Test  
A 12-lead ECG will be examined by the investigator at screening. ECG monitoring will be 
performed for all participants at infusion sessions, before and after administration of the IMP.  
Abnormal findings will be noted for clinical significance, and the report will be signed by the 
investigator.  
 
Clinical Laboratory Tests  
Clinical laboratory tests will not be performed as part of this trial. All participants will have had 
recent laboratory investigations (FBC, UE, LFT, TFT) at admission, and these will be examined by 
a researcher at screening and also by the anaesthetist prior to the first infusion clinic.  
 
Pregnancy Tests  
Women of child-bearing potential who participate in the study are requested to inform 
researchers if there is any possibility they may be pregnant. At this point, urine pregnancy test 
may be performed with consent. Date of last menstrual period (LMP) will be documented at the 
first infusion clinic. Information relating to the importance of contraception during the trial is 
provided in the Participant Information Sheet.  
 
Concomitant Medication and other therapies   
All over-the-counter or prescription medication, vitamins, and/or herbal supplements will be 
recorded on CRFs. The indication for treatments will be recorded. Contraindicated medications 
are listed in this Protocol. The Maudsley Staging Method for Treatment-Resistant Depression 
(MSTRD) will be used as a measure of treatment resistance in participants at admission baseline 
and prior to the first infusion clinic, and repeated at each infusion clinic and follow-up session.  
 
Cognitive Assessments  


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Cognitive measures including Addenbrooke’s Cognitive Examination- Revised (ACE-R)34; Digit 
Spans 35; Trails A and B 36 will be performed at baseline and end-of-inpatient-treatment, and at 
baseline and final infusion session, as well as at final follow-up at week 26. Parallel versions will 
be used where available37. These validated cognitive measures will be performed and scored by 
trained researchers, and have been chosen as each assesses an important aspect of cognition.  
 
Psychiatric Assessments  
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID)24 will be performed once by 
trained researchers at baseline assessment. SCID is a structured interview which is diagnostic for 
disorders in DSM-IV and will be used in this study to confirm a diagnosis of recurrent depressive 
disorder.  
 
Childhood Trauma Questionnaire  
Childhood Trauma Questionnaire (CTQ) is a validated measure to assess for adverse early life 
events and will be completed once at baseline assessment.  
 
Hamilton Depression Rating Scale, 24-item (HRSD-24)25,26 
A validated depression rating measure which will be performed on a repeated basis by trained 
researchers at various points throughout the trial as a measure of depressive symptomatology 
and response to treatment.  
 
Quick Inventory of Depressive Symptoms, self-report version (QIDS-SR) 39 
A validated self-report measure of depressive symptoms. It is best practice to include both self- 
and clinician-rated measures of depressive symptoms to assess treatment response in 
depression.  
 
National Adult Reading Test 33 
National Adult Reading Test (NART) is a measure of premorbid intelligence relative to expected 
intelligence (i.e. NART assesses IQ) and will be performed once at baseline assessment.  
 
Side Effect Measures  
During infusion sessions, adverse or psychotomimetic effects of either ketamine or midazolam 
will be monitored using validated scales comprising: Clinician-Administered Dissociative States 
Scale (CADSS)30, Brief Psychiatric Rating Scale (BPRS)31, Young Mania Rating Scale 32, and 
Patient-Rated Inventory of Side Effects (PRISE), administered before, during and after infusions 
in order to capture the range of possible subjective and objective side effects of either agent 
 
Neuroplasticity Biomarkers  
At the first infusion session, changes in blood levels of markers including BDNF, pMTOR, 
pGSK3beta and peEF2 in response to the ketamine/midazolam will be compared at time points -
60, +40, +120 and +240 minutes. A final sample will be taken prior to the fourth and final 
infusion clinics to assess for the possibility of a sustained response over the course of repeated 
infusions. Blood samples will be collected using EDTA vacutainer tubes and centrifuged to 
generate plasma that will be aliquoted and stored at -80oC. BDNF levels will be determined 
using ELISA (ChemiKine, USA) following the manufacturer’s instructions. PBMCs will be collected, 
pelleted and stored at -80oC as described above. Semi-quantitative immunoblotting of PBMC 
lysates will be used to measure changes in levels of the other ketamine-induced proteins using 
antibodies against activated mTOR phosphorylated at serine residue 2448 (AbCam, USA), 
inhibitory serine-9 phosphorylated GSK-3beta (Cell Signalling Technology, USA), and phospho-


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eEF2 (Thr56; Cell Signalling Technology, USA) with appropriate secondary antibodies and 
controlling respectively for total levels of mTOR, GSK-3beta and eEF2 measured using relevant 
antibodies. Protein bands will be identified using standard chemiluminescent techniques 
(Millipore) visualised in a darkbox imager (LAS 3000, Fujifilm) and analysed using ImageJ (Image 
Processing and Analysis in Java) software. One blood sample in a PAXgene tube will also be 
collected at time points -60 & +120 minutes for extraction of total RNA to examine RNA species 
such as mRNA or miRNA using reverse transcription PCR.  
 
Epigenetics  
Blood samples will be collected using one PAXgene tube and one EDTA tube at baseline to 
analyse epigenetic modulation of depression/stress-related gene expression. Epigenetic 
modifications that will be examined may include DNA methylation, measured by 
pyrosequencing, a DNA sequencing technique that identifies methylated DNA nucleotide bases. 
A second type of epigenetic modification that may be measured is chromatin activation status, 
using chromatin immunoprecipition  whereby genomic DNA associated with chromatin in its 
open or closed state can be precipitated with targeted antibodies and analysed by quantitative 
PCR. Small non-protein coding RNA molecules known as microRNAs that also act as epigenetic 
modulators of gene expression, by suppressing messenger RNA translation to protein, may be 
measured using reverse transcription PCR. 
 
12.3.2 Endpoints assessments 
 
Efficacy Assessment 
This pilot trial is not designed to assess efficacy. Rather, a 95% confidence interval for the 
difference between relapse rates between ketamine and midazolam groups will be obtained, to 
inform a future definitive trial. This will be based on the following clinical outcomes.  
The following will be used to obtain baseline, intra-treatment, and end-of-treatment and follow-
up data at timepoints indicated in Table 1.  
(i) Diagnosis and treatment history: Diagnosis of recurrent depressive disorder will be confirmed 
using the mood episodes module of the Structured Clinical Interview for DSM-IV Axis I Disorders 
(SCID) at admission baseline.  
Additional demographic data obtained at admission baseline from patient interview and case-
note review will include: age, gender, weight, height, occupation, educational attainment, 
duration of index depressive episode, number of previous depressive episodes, history of 
medical illness and surgical treatments, personal and family history of alcohol/substance 
dependency, presence of psychotic symptoms (detected by SCID), current medications and 
other therapies. Changes in medications will be documented at follow-up interviews. 
(ii) Depression outcomes: The primary clinical outcome measure is the relapse rate at six months 
as measured using the objectively-rated 24-item Hamilton Rating Scale for Depression (HRSD-
24). To enter the study patients must score ≥21 at baseline. 
 
