Conditions: Major Depressive Episode Unipolar Depression Bipolar Depression
Keywords: ketamine glutamate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. midazolam as an adjunctive therapy for depression. The main purpose of the pilot study is to assess trial processes to help inform a future definitive trial.

Detailed description:
Pragmatic, randomised, controlled, parallel-group, pilot trial. Trial participants will be patients admitted to St Patrick's University Hospital for treatment of a depressive episode. The investigators aim to recruit up to 20 participants who will be eligible for this study and randomly allocate 10 patients to each group. The participants will undergo usual inpatient care as prescribed by their treating team for the index acute depressive episode. Both participants and assessors will be blind to treatment allocation. Consented participants will be randomly allocated in a 1:1 ratio to a four week course of either once-weekly ketamine or midazolam 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. Both groups will continue treatment as usual. Participates will also be followed up over a three month period.

Arms:
arm 1: Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. arm 2: Participants will receive four once-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 one week apart. intervention 2: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.

Protocol document:
Prot_SAP_000.pdf: 
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Clinical Trial Protocol Template 
 
 
1 
INFORMATION ON CLINICAL TRIAL PROTOCOL TEMPLATE 
 
This protocol template has been designed for clinical trials which are 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 as an adjunctive therapy for Major Depression - a randomised controlled pilot trial: The 
KARMA-Dep 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 as an adjunctive therapy for Major Depression - a randomised controlled pilot trial: The 
KARMA-Dep Trial 
4.2 Reference numbers 
Protocol identification (code or reference number): 01-17 
 
EudraCT number: 2016-004764-18 
 
 
 
 
 
Date and version number: Version 3.0   13.6.17 
 
 
 
 
4.3 Applicant details 
 
Chief investigator/ Co-ordinating investigator 
Name/title: Professor Declan McLoughlin, Research Professor of Psychiatry, Trinity College 
Dublin 
 
Contact details: Dept of Psychiatry, Trinity College Dublin, St Patrick’s University Hospital, 
James’s Street, Dublin 8 
T: 01 2493385  
E: d.mcloughlin@tcd.ie 
 
 
Principal Investigators  
Name(s)/ titles: Professor Declan McLoughlin, Research Professor of Psychiatry, Trinity College 
Dublin 
 
 
Contact details: 
Dept of Psychiatry, St Patrick’s University Hospital, James’s Street, Dublin 8 


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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’s Street, 
Dublin 8 
E: jbraddock@stpatsmail.com 
 
 
Funder :  
 
Name: St Patrick’s Mental Health Services 
 
Contact details: St Patrick’s University Hospital, James’s Street, Dublin 8 
T: 01 2493200  
 
 
 
4.4 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: 
4.5 Other relevant information 
4.6  
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 
 
 


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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. 
 
6 
TABLE OF CONTENTS 
 
7 
DOCUMENT HISTORY 
4 
8 
SYNOPSIS 
4 
9 
ABBREVIATIONS 
6 
10 
INTRODUCTION 
7 
11 
STUDY OBJECTIVE 
12 
12 
TRIAL DESIGN 
13 
13 
TREATMENT OF TRIAL SUBJECTS 
24 
14 
SAFETY REPORTING 
27 
15 
STATISTICS 
31 
16 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
34 
17 
DATA HANDLING AND RECORD KEEPING 
34 
18 
RETENTION OF ESSENTIAL DOCUMENTS 
345 
19 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
345 
20 
AUDITS AND INSPECTIONS 
36 
21 
ETHICS 
36 
22 
FINANCING AND INSURANCE/INDEMNITY 
378 
23 
CLINICAL STUDY REPORT AND PUBLICATION POLICY 
378 
24 
REFERENCES 
39 
 
 
 
 


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7 
DOCUMENT HISTORY 
 
 
Document 
Date of Issue 
Summary of Change 
Original protocol Version 1.0 
15.11.16 
N/A 
 
 
8 
SYNOPSIS 
 
 
Title of study 
Ketamine as an adjunctive therapy for Major Depression - a randomised 
controlled pilot trial: The KARMA-Dep 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 as an adjunctive therapy for a major 
depressive episode. 
 