Response to antidepressant treatment is defined as achieving ≥60% decrease from 
baseline HRSD-24 and score ≤16 
 
Remission criteria are ≥60% decrease in HRSD from baseline and score ≤10 
 
Criteria for relapse are ≥10 point increase in HRSD-24 compared to responder baseline 
score plus HRSD ≥16; in addition, increase in the HRSD should be maintained one week 
later (if indicated, additional follow-ups will be arranged). 


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During the infusion sessions in the pilot trial HRSD-24 scores will be obtained 60 minutes before 
the infusion begins and at +120 and +240 minutes afterwards. Baseline scores on sleep and 
appetite items will be maintained for repeated measures within one day. The +240 HRSD-24 
scores will serve as the weekly HRSD scores up to follow-up-week 4. Depression measures will 
be repeated at weeks 6, 8, 12, 20 and 26 during the six-month follow-up. Subjective mood 
ratings will be measured at the above timepoints using the Quick Inventory of Depressive 
Symptoms, self-report version (QIDS-SR16).4 
 
Safety Assessment 
 
Psychotomimetic and dissociative symptoms 
 
Acute psychotomimetic effects of ketamine are usually short-lived and restricted to the infusion 
period, resolving within one hour.6 An extensive review of safety in healthy volunteers showed 
adverse mental status events in only 1.45% of infusions. In line with previous ketamine trials we 
will use the following instruments before, during (+35-40 mins) and after (+240 mins) ketamine 
infusions (WP2.1): 
 
 
Dissociative effects: Clinician-Administered Dissociative States Scale (CADSS). 
 
Psychotomimetic effects: positive symptoms subscale of the Brief Psychiatric Rating 
Scale (BPRS). The 4-item positive symptoms subscale measures suspiciousness, 
hallucinations, unusual thought content, and conceptual disorganisation. 
 
Mood elevation: Young Mania Rating Scale (YMRS; mood item). 
 
Cognitive Effects 
 
Our population of responders to antidepressant treatment are at high risk of relapse but are not 
depressed at the time of ketamine administration. Cognitive assessment is an important aspect 
of investigating potential effects of ketamine in the novel role of relapse prevention. Ketamine in 
healthy volunteers can cause transient impairment in working and episodic memory, procedural 
and semantic memory, executive function, verbal fluency, and verbal memory, resolving shortly 
after the infusion. Procognitive effects of repeated doses of ketamine have been suggested in 
some studies. Baseline and acute neurocognitive performance are associated with likelihood of 
antidepressant response to ketamine in depressed patients, however it is not known whether 
this is the case in recovered depressed patients. 
 
The following validated instruments will be used to assess cognitive outcomes at responder 
baseline (prior to randomisation) and during the pilot trial: one day after the first and fourth 
infusions and at six-months (Table 1). Parallel versions will be used to reduce practice effects. 
The National Adult Reading Test (NART) will measure premorbid ability at responder baseline. 
 
 
Addenbrooke’s Cognitive Examination III (ACE-3): global cognition, also generates 
verbal fluency scores (letter and category). The ACE-3 provides a total score 
(maximum=100) plus subscale scores for different aspects of cognition including 
attention and orientation, and has been used to study cognition in depression. 
 
Forward and Backward Digit Spans: immediate short-term memory, attention and 
working memory 
 
Trail Making Test (Part A): motor and psychomotor speed 


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 
Trail Making Test (Part B) plus letter and category verbal fluencies: frontal executive 
function 
 
Physical Side Effects 
In a recent review, the most common adverse events of single ketamine infusions were 
drowsiness, dizziness, incoordination, blurred vision, and dissociative symptoms, with only 1.95% 
of 205 infusions discontinued. Approximately 33% of participants experienced mild 
haemodynamic changes (systolic or diastolic blood pressure (BP)>180/100 or >20% increase 
above pre-infusion reading or tachycardia >110 beats/min). The following monitoring will take 
place to assess physical side-effects 
 
 
Heart rate, blood pressure, pulse oximetry, and ECG before and during infusions and for 
a further 200 minutes, to measure haemodynamic changes  
 
The Patient-Rated Inventory of Side Effects (PRISE) will be used to document other 
general adverse events by patients before, during (+35-40 mins) and after (+240 mins) 
infusions 
 
All adverse medical, psychotomimetic and general events will be reported to Trial Steering and 
Data Monitoring and Ethics Committees. 
 
12.3.3 Screening procedure  
 
All patients admitted for treatment of acute depression will be screened by means of a chart 
review to ascertain whether they have a history of recurrent depressive disorder or any exclusion 
criteria are present. This chart review will be conducted by a researcher within three days of 
admission. Laboratory and ECG results will also be noted – these are routinely performed on all 
patients at admission. Date of screening, subject age, gender and reason for ineligibility (if 
subject is not eligible) will be recorded. The results of the screening evaluation must meet the 
inclusion/exclusion criteria for the subject to continue in the study.  
 
Following screening, eligible patients will be approached on the ward by a researcher and 
provided with information about the study. If agreeable to participate, informed consent will be 
obtained and the initial HRSD-24 and SCID assessment performed to ensure further eligibility 
criteria are met.  
 
12.3.4 Baseline assessments 
 
The following pre-treatment Baseline assessments will be performed at recruitment:  
 
- 
confirmation of eligibility (review inclusion/exclusion criteria)  
- 
recording of demographics, medical history and concomitant medications  
- 
Structured Clinical Interview for DSM IV Disorders  
- 
National Adult Reading Test 
- 
Hamilton Rating Scale for Depression, 24-item 
- 
Quick Inventory of Depressive Symptoms – Self-Rated (QIDS-SR) 
- 
Childhood Trauma Questionnaire  
- 
blood collection for biomarkers as detailed above  
 
12.3.5 Subsequent study visits and procedures 


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Participants will undergo usual inpatient care as prescribed by their treating team during the 
admission for treatment of the index acute depressive episode. Following the baseline 
assessment above, participants will be assessed weekly during their ongoing inpatient 
treatment, using the HRSD-24 and QIDS-SR.  
 
Those who are identified as responders to inpatients treatment for the acute episode of 
depression and continue at weekly assessment to meet eligibility criteria, will be invited to be 
randomised. Participants must score ≥21 at baseline to be eligible for the study and achieve at 
least response to antidepressant treatment to participate, i.e. ≥60% decrease from baseline 
HRSD-24 and score ≤16. Following randomisation and prior to the commencement of the 
randomised treatment phase, cognitive outcomes will be assessed (ACE-III; Trails A+B; Digit 
Spans). Treatment review will take place at each subsequent study visit to monitor changes in 
medications. A detailed description of each of the assessments is provided in section 
12.3.1. Randomisation will take place as detailed below. Participants will attend the 
hospital for four infusion clinics at which time they will receive an infusion of either 
ketamine or midazolam. Participants will be asked to fast for 8 hours prior to infusion 
clinics and to have a nominated adult who can drive them home and stay with them for 
24 hours after infusions. Pre-infusion monitoring will be performed and the infusion will 
take place over 40 minutes as detailed below. Ongoing monitoring of safety and 
tolerability outcomes will continue for 200 minutes after completion of the infusion. A 
researcher will contact each participant 24 hours after each infusion to check for 
potential adverse effects. Travel expenses incurred by participants will be reimbursed 
and breakfast and lunch provided for infusion sessions. 
 
Ketamine (ketamine hydrochloride 0.5 mg/kg; Pfizer Healthcare Ireland)) and midazolam (0.045 
mg/kg; Roche Products Ireland Ltd) will be made up as 50 ml colourless saline solutions and 
administered as slow infusions over 40 minutes using a syringe driver pump, as per previous 
similar studies. The drugs will be securely stored in the Hospital pharmacy and made up for use 
by the Consultant Anaesthetist (Dr Enda Shanahan) on the mornings when infusions will be 
given, using the St Patrick’s University Hospital Electroconvulsive therapy clinic as the treatment 
facility. Like ketamine at 0.5 mg/kg, midazolam at 0.045 mg/kg has anaesthetic effects and 
causes some sedation and disorientation with a similar time course and adverse effect profile. In 
subanaesthetic doses, ketamine is a safe drug but can cause transient rises in pulse and blood 
pressure during infusion and for up to 80 minutes afterward. All patients will therefore be 
monitored for heart rate, blood pressure, pulse oximetry, and ECG before and during infusions 
and for a further 200 minutes. Infusions will be discontinued by the Anaesthetist if there are 
persisting haemodynamic changes (i.e. heart rate >110/minute or systolic/diastolic blood 
pressure >180/100 or >20% increase above pre-infusion BP for more than 15 minutes) that do 
not respond to beta-blocker therapy. Assessments including cognitive and mood assessment 
will be performed as outlined in section 12.3.1, before, during and after infusions.  
 
Patients will be withdrawn from the trial if: (i) an infusion is discontinued for the above 
haemodynamic reasons or other serious medical contra-indications, e.g. over-sedation, hypoxia, 
intolerable adverse physical reactions; (ii) the patient develops mania or psychosis; (iii)the 
patient becomes severely depressed and/or suicidal. To ensure patient safety, the first infusion 
session will take place while an in-patient within one week of meeting response criteria. If there 
are no major adverse effects, subsequent sessions can happen as out-patients. Participants will 


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be advised not to drive or operate heavy machinery for 24 hours post-commencement of 
infusions, and provided with information on recent changes to the Road Traffic Act 2014, which 
includes provisions for roadside intoxication testing. Participants will be asked to ensure they 
have a nominated adult who can stay with them for 24 hours on outpatient treatment days, and 
will be contacted by a researcher 24 hours after each session to enquire about side-effects. 
 
Participant will be followed up over six months to assess for relapse. Cognitive assessment will 
be repeated at week 26 and this assessment will take place in person, either at the site or via 
home visit by two researchers and according to the Home Visit Protocol developed by the 
Research Department at St Patrick’s University Hospital. HRSD-24 and QIDS will be repeated at 
weeks 6,8,12, 20 and 26. Assessments other than the final follow up at week 26 can take place 
over the telephone. Reasonable meal and travel expenses incurred by participants attending for 
follow-up appointments will be reimbursed.  
 
12.3.6 Method of assigning Subjects to treatment groups 
  
Participants will be recruited at admission for treatment of a depressive episode and assessed 
weekly. Those identified as responders according to the criteria defined above, will be invited to 
be randomly assigned to one of two treatment groups in a 1:1 ratio. 
 
Randomisation 
Computerised random allocation, using randomly permuted blocks will be done independently 
by the Centre for Support and Training in Analysis and Research (CSTAR, University College 
Dublin, www.cstar.ie). To ensure allocation concealment, allocation information will be provided in 
a randomisation list available only to the anaesthetist. This will be stored in a locked cabinet to 
which only the anaesthetist has the key. A matching set of opaque randomisation envelopes will 
also be provided by CSTAR to be accessed by clinical staff in the event of emergency unblinding, 
This system has been successfully piloted in an existing trial at St Patrick’s University Hospital 
(NCT02414932).  
 
Blinding 
Study treatment assignment will be blinded for both the raters and the participants. To ensure 
patient safety during infusions and in the post-infusion period, the anaesthetist administering the 
ketamine/midazolam infusions will not be blinded but he will not be involved in assessments or 
data analysis. Infusions will be prepared by the anaesthetist in a location separate to the infusion 
area and labelled as “trial infusion” prior to transfer to the infusion area. Success of blinding for 
patients and raters will be assessed after the first and final treatments and at the end of the six-
month follow up. 
The matching set of envelopes containing allocation information will remain unopened but may 
be used where emergency unblinding is indicated. Unblinding for one or all participants will take 
place if it is in the best interests of the participants. In the case of an emergency, when knowledge 
of the treatment assignment is essential for the clinical management of the subject, any 
investigator may unblind a single subject. Please see further details in section 13.7.2. 
Circumstances in which unblinding for multiple or all subjects may take place include – multiple 
SAEs or SUSARs, new information regarding safety of the investigative medicinal products, and 
unsatisfactory progression of the trial. 
Any breaking of the blind, whether intentional or unintentional, will be recorded and reported to 


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the sponsor as soon as possible. Unblinding for multiple or all subjects will be discussed by the 
trial steering committee at the next meeting. Unblinding will be recorded and justified in the final 
report. 
 
12.4 
Definition of end-of-trial 
 
End-of-trial is defined as the final follow-up visit/ home visit/telephone assessment of the last 
participant. End-of-trial will be reported to the REC, TSC, DMC and HPRA within 90 days, or 15 
days if the study is terminated prematurely. The investigators will inform subjects and ensure 
that the appropriate follow-up is arranged for all involved. A summary report of the study will be 
provided to the REC, Sponsor and HPRA within 1 year of end-of-trial. 
 
The end-of-study visit form will include: 
- Assessment of endpoints i.e. clinical (HRSD-24, QIDS-SR) and cognitive (ACE-R, digit spans, 
Trails A and B) outcomes 
- Assessment of safety - check for any adverse effects 
- Recording of concomitant medication 
 
The Sponsors and/or the trial steering committee (TSC) have the right at any time to terminate 
the study for clinical or administrative reasons. 
 
 
 
12.4.1 Premature termination of the study 
 
The Sponsor and/or the TSC have the right at any time to terminate the study for clinical or 
administrative reasons. The DMC may request that the trial be prematurely terminated and this 
request will be discussed in a timely manner by the TSC. 
Premature termination of the trial may take place in the event of the following: 
 
(i) New information regarding safety of investigative medicinal products 
(ii) Multiple SAEs or SUSARs 
(iii) Unsatisfactory progression of the trial 
(iv) Major breach of data confidentiality 
(v) Any situation in which premature termination of the trial is judged by the investigators 
and/or Sponsor to be in the best interests of trial participants. 
Premature termination of the trial will be reported to the REC, TSC, DMC, HPRA, and Sponsor 
and justified in the final report.  
 
12.5 
Discontinuation/withdrawal of subjects from study protocol 
 
Subjects have the right to voluntarily discontinue study treatment or withdraw from the study at 
any time for any reason without any consequences. The investigator has the right to discontinue 
a subject from study treatment or withdraw a subject from the study at any time if it is in the 
best interest of the subject. 
 