Objective 1: To perform a pragmatic randomized patient and rater-
blinded pilot trial of once-weekly adjunctive ketamine vs. midazolam 
infusions over four weeks for reducing depressive  
symptoms. This pilot study will assess the feasibility of this study to 
inform a future definitive trial.  
  
Objective 2: To assess the safety and tolerability of repeated (x4) once-
weekly infusions of ketamine vs. midazolam in this patient population.  
 
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 treating depression. 
 
Objective 4: To investigate epigenetic modulation of depression/stress-
related genes in patients being treated with ketamine. 
 
Trial design 
Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. 
Midazolam as an adjunct treatment for a major depressive episode. The 
main purpose of the pilot study is to assess trial processes to help inform a 
future definitive trial. 
 
Participants will be recruited within ten days of admission to St Patrick’s 
Mental Health Services for treatment of a Diagnostic and Statistical 
Manual of Mental Disorders – fourth edition (DSM-IV) diagnosed 
depressive episode. Treatment-as-usual will continue throughout the 
entire trial. Participants will be invited to be randomised to a course of 
four once-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. 


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Blood samples will be taken at three time-points in the first infusion 
session and 1-2 days after the final fourth infusion for neuroplasticity 
biomarker studies. 
 
Trial Interventions: participants will receive four once-weekly infusions 
of either ketamine at 0.5mg/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 at three months to assess for relapse according to 
standardised criteria.  
 
We wish to test the hypothesis that weekly infusions of sub-anaesthetic 
doses of ketamine as adjunctive therapy to routine care will help 
accelerate recovery in patients with severe depression admitted to 
hospital. 
Key inclusion criteria 
• 
≥18 years old 
• 
Hamilton Rating Scale for Depression-24 item version (HRSD-24) 
score of ≥21 
• 
Voluntary admission for treatment of an acute depressive episode 
• 
Meet DSM-IV criteria for a major depressive disorder (MDD) and 
bipolar affective disorder (current episode depression) 
Key exclusion criteria 
• 
Current involuntary admission 
• 
Medical condition rendering unfit for ketamine/midazolam 
• 
Active suicidal intention 
• 
Dementia 
• 
History of Axis 1 diagnosis other than major depression 
• 
Electroconvulsive Therapy (ECT) administered within the last 
two months 
• 
Alcohol/substance dependence in previous six-months 
• 
Pregnancy or inability to confirm use of adequate contraception 
during the trial 
• 
Breastfeeding women  
Number of subjects 
We aim to recruit 40 patients on admission who will be eligible for this 
study and randomly allocate 20 patients to each 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 a four-week course of four 
infusions 
Duration of treatment 
Four weeks 
Statistical methods 
Data analyses will be performed blinded to allocation by Prof Leslie Daly 


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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. As this is a pilot trial and 
insufficiently powered to achieve statistical significance, there will be no 
formal comparison of the two treatment groups.  
We would like to report the confidence intervals of the HRSD scores 
between the two treatment groups at various timepoints in the study. 
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.  
 
 
9 
ABBREVIATIONS 
 
 
AE 
 
Adverse event 
AR 
 
Adverse reaction 
BDNF   
Brain Derived Neurotrophic Factor 
BPRS   
Brief Psychiatric Rating Scale 
CA 
 
Competent authority 
CADSS   
Clinician-Administered Dissociative States Scale 
CI 
 
Chief investigator/Co-ordinating investigator 
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 
DSM-IV  
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG  
 
Electrocardiogram 
ECT  
 
Electroconvulsive therapy 
EU  
 
European Union 
e-CRF  
Electronic case report form 
eEF-2   
Eukaryotic elongation factor 2 
GCP 
 
Good Clinical Practice 
GP 
 
General Practitioner 
GSK-3   
Glycogen Synthase Kinase 3 
HPRA  
Health Products Regulatory Authority 
HRSD-24  
Hamilton Depression Rating Scale, 24-item version 
HSE 
 
Health Service Executive 
IB 
 
Investigators brochure 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonisation 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational medicinal products 


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IMPD  
Investigational medicinal product dossier 
MDD   
Major depressive disorder 
MMSE   
Mini Mental State Exam 
MSTRD  
 