Subjects must discontinue the investigational medicinal product(s) and be withdrawn from the 
study for any of the following reasons: 
- withdrawal of consent by the subject 


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- any medical condition that the investigator or sponsor determines may jeopardize the 
subject’s safety if she or he continues receiving the study treatment 
- pregnancy 
- ineligibility (either arising during the study or retrospectively having been overlooked at 
screening) 
- an adverse event which requires discontinuation of the study medication 
- treatment failure and disease progression 
- Lack of compliance with the study and/or study procedures (e.g., dosing instructions, 
study visits). 
- Lost to follow-up – at least three documented attempts must be made to contact any 
subject lost to follow-up. 
 
Ideally all subjects who discontinue should comply with specified follow-up procedures as 
detailed in this protocol, i.e. assessment via interview comprising clinical and cognitive 
measures. The only exception to this requirement is when a subject withdraws consent for all 
study procedures. There is no mandatory physical health monitoring to be performed in the 
event of a subject withdrawing consent after a complete infusion session including 200 minutes 
post-infusion monitoring, or between infusion sessions. However, in the event that consent is 
withdrawn during an infusion session, monitoring of vital signs and mental health must be 
performed for 200 minutes following the end of the infusion.  
If a subject is withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page. If a subject is withdrawn due to an 
adverse event, the investigator will arrange for follow-up visits until the adverse event has 
resolved or stabilised.  
 
 
13 TREATMENT OF TRIAL SUBJECTS 
 
13.1 
Description of study treatments 
 
Investigative Medicinal Product - Ketamine Hydrochloride 10 mg/ml infusion at 0.5mg/kg 
(Pfizer Healthcare Ireland) made up as 50ml colourless saline solution and administered 
intravenously over 40 minutes via syringe driver pump. 
 
Active Comparator - Midazolam Hydrochloride (Hypnovel) 10mg/5ml solution at 
0.045mg/kg (Roche Products Ireland Ltd) made up as 50ml colourless saline solution and 
administered intravenously over 40 minutes via syringe driver pump. 
 
13.2 
Formulation, packaging and handling 
 
Commercial labels will remain on both study treatments. These detail the component, date of 
expiry and manufacturer. Further labels will be attached to each unit of product indicating: 
(i) 
Use of the treatment in this trial 
(ii) 
Name of sponsor, and principal investigator; 
(iii) 
Trial reference code allowing identification of the trial site, investigator and trial 
subject. 
These labels will be added by pharmacy staff to each vial on receipt of delivery of the treatment 
to St Patrick’s University Hospital Pharmacy, in accordance with Annex 13 (EU Guidelines to 
Good Manufacturing Practice, Investigational Medicinal Products). 


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Suppliers: 
Ketamine: Pfizer Healthcare Ireland, 9 Riverwalk, Citywest Business Campus, Dublin 24. 
Midazolam: Roche Products (Ireland) Ltd., 3004 Lake Drive, Citywest, Naas Rd., Dublin 24. 
 
Pharmacy performing additional packaging:  
St Patrick’s University Hospital Pharmacy, James’ St, Dublin 8. 
 
13.3 
Storage and disposition of study treatments 
 
The treatments will be stored securely in a clean dry area of the pharmacy department at St 
Patrick’s University Hospital. Ampoules will be stored in the outer carton (labelled as above) in 
order to protect from light. Products will be prepared into infusions in the clinic room of the ECT 
department by the consultant anaesthetist who will administer them. The anaesthetist will be 
unblinded throughout and patients and raters will remain in a separate area for infusions and 
assessments. Once made up as identical colourless solutions, the underlying labels will be 
obscured by bags and infusions will begin within one hour of preparation. Any unused product 
will be returned to pharmacy and disposed of according to the protocols specified by the 
pharmacy for destruction of unused pharmaceutical products. 
The study treatment will be stored at St Patrick’s University Hospital Pharmacy Dept. under the 
responsibility of Ms. Amanda Fitzpatrick, Chief Pharmacist, St. Patrick’s University Hospital. 
Temperatures in the storage area of the pharmacy are monitored constantly by electronic 
thermostat and a printed record is available. An alarm process is instigated if the temperature 
varies from the specified room temperature. The study treatment will be stored locked in a 
secure area until dispensed for use or returned to the sponsor. The IMP ketamine is for 
investigational use only and is only to be used within the context of this study. 
 
13.4 
Accountability of the study treatments 
 
The study medication will be supplied to the pharmacy by Pfizer Healthcare Ireland (ketamine) 
and Roche Products (Ireland) Ltd (midazolam). Standard shipment arrangements will continue. 
Upon delivery, receipt of the products will be recorded by pharmacy staff and labels applied as 
described here, with products then transferred to the secure storage area. Unopened products 
which are unused by end-of-trial will be returned to the manufacturer. Opened unused products 
will be destroyed in the pharmacy following the protocol for destruction of pharmaceutical 
products at the end of every infusion session. 
The investigator is responsible for the control of the treatments under investigation. Adequate 
records for the receipt and disposition of the IMP will be maintained. 
The investigator will use a standard prescription form and the investigator/research nurse will 
collect the medication from the pharmacy no more than three hours before dosing. 
Accountability and subject compliance with study treatments will be assessed by maintaining 
dispensing and return records. Discrepancies in these return records will be dealt with initially by 
re-checking and communication with pharmacy. Should a discrepancy arise which cannot be 
accounted for, this will be recorded and discussed by the TSC at their next four-monthly 
meeting.  
 
13.5 
Assessment of compliance 
 


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In this study, interventions will be administered intravenously by the research team and thus 
there is no opportunity for non-compliance. The investigator is responsible for ensuring that the 
study treatment is administered in compliance with the protocol. Subject compliance will be 
assessed by maintaining dispensing records. 
 
13.6 
Overdose of study treatment 
 
Given the safeguards in place (consultant anaesthetist to prepare and administer infusions, 
assisted by members of the research team), it is deemed unlikely that an overdose of study 
treatment could occur. In the improbable event of an overdose, the study subject will be 
monitored for any change in neurological status or vital signs by the consultant anaesthetist and 
research team members. If there are signs of change, e.g. drowsiness, change in blood 
pressure/heart rate and a known overdose has occurred, the subject will be counselled and 
accompanied by a member of the research team to the local emergency department (St. James’ 
Hospital) for medical investigation. A letter detailing treatment and doses administered will be 
provided. Reasonable efforts will be made to contact the NOK/RA if the subject consents. 
Should the subject require medical investigation and/or treatment due to an overdose of study 
treatment, cost will be covered by the SPUH indemnity policy, unless due to negligence or 
malpractice. 
 
13.7 
Prior and concomitant therapy 
 
Any medication, other than the study medication taken during the study will be recorded in the 
CRF. Medications will be documented at the point of consent, at Baseline, and changes will be 
noted at every assessment or intervention appointment thereafter. 
 
13.7.1 Permitted medications/non- investigational medicinal products 
 
All medications aside from those listed in section 13.7.2 are permitted. Treatment-as-usual will 
continue for all participants during this study. No non-investigational medicinal products will be 
used outside authorisation for the purposes of this trial. 
 
13.7.2 Prohibited medications 
 
The following medications are contraindicated during the randomised treatment period as they 
may alter the pharmacokinetics of ketamine. Additionally, the medication theophylline is 
contraindicated as concomitant use of ketamine and theophylline may significantly reduce the 
seizure threshold with reports of unpredictable extensor-type seizures.  
 
Contraindicated medications:  
 
Ketoconazole  
Voriconazole  
Itraconazole  
Telithromycin  
Clarithromycin  
Saquinavir  
Nefazodone  
Erythromycin  
Diltiazem  
Fluconazole  
Verapamil  
Theophylline 
 
Participants taking any of these medications on randomisation will be excluded from the trial. 
Medication history will be checked at Baseline and each subsequent assessment, and 
participants who have been prescribed these medications during the trial will not receive further 


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interventions (i.e. infusions of ketamine or midazolam), however will be followed up according 
to the framework presented here. Data collected will be included in intention-to-treat analyses if 
one infusion and one follow-up assessment have been completed. It is not permitted for 
subjects to participate in investigational treatment studies while participating in this study.  
 
14 SAFETY REPORTING 
 
 
14.1 
Definitions 
 
14.1.1 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. 
An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product  
 
14.1.2 Adverse reaction (AR) 
All untoward and unintended responses to a medicinal product related to any dose. 
The phrase ‘responses to a medicinal product’ means that a causal relationship between a study 
medication and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the sponsor as having 
a reasonable suspected causal relationship to the study medication qualify as adverse reactions.   
 
14.1.3 Serious adverse event  
Any untoward medical occurrence or affect that at any dose:  
- 
results in death,  
- 
is life-threatening*,  
- 
requires hospitalisation or prolongation of existing hospitalisation,  
- 
results in persistent or significant disability or incapacity,  
- 
is a congenital anomaly or birth defect 
- 
important medical events** 
 
*Regarding a life-threatening event, this refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.  
 
**Some medical events may jeopardise the subject or may require an intervention to prevent one 
of the above characteristics/consequences. Such events (hereinafter referred to as ‘important 
medical events’) should also be considered as ‘serious’ in accordance with the definition  
 
14.1.4 Severe adverse events 
The term ‘severity’ is used here to describe the intensity of a specific event. This has to be 
distinguished from the term ‘serious.  
 
14.1.5 Suspected unexpected serious adverse reactions 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. investigator’s brochure for an unauthorised investigational medicinal product or 
summary of product characteristics for an authorised medicinal product. 


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14.2 
Evaluation of AEs and SAEs 
 
14.2.1 Assessment of seriousness 
The investigator should make an assessment of seriousness as defined in section 12.1.4. 
 
14.2.2 Assessment of casualty 
All adverse events judged by either the investigator or the sponsor as having a reasonable 
suspected causal relationship to an investigational medicinal product qualify as adverse 
reactions. 
The causality assessment given by the investigator should not be downgraded by the sponsor. 
The investigator/sponsor must make an assessment of whether the AE/SAE is likely to be related 
to treatment according to the following definitions: 
 
Unrelated 
Where an event is not considered to be related to the study medication. 
 
Possibly 
Although a relationship to the study medication cannot be completely ruled out, the nature of 
the event, the underlying disease, concomitant medication or temporal relationship make other 
explanations possible. 
 
Probably 
The temporal relationship and absence of a more likely explanation suggest the event could be 
related to the study medication. 
 
All AEs/SAEs judged as having a reasonable suspected causal relationship (e.g. possibly, 
probably) to the study medication will be considered as ARs/SARs. 
 
All AEs/SAEs judged as being related (e.g. possibly, probably) to an interaction between the 
study medication and another medication will also be considered to be ARs/SAR. 
 
Alternative causes such as natural history of the underlying disease, concomitant therapy, other 
risk factors and the temporal relationship of the event to the treatment should be considered. 
 
14.2.3 Assessment of severity 
The investigator will make an assessment of severity for each AE/SAE and record this on the CRF 
according to one of the following categories: 
 
Mild 
An event that is easily tolerated by the subject, causing minimal discomfort and not interfering 
with every day activities. 
 
Moderate 
An event that is sufficiently discomforting to interfere with normal everyday activities. 
 
Severe 
An event that prevents normal everyday activities. 
Note: the term ‘severe’, should not be confused with ‘serious’ which is a regulatory definition 


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based on subject/event outcome or action criteria 
 
14.2.4 Assessment of expectedness 
 
The expectedness of an adverse reaction will be determined by the sponsor according to the 
reference document e.g. the investigator's brochure for a non-authorised investigational 
medicinal product, or the summary of product characteristics for an authorised medicinal 
product which is used according to the terms and conditions of the marketing authorisation. 
 
14.2.5 Emergency unblinding procedures 
 
Emergency unblinding can be performed by any investigator by opening one or all of the set of 
envelopes containing allocation information. These will be securely stored in the ECT 
department where infusions are to be administered. Instructions for emergency unblinding will 
be included on each CRF/ e-CRF, and will also be prominently displayed in the ECT department. 
A successful trial run of this system with the clinical staff group involved in out-of-hours 
procedures has taken place.  
 
14.3 
Reporting procedures for all adverse events 
 
All AEs occurring during the study observed by the investigator or reported by the subject, 
whether or not attributed to the study medication, will be recorded on the CRF. 
 
The following information will be recorded: description, date of onset and end date, severity, 
assessment of relatedness to the study medication, other suspect medication or device and 
action taken. Follow-up information should be provided as necessary. 
 
AEs considered related to the study medication as judged by an investigator or the sponsor will 
be followed until resolution or until the event is considered stable. All related AEs that result in a 
subject’s withdrawal from the study or are present at the end of the study, should be followed 
up until a satisfactory resolution occurs. 
 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity 
to require the subject’s removal from treatment. A subject may also voluntarily withdraw from 
treatment due to what he or she perceives as an intolerable AE. If either of these occurs, the 
subject must undergo an end-of-study assessment and be given appropriate care under medical 
supervision until symptoms cease or the condition becomes stable. 
 
The severity of events will be assessed on the following scale:   mild, moderate, severe. 
 
The relationship of AEs to the study medication will be assessed by the investigator. 
 
Any pregnancy occurring during the clinical study and the outcome of the pregnancy should be 
recorded and followed-up for congenital abnormality or birth defect. 
 
14.4 
Reporting procedures for serious adverse events 
 
The investigator will report all serious adverse events immediately to the sponsor except for 
those that the protocol or investigator’s brochure identifies as not requiring immediate 


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reporting. The immediate report will be followed by detailed, written reports. The immediate 
and follow-up reports will identify subjects by unique code numbers assigned to the latter. 
 
The immediate report will be made by the investigator within a very short period of time and 
under no circumstances should this exceed 24 hours following knowledge of the serious 
adverse event. 
 
All SAE information must be recorded on an SAE forms and sent expeditiously to the sponsor. 
Additional information received for a case (follow-up or corrections to the original case) need to 
be detailed on a new SAE form and sent expeditiously to the sponsor. 
 