Maudsley Staging for Treatment-Resistant Depression 
mTOR   
Mammalian target of Rapamycin 
NMDA   
N-methyl-D-aspartate 
NOK  
 
Next of kin 
PI 
 
Principal Investigator 
PIL 
 
Patient/subject information leaflet 
PRISE   
Patient-Rated Inventory of Side Effects 
QIDS-SR 16  
Quick Inventory of Depressive Symptoms, Self-Report, 16-item 
RDD 
 
Recurrent Depressive Disorder 
REC 
 
Research ethics committee 
RNA  
 
Ribonucleic acid 
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  
Major Depressive Disorder (MDD) is a common psychiatric disorder and causes significant disability. 
According to the World Health Organisation, unipolar depression is expected to become the second 
greatest cause of disability worldwide by 2020 [1]. The World Mental Health Survey conducted in 17 
countries found that on average, about 1 in 20 people reported having an episode of depression in the 
previous year. 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 economy [2]. Indeed, depression is currently the second largest cause globally for years 
lived with disability [1]. 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 ). 
 
KETAMINE AND DEPRESSION  
 
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed that only 30% 
of patients achieved remission after first line Selective Serotonin Re-uptake Inhibitor (SSRI) 


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treatment and approximately half of patients with MDD do not meet criteria for remission even after 
two trials of antidepressants [3]. This is a major concern as depression can lead to suicide and chronic 
disability.  
The standard medical care for depression over the past 50 years has focused on monoamine 
neurotransmitters, including selective serotonin reuptake inhibitors and serotonin-norepinephrine 
reuptake inhibitors.  However, these treatments can take weeks to take effect. Multiple studies 
conducted in patients with MDD indicate that less than 40% of patients treated with standard 
antidepressants achieved remission within 10-14 weeks, thereby highlighting the need for novel 
treatment approaches [4]. One such novel approach might be ketamine. 
Ketamine was approved by the FDA in 1970 and since this is has been used routinely as an 
anaesthetic, particularly in children. Ketamine acts as an antagonist of the N-methyl-D-asparate 
(NMDA) receptor and thus targets the excitatory amino acid neurotransmitter glutamate. It has a half 
life of 2-3 hours. Since the first reporting of a rapid antidepressant response to a single intravenous 
dose of ketamine in nine depressed patents in 2000 [5], there have been a number of case reports and 
multiple clinical trials that have supported this effect.  Ketamine has been shown to produce rapid, 
though transient, antidepressant effects [6].  It is a psychotomimetic (with abuse potential) but at low 
doses it is safe [6-8].  Only 1.5% 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 [9, 10]. A single infusion of low dose intravenous ketamine rapidly improves depressive 
symptoms with efficacy onset within one hour post infusion, peak effect sizes at 24 hours and lasting 
effects for depression symptom ratings of up until 5-8 days [11].  
The antidepressant effects of ketamine have been noted much beyond its short half-life of 2-3 hours. 
Chronic, mostly recreational, high-dose ketamine use can cause uropathy and dependency [12]. 
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 [7]. It 
has been shown that a single dose of iv ketamine can rapidly improve depressive symptoms (as 
quickly as an hour) [13]. However, the effect of ketamine does not appear to last longer than a week 
[11].  A number of clinical trials have shown that response rates are much higher with more than one 
infusion of ketamine [14]. 
The PI currently has two HPRA approved trials underway of ketamine for depression relapse 
prevention (NCT024114932 and NCT02661061).  
To date, there have been only three trials that have used ketamine as an augmentation agent in the 
treatment of depression. One such trial [11] used a single dose of iv ketamine augmentation in 
patients who were newly initiated on escitalopram. The results showed that depression scores were 
significantly lower with ketamine from 2 hours post infusion until 2 weeks. This was a randomised 
double-blind controlled trial comparing ketamine with placebo (saline). Limitations to this study 
included the antidepressant being restricted to escitalopram, small sample size of 30 and inactive 
placebo which may have compromised blinding. 
Another randomised placebo-controlled double blind add-on study [15] used iv ketamine and placebo 
(saline) two weeks apart in patients with a diagnosis of treatment resistant bipolar depression who 
were on therapeutic levels of lithium and valproate. The results showed that depressive symptoms 
improved significantly in subjects receiving ketamine until day 3. Limitations to this study include 
small group size (9 per group).  Additionally, these patients had treatment resistant bipolar depression 
who were late in their course of illness and thus results may not be generalizable.  