The sponsor will keep detailed records of all adverse events which are reported to him by the 
investigator or investigators. 
 
In cases where reporting is not required immediately the investigator will report within the 
appropriate time frame, taking account of the specificities of the trial and of the serious adverse 
event, as well as possible guidance in the protocol or the IB. 
 
The sponsor will report all SUSARs to the competent authorities (the HPRA in Ireland) and the 
ethics committees concerned. Fatal or life-threatening SUSARs must be reported within 7 days. 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days. The 
sponsor will also inform all investigators concerned of relevant information about SUSARs that 
could adversely affect the safety of subjects. 
If the initial report is incomplete, e.g. if the sponsor has not provided all the 
information/assessment within seven days, the sponsor  will submit a completed report based 
on the initial information within an additional eight days. 
 
If significant new information on an already reported case is received by the sponsor, the clock 
starts again at day zero, i.e. the date of receipt of new information. This information will be 
reported as a follow-up report within 15 days. 
 
In addition to the expedited reporting above, the sponsor shall submit once a year throughout 
the clinical trial or on request, a safety report to the competent authority (the HPRA in Ireland) 
and ethics committees. The annual safety report will be presented in the DSUR format as per 
ICH guideline E2F - Note for guidance on development safety update reports. This is a legal 
requirement. 
 
14.5 
Data Monitoring Committee, Trial Steering Committee  
 
The independent Data Monitoring Committee will review blinded data on a six-monthly basis 
during the trial and will act according to the DMC Charter which will be ratified at the 
organisational meeting. Data Monitoring Committee  
 
The DMC will be an independent committee established prior to the commencement of the trial 
to assess progress, safety data and data security and will meet every six months during the trial. 
The DMC will hold an organisational meeting prior to recruitment, at which time the DMC. The 
Trial Management Group and trial statistician will prepare a report for the Committee circulated 
two weeks prior to each meeting. Charter will be ratified. No member of the DMC will have a 
conflict of interest with the Sponsor. Blinded data will be presented to the DMC for safety 


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evaluation every six months. Adverse events will be reported on individually. Should the 
Committee wish to review unblinded data, this will be provided. The DMC will report to the TSC, 
which has authority to decide whether the trial should be suspended or ended. Minutes of the 
DMC meetings including safety evaluations will be presented to the TSC at every meeting.  
 
The advice of the DMC will be notified upon receipt by the sponsor to the REC and CA that 
approved the protocol. With this notification a statement will be included indicating whether the 
advice will be followed. The composition of the DMC will include an independent statistician, an 
independent trial methodologist, and an independent clinical investigator.   
 
The Trial Steering Committee will comprise investigators, clinical experts not directly involved in 
the trial, a service user representative, and staff nominated by the Sponsor. The committee will 
include members who are independent of the investigators, SPUH, funders and the Sponsor. The 
TSC will consider and act, as appropriate, upon the recommendations of the DMC and ultimately 
carries the responsibility for deciding on premature termination of the trial. The TSC will take 
responsibility for the scientific validity of the study protocol, assessment of study quality and 
conduct as well as for the scientific quality of the final study report. 
This section will be updated with details of the members of the DMC and TSC once established. 
 
14.6 
Pregnancy 
 
Pregnancy is not considered an AE or SAE however the investigator will collect pregnancy 
information for female trial subjects or female partners of male trial subjects who become 
pregnant while participating in the study. 
The investigator will record the information on a Pregnancy Notification Form and submit this to 
the sponsor. Any pregnancy that occurs in a trial subject or a trial subject’s partner during a trial 
will be followed to outcome. It may be necessary to monitor the development of the new-born 
for an appropriate period post-delivery. 
 
While ketamine has been shown to be teratogenic in rats, there are no data of its use during 
human pregnancy, particularly at sub-anaesthetic doses. Insufficient data are available on 
Midazolam to assess its safety in pregnancy; however other benzodiazepines have been 
associated with teratogenicity. There have been no studies of sub-anaesthetic doses of 
midazolam in pregnancy. Date of last menstrual period (LMP) will be recorded at recruitment 
and the first ketamine infusion. Information regarding the importance of adequate 
contraception during the trial and informing researchers if there is any possibility of pregnancy 
is provided in the Participant Information Leaflet (Appendix).  
 
15 STATISTICS 
 
 
15.1 
Description of statistical methods 
 
Descriptive statistics will be used to report: rates of recruitment, willingness to be randomised, 
willingness to complete assessments, medical/ cognitive/ psychotomimetic/ general adverse 
events between groups, adherence to allocated treatments, adherence to follow-up between 
groups, and reasons for drop-outs between groups. Relapse-free survival times will be 
compared between groups using Kaplan-Meier survival curves and log-rank test. 
 


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As this is a pilot trial and insufficiently powered to achieve statistical significance 40, there will 
be no formal comparison of the two treatment groups. However, Cox proportional hazard 
regression analysis will provide a 95% confidence interval for an unadjusted hazard ratio for 
ketamine versus midazolam groups. This will be used to inform a future definitive trial. 
 
Secondary exploratory analyses (Cox proportional hazards regression models) will be used to 
identify pre-randomisation clinical factors or covariates (e.g. Family history of alcohol 
dependence; gender; age; presence of psychosis and extent of treatment-resistance in index 
depressive episode; remission status) that might influence response and help guide 
randomisation stratification in a future definitive trial. 
 
Comparative descriptive statistics will be used to compare scores on cognitive and tolerability 
assessments. For the neuroplasticity biomarker studies, changes in protein/activity levels will be 
compared between groups over different timepoints by ANCOVA; linear models will test 
relationships between these changes and relapse during six-month follow-up.  
 
15.2 
Determination of sample size subjects 
 
We wish to recruit 20 patients per group, a total of 40, an acceptable number for the purposes 
of a pilot trial. A formal sample size calculation is not appropriate as per the Medical Research 
Council Guidelines. Response rates to inpatient depression treatment are approximately 80%29. 
However, as this is a heterogeneous sample with RDD, we expect response rates to be lower at 
50-60%. Allowing for a 15% drop-out rate, we seek to recruit 98 patients upon admission, 
expecting that at least n=51 will meet response criteria and that n=40 will consent to be 
randomised. Prof McLoughlin’s team recently finished recruiting severely depressed inpatients 
(n=140) to an RCT of ECT at St Patrick’s University Hospital (see http://www.controlled-
trials.com/isrctn/pf/23577151 ). 60 patients were recruited in the first 16 months. As the 
proposed study is less intensive, with the attraction of an additional therapy and a wider cohort 
to recruit from, the recruitment rate is expected to be higher at 98 participants within 16 
months. 
 
15.3 
Analysis sets 
 
Pilot trial data will be analysed on an intention-to-treat basis for all Phase II participants who 
complete at least one infusion and one post-infusion evaluation. Data analyses will be 
performed blinded to allocation, by Prof. Leslie Daly in CSTAR (above). 
 
15.4 
Demographic and baseline disease characteristics 
 
Demographic and Baseline disease characteristic data will be summarized for each treatment 
group by presenting descriptive statistics.  
 
15.5 
Efficacy analysis 
 
No formal interim analysis is proposed due to the pilot trial design, short recruitment phase and 
small trial numbers.  
 
15.5.1 Primary efficacy endpoint 
 


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This pilot trial is not designed to assess efficacy. The focus is on trial process with assessment of 
the primary clinical outcome being secondary. However, efficacy data will be collected in the 
course of the trial and will be reported as part of the study findings. 
 
The primary outcome relating to efficacy (the assessment of which is not a primary objective) is 
the relapse rate at six months as measured by HRSD-24. Criteria for relapse are ≥10 point 
increase in HRSD-24 compared to baseline Phase 2 score plus HRSD ≥16; in addition, increase in 
the HRSD should be maintained one week later (if indicated, additional follow-ups will be 
arranged). Hospital admission, further ECT, and deliberate self-harm/suicide also constitute 
relapse. Timing of these events will be recorded. 
 
15.5.2 Secondary efficacy endpoint 
 
(i) 
Subjective mood ratings as measured by scores on QIDS-SR. 
(ii) 
Tolerability of ketamine vs. midazolam in terms of cognitive outcomes as measured 
by scores on ACE-R, digit spans, Trails A and B, FCSRT, and AMI. 
(iii) 
Tolerability of ketamine vs. midazolam in terms of psychotomimetic effects as 
measured by scores on CADSS, BPRS, YMRS, and PRISE. 
(iv) 
Number of adverse effects in ketamine vs. midazolam groups. 
 
Secondary efficacy endpoints will be analysed by descriptive methods. 
 
15.6 
Safety analysis 
 
Descriptive statistics will be used to report the results of clinical monitoring (heart rate, blood 
pressure, pulse oximetry, and presence of ECG changes), cognitive assessments (ACE-R, digit 
spans, Trails A and B), monitoring for psychotomimetic effects (CADSS, BPRS, YMRS, PRISE), and 
adverse effects between groups. Blinded data will be presented to the DMC for safety evaluation 
every four months. Minutes of the DMC meetings including safety evaluations will be presented 
to the TSC at every meeting.  
 
15.7 
The level of statistical significance 
 
As this is a pilot trial there will be no formal comparison of the two groups but Cox proportional 
hazard regression analysis will provide a 95% confidence interval for an unadjusted hazard ratio 
that will allow interpretation of statistical difference between ketamine and midazolam groups.  
 
15.8 
Criteria for the termination of the trial 
 
The trial will be terminated once 20 subjects have been allocated to each arm of the randomised 
treatment phase.  
 
15.9 
Procedure for accounting for missing, unused and spurious data 
 
As this is a pilot trial and small numbers of participants are involved, no missing values will be 
imputed.  
 
15.10 Procedure for reporting any deviation(s) from the original statistical plan 


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Deviations from the original statistical plan will be reported to the Sponsor within a timely 
interval and discussed by the Trial Steering Committee at the next meeting. These will be 
recorded and justified in the final report. Where a deviation from the original statistical plan is 
judged by the investigators or Sponsor to comprise a substantial amendment to the trial 
protocol, the standard procedure for reporting substantial amendments to the HPRA will be 
followed.  
 
16 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
Direct access will be granted to authorised representatives from the sponsor, host institution 
and the regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
 
17 DATA HANDLING AND RECORD KEEPING 
 
Data will be entered, handled and stored at St Patrick’s University Hospital. It will be anonymised 
and then processed by members of the research team at Trinity College Institute of 
Neuroscience and at the Centre for Support and Training, University College Dublin. 
 
 
17.1 
Data collection, source documents and case report forms (CRF) 
 
Source documents for this study include clinical notes, medication records, and study-specific 
data collection documents. Information will be extracted from these documents and recorded 
legibly on CRFs/ secure eCRFs. If an error is made, the error will be crossed through with a single 
line in such a way that the original entry can still be read. The correct entry will then be clearly 
inserted, and the alterations will be initialled and dated by the investigator. Data reported on the 
CRF that are derived from source documents must be consistent with the source documents or 
the discrepancies must be explained.  
All documents will be stored safely in a designated locked filing cabinet in a locked office within 
the Research Building at St Patrick’s University Hospital and confidentiality will be observed at all 
times. With the exception of the informed consent form, subjects will be referred to only by their 
subject identification number on all study-specific documents, whether hard copies or 
electronic. Anonymised biological materials will be stored and processed in Professor 
McLoughlin’s laboratory facilities in Trinity College Institute of Neuroscience and the Institute for 
Molecular Medicine in St James’s Hospital. Data analysis will take place in another facility (Centre 
for Support and Training in Research and Analysis (CSTAR), University College Dublin), however 
data will be anonymised prior to secure transfer to CSTAR for analysis.  
 
17.2 
Data reporting  
 
The trial DMC will be responsible for overseeing data security. Subjects will be identified by a 
study specific subject number and/or code in the database. The name and any other identifying 
detail will not be included in any study data electronic file. A trial-specific Data Entry and Quality 
Assurance Protocol will be followed by all researchers. This involves eight levels of assurance 
and checking.  
 
 


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18 RETENTION OF ESSENTIAL DOCUMENTS 
 
Biological material will be retained securely following the protocols in place at Trinity College 
Dublin, for a period of four years following trial termination, and disposed of by staff authorized 
to do so by Trinity College Dublin and in accordance with the institution’s policies and data 
protection legislation. Data derived from biological material and essential trial documents will be 
retained for a period of at least five years in accordance with Article 17 of EU Directive 
2005/28/EC. These will be retained for no longer than ten years and will then be destroyed in 
accordance with data protection legislation at that time. This is included in the Participant 
Information Leaflets and consent forms. The essential documents are defined as those that 
individually and collectively permit evaluation of the conduct of the trial and the quality of the 
data produced. These documents will be filed in an organised way that facilitates management 
of the clinical trial, audit and inspection by competent authorities and will be readily available on 
request. 
As this is an academic study, recommendations regarding retention of essential documents for 
EMA approval/ clinical development of the IMP are not of concern here. Essential documents 
should be retained until at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. These documents should be retained for a longer period however 
if required by the applicable regulatory requirements or by an agreement with the sponsor.  
The investigator/institution should agree to retain the trial-related essential documents as 
required by the applicable regulatory requirements and until the sponsor informs the 
investigator/institution these documents are no longer necessary. 
 
19 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
 
This study will be conducted in accordance with the current approved protocol, ICH GCP, 
relevant regulations and standard operating procedures. The measures taken to ensure data 
obtained is accurate, complete and reliable include: 
 
(i) 
Researchers will attend Good Clinical Practice training 
(ii) 
Researchers will be trained in administration of the primary assessment tool used in 
this study, the HRSD-24. Administration will be according to specified guidelines 
and training will be repeated every 6 months to ensure inter-rater reliability. 
(iii) 
Quality assurance in the laboratory is assured by adherence to protocols outlined by 
Molecular Medicine Ireland 
(http://www.molecularmedicineireland.ie/libraries/libgroup/8 ) and manufacturers' 
instructions for any laboratory assay products used. 
(iv) 
A trial-specific Data Entry and Quality Assurance Protocol will be followed by all 
researchers. This involves eight levels of assurance and checking.  
 