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The third trial [16] looked at ketamine augmentation in treatment resistant depression, using a two-
step escalating dose but with an open non-randomised design. The results showed that depressive 
symptoms improved and the effect was more pronounced during the escalated dose phase. 
Limitations to the study included small sample size (14 in total), open design, no placebo arm and the 
interval between infusions varied between and within patients. 
 
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, e.g. BDNF as well as phosphorylated species of mTOR, 
eEF2 and GSK-3β. Additionally, several meta–analyses have established that both serum 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 [17, 18]. We will examine epigenetic modulation of 
depression/stress-related genes (e.g. BDNF, FKBP5) in our sample of inpatients with a major 
depressive episode and being treated with ketamine. 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 pyrosequencing [19] 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 immunoprecipition [20] 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 and response to ketamine. 
 
 
OUTCOMES, OUTPUTS AND TIMESCALE 
The purpose of this research programme is to conduct a randomised pilot trial of ketamine as an 
adjunctive therapy in depression. 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 treatment group. 


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This study has the potential to directly impact on clinical practice by testing a novel therapeutic 
strategy. Developing a new therapy for a more rapid recovery from depression 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 
 
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 a four-week course of four once-
weekly 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. It is hypothesised that a course of ketamine infusions over this schedule may 
accelerate recovery in patients with severe depression admitted to hospital 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 [21, 22].  
 
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 staff trained in phlebotomy procedures and the 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 (see section 12.3). 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 [23].  
Classification: Transient to serious.  
Probability: Serious adverse effect=Rare. Non-serious adverse effect=Unlikely.  
Transient adverse effect=Common.  
 


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(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” (see section 12.3) have been put in place to 
ensure any 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.  
 
(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 
 


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The overall aim is to assess the feasibility of this study of ketamine as an adjunctive therapy for 
depression, to inform a future definitive trial. 
 
11.1 Primary objective 
 
To conduct a randomised controlled patient- and rater-blinded pilot trial of weekly ketamine vs. 
midazolam over four-weeks as an adjunctive therapy in the treatment of a major depressive episode.  
 
 
11.2 Secondary objective 
 
To assess safety and tolerability of repeated (x4) once-weekly infusions of ketamine vs. midazolam in 
this depressed population. 
 
11.3 Exploratory objectives 
 
(a) 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 treating depression. 
 
(b) To investigate epigenetic modulation of depression/stress-related genes in patients with 
depression receiving ketamine. 
 
11.4 Primary and secondary/exploratory endpoints/outcome measures 
 
The primary outcomes for this pilot trial are process outcomes to inform a future definitive trial [24], 
e.g. completion of assessments; success of blinding. Although some attrition can be expected during 
the three 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 a decrease in depressive symptoms, 
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 three-month follow-up schedule which involves the 
HRSD-24 and other instruments at weeks 6 and 12 post final infusion. 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 neuroplasticity 
molecules, including total Shank3, phosphorylated and total BDNF, pMTOR, pGSK3β and peEF2 in 
response to the first ketamine/midazolam infusion following immunoassays performed on blood 
samples collected -60, +40 and +240 minutes after the first infusion and after the final infusion. 
 
 
12 TRIAL DESIGN 
 
12.1 General considerations 
 


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This single-site, randomised, controlled, parallel-group pilot trial will take place at St Patrick’s 
University Hospital.  
 
 
 
 
 
Figure 1:  CONSORT Trial Flow Diagram, Pilot Clinical Trial [26] 
 
 
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 Mental Health Services (St 
Patrick’s University Hospital and St Edmundsbury Hospital) for treatment of a major depressive 
episode.  
 
12.2.2 
Inclusion criteria 
 
- ≥18 years old 
- HRSD-24 score of ≥21 


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- Voluntary admission for treatment of acute depressive episode 
- Meet DSM-IV criteria for major depressive disorder (MDD) and bipolar affective disorder 
(current episode depression) 
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 (Contraindications to 
ketamine, as per Summary of Product Characteristics, include hypersensitivity to the 
active substance, elevated blood pressure, severe coronary or myocardial disease, C.V.A 
and cerebral trauma. Contraindications to midazolam include known hypersensitivity to 
benzodiazepines, severe respiratory failure or acute respiratory depression.) 
(iii) 
Active suicidal intention 
(iv) 
Dementia 
(v) 
History of Axis 1 diagnosis other than a major depressive episode 
(vi) 
ECT administered within the last two months 
(vii) 
Alcohol/substance dependence in previous six-months 
(viii) 
Pregnancy or inability to confirm use of adequate contraception during the trial 
(ix) 
Breastfeeding women 
 
 
 
 
 
 
 
 
 
 
 
 
12.3 Study assessments and procedures 
 
Table 1: Schedule of events 
 
 
Inpatient 
Follow up 
Assessment 
Baseline 
Pre infusion 
Post 
infusion 
6 weeks 
12 weeks 
Diagnosis and Treatment 


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Background, MINI, 
MSM 
P 
 
 
 
 
Clinical Outcomes 
HRSD-24 
P 
PPPP 
(1-4) 
PPPP 
(1-4) 
P 
P 
QIDS-SR 
P 
PPPP 
(1-4) 
PPPP 
(1-4) 
P 
P 
Cognitive Outcomes 
MOCA 
P 
 
PP (1&4) 
 
P 
Ketamine effects 
CADSS 
 
 
PPPP 
(1-4) 
 
 
BPRS 
 
 
PPPP 
(1-4) 
 
 
YMRS 
 
 
PPPP 
(1-4) 
 
 
Physical effects 
PRISE 
 
 
PPPP 
(1-4) 
 
 
HR,BP,O2,ECG 
 
PPPP 
(1-4) 
PPPP 
(1-4) 
 
 
Blood Samples 
Phlebotomy  
P 
PP  
(1 and 4) 
 
 
 
Consent 
Informed consent 
P 
PPPP 
 
 
 
Eligibility  
Eligibility check 
P 
P 
P 
P 
P 
Randomisation 
Allocation 
P 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following windows constitute a protocol violation:  
(i) 
Recruitment more than fourteen days after admission 
(ii) 
Any more than four infusions 
MINI: The Mini-International Neuropsychiatric Interview 
HRSD: 24-item Hamilton Rating Scale for Depression  
QIDS-SR: Quick Inventory of Depressive Symptoms. Self-rated 
CADSS: Clinician-administered Dissociative States Scale 
BPRS: Brief Psychiatric Rating Scale 
YMRS: Young Mania Rating Scale 
PRISE: Patient Rated Inventory of Side-effects 
MoCA: Montreal Cognitive Assessment 
MSM: Maudsley Staging Method for Treatment Resistant 
Depression 
HR: Heart Rate 
BP: Blood Pressure 
O2: Oxygen Saturation 
ECG: Electrocardiogram  


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(iii) 
Infusions taking place less than one week apart 
(iv) 
Final follow-up assessment taking place more than four 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, U&E, 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  
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 (see section 13.7.2). 
 
Cognitive Assessments  
Cognitive measures will include the Montreal Cognitive assessment (MOCA) [27] and will be 
performed at baseline, after infusions two and four as well as at final follow-up at 3 months.  This 
validated cognitive measure will be performed and scored by trained researchers, and has been 
chosen as it provides a standardised measure of global cognition and includes measures of executive 
function.  


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Psychiatric Assessments  
The Mini-International Neuropsychiatric Interview (MINI) will be performed once by trained 
researchers at baseline assessment. MINI is a structured interview which is diagnostic for disorders in 
DSM-IV and ICD-10 and will be used in this study to confirm a diagnosis of major depressive episode 
due to either unipolar major depressive disorder or bipolar disorder [28].   
 
Hamilton Depression Rating Scale, 24-item (HRSD-24)[25, 29] 
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) [30]  
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.  
 