The trial site, laboratory and Sponsor’s/research team’s offices are subject to GCP inspection at 
any time. In accordance with the legislation, the trial master file comprising the essential 
documents which enable both the conduct of the trial and the quality of the data produced to 
be evaluated will be available to provide the basis for the GCP inspection. Responses to a GCP 
inspection report will be provided within 30 working days of the date of issue.  
 
 


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20 AUDITS AND INSPECTIONS 
 
This trial may be subject to internal or external auditing or inspections procedure to ensure 
adherence to GCP. Access to all trial-related documents will be given at that time. 
 
 
21 ETHICS 
 
21.1 
Declaration of Helsinki 
 
The sponsor will ensure that this study is conducted in accordance with the ethical principles 
that have their origins in the Declaration of Helsinki. 
 
21.2 
Good Clinical Practice 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and 2005/28/EC. 
 
21.3 
Approvals 
 
Required documents including the protocol, informed consent form, subject information leaflet, 
investigational medicinal product dossier, investigators brochure and any other required 
documents will be submitted to a recognised research ethics committee (here, the REC of the 
Mater Misericordiae Hospitals Group)  and the competent authority for written approval. The 
sponsor will submit and obtain approval from the above parties for substantial amendments to 
the original approved documents.  
 
21.4 
Informed consent 
 
Written consent will be obtained by members of the research team using the study-specific 
consent form (Appendix). Potential participants will be provided with an information leaflet and 
letter of invitation (Appendix) and verbal information at the first point of contact with a member 
of the research team. This process will take place following screening. Verbal assent will be 
sought at each treatment step. Time will be provided to address questions. Every effort will be 
made to provide adequate time for the participant to consult with family, friends and their 
general practitioner prior to making a decision, however as it is common for treatment for 
depression to begin on the same day as admission to hospital for treatment, in some cases, 
provision of information and the process of obtaining consent may take place on the same day. 
Participants will be encouraged to reflect on the information provided and ask questions but it is 
recognised that some participants may prefer to make a decision at the first point of contact 
and this will also be accommodated.  
Prior to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject and investigator. 
Informed consent will be obtained verbally at each intervention e.g. phlebotomy, infusion, by 
the member of the research team who will perform the intervention 
 
21.5 
Benefits and risks assessment  
 


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This study may further the understanding of the pathogenesis of depression, a major public 
health issue, and provide further information about a potential treatment to reduce relapse 
rates. In designing this study, all efforts have been made to reduce the risk to and burden for 
participants. It is believed that risk to and burden for the subject will be in proportion to the 
potential value of this research. There are no guaranteed direct benefits to participants. However 
all participants may benefit indirectly from participation in terms of increased awareness of 
mental health issues. Some participants may benefit from the administration of ketamine in 
terms of reduced six-month relapse rates, but this is not guaranteed. This study will not include 
incapacitated adults or minors. Issues regarding specific vulnerable populations are addressed 
individually below.  
 
(i) 
This study requires inclusion of adults with mental illness to address the research 
question. Only those who have capacity to provide valid informed consent will be 
invited to participate. Where there is any concern expressed about the capacity of a 
person to make his/her own treatment decisions, a capacity assessment is 
performed by the treating team. This assessment will guide investigators in 
selecting those who have capacity to consent to enrolment in the trial. The trial is 
expected to benefit participants who have a mental illness indirectly by improving 
scientific knowledge of a major mental health issue. There are possible direct and 
indirect benefits to participants with a mental illness in terms of reduced relapse 
rate and increased awareness of mental health through participation, however there 
is no guaranteed direct benefit. 
(ii) 
Women of childbearing age are defined by the Irish Central Statistics Office as 
women of ages 15-49 (Census 2011 This is Ireland (Part 1) - CSO - Central Statistics 
Office). Women of this age group will not be excluded from this study as this group 
constitutes a significant proportion of the population of interest, i.e. people with 
treatment resistant depression. Irish women are more likely to suffer from 
depression than men and 25% of women in Ireland will require treatment for 
depression in their lifetime. Thus the primary study objective cannot be accurately 
achieved without inclusion of women of childbearing age. Previous studies of 
ketamine have included women of childbearing age and precautions will be taken 
as detailed here to ensure adequate contraception is in place throughout the trial.  
21.6 
Subject confidentiality 
 
The trial staff will ensure that the subjects’ anonymity is maintained. The subjects will be 
identified only by initials and a subject’s identification number on the CRF and any database. All 
documents will be stored securely. The study will comply with the Data Protection Act. 
 
21.7 
Other ethical considerations 
 
Use of placebo/active comparator: Participants in this pilot trial will continue usual care as 
recommended by their responsible clinical team. They may receive an additional treatment as 
part of this pilot trial but will not be denied any treatment for the purposes of this trial. 
Participants will be provided with verbal and written information regarding the 1:1 
randomisation strategy and the possibility of being randomised to a placebo group. There is no 
evidence to suggest that subjects who are randomised to the placebo arm of the study will 
suffer poorer outcomes, as a study of this nature has not yet been performed. The DMC will 
monitor data for safety parameters throughout the trial including the possibility of a large 


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discrepancy between placebo and ketamine groups, and in the event of such a circumstance, 
will follow the specifications in this protocol. 
 
22 FINANCING AND INSURANCE/INDEMNITY 
 
Details of funding will be updated once formal funding has been secured. Insurance is provided 
by indemnity cover for research in place at St Patrick’s University Hospital. This will be in place 
once the trial is approved by the St Patrick’s Mental Health Services REC, an application for 
which will be submitted following approval by the authorised clinical trials REC of St. James’ and 
Tallaght Hospitals. 
Please see Appendix, “St Patrick’s Mental Health Services Indemnity Policy”.<Describe financing 
and insurance arrangements. 
 
 
23 CLINICAL STUDY REPORT AND PUBLICATION POLICY 
 
The publication policy involves formal presentation of preliminary study findings at national and 
international neuroscience and psychiatry meetings. Final findings will be submitted for peer-
review and publication in relevant high-impact scientific journals and upon publication they may 
be further publicized in national and international print and electronic media through the TCD 
and SPUH websites and public relations departments. Further knowledge dissemination will 
include registering the trial in the EudraCT database and publication of the trial protocol in a 
peer-reviewed journal. 
During the trial itself, a six-monthly newsletter will be sent to all participants, detailing progress 
in recruitment with lay summaries of research findings relevant to the study. Research progress 
and developments will be regularly presented at medical “grand rounds” in St. Patrick’s 
University Hospital (SPUH), and in-house research meetings and seminars in Trinity College 
Institute of Neuroscience (TCIN). Information about the research programme and other ongoing 
related depression research will also be contributed through our group’s website 
(http://www.medicine.tcd.ie/psychiatry/research/projects/depression-neurobiology.php ) 
available to the general public. 
The clinical study report will be presented to the REC and HPRA within one year of the 
completion or cancellation of the trial. The format of this summary will comply with the EU Note 
for Structure and Content of Clinical Study Reports (CPMP/ICH/137/95). The clinical study report 
will be signed by the principal investigator.  
 
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