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) [31], Brief Psychiatric Rating Scale (BPRS) [32], Young Mania Rating Scale [33], and 
Patient-Rated Inventory of Side Effects (PRISE) [34] , 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 neuroplasticity markers (e.g.  BDNF, pMTOR, 
pGSK3beta and peEF2) in response to the ketamine/midazolam will be compared. A final sample will 
be taken 1-2 days after after the fourth and final infusion clinic 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 and 
samples will be analysed using relevant immunoassays.  For example, 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, for example, activated mTOR phosphorylated at serine residue 2448 (AbCam, USA), 
inhibitory serine-9 phosphorylated GSK-3beta (Cell Signalling Technology, USA), and phospho-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 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 


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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 HRSD-24 scores between ketamine and midazolam groups, at various timepoints, will be 
obtained, to inform a future definitive trial. We will measure these HRSD-24 scores at baseline, 
during after infusions 1-4, one week after the final infusion and at 6 and 12 weeks post final infusion.  
 
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 major depressive disorder will be confirmed using 
the Mini-International Neuropsychiatric Interview (MINI) 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 MINI), 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 change in score of 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). 
 
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 -60 HRSD-24 scores for infusions 1-4 
plus the +1 week measure will serve as the weekly HRSD scores during the acute ketamine treatment 
phase. For longer-term follow-up, depression measures will be repeated at weeks 6, and 12 during the 
three-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). 
 
Safety Assessment 
 
Psychotomimetic and dissociative symptoms 


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Acute psychotomimetic effects of ketamine are usually short-lived and restricted to the infusion 
period, resolving within one hour. An extensive review of safety in healthy volunteers showed 
adverse mental status events in only 1.5% of infusions. In line with previous ketamine trials, we will 
use the following instruments before, during (+30 mins) and after (+60 mins) ketamine infusions: 
 
• 
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 
 
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 [35]. Procognitive effects of repeated doses of ketamine have been suggested 
in some studies.  
 
The following validated instrument will be used to assess cognitive outcomes at baseline (prior to 
randomisation) and during the pilot trial: one day after the first and fourth infusions and at 12 weeks 
(Table 1).  
 
• 
Montreal Cognitive Assessment (MoCA) [27] was designed as a rapid screening instrument 
for mild cognitive dysfunction. It assesses different cognitive domains: attention and 
concentration, executive functions, memory, language, visuoconstructional skills, conceptual 
thinking, calculations, and orientation.  
 
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 [23]. 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 (+30 mins) and after (+60 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 a depressive episode will be screened by means of a chart 
review to ascertain whether they have a history of major depressive disorder or bipolar disorder and 
if any exclusion criteria are present. This chart review will be conducted by a researcher within ten 


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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 MINI 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  
- 
Mini-International Neuropsychiatric Interview (MINI)  
- 
Hamilton Rating Scale for Depression, 24-item 
- 
Quick Inventory of Depressive Symptoms – Self-Rated (QIDS-SR) 
- 
blood collection for biomarkers as detailed above 
 
12.3.5 
Subsequent study visits and procedures 
 
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.  
 
Participants must score ≥21 at baseline to be eligible for the study. Following randomisation and prior 
to the commencement of the randomised treatment phase, cognitive outcomes will be assessed 
(MoCA). Treatment review will take place regularly 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 (see section 12.3.6). Participants will be inpatients in the hospital for the 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. 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.  
 
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. 


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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 infusions will take place 
while an in-patient. Patients will be advised not to drive or operate heavy machinery for 24-hours 
post-infusions and will be contacted by the researcher 24-hours after each session to enquire about 
side-effects. 
 
Participants will be followed up over three months to assess for relapse. Cognitive assessment 
(MoCA) will be repeated at weeks 6 and 12 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 and 12. Assessments other than the final follow up at week 12 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 who meet eligibility criteria and are willing to participate in the study, 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 three-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 14.2.5. 


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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 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 Research ethics committee (REC), Trial Steering 
Committee (TSC), Data Monitoring Committee (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 (MoCA) 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: 


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- withdrawal of consent by the subject 
- 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 treatment(s) 
 
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. 


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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). 
 
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’s St, Dublin 8. 
 
13.3 Storage and disposition of study treatment(s) 
 
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 treatment(s) 
 
 
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-


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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 
 
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’s Hospital) for medical investigation. A letter detailing 
treatment and doses administered will be provided. Reasonable efforts will be made to contact the 
next of kin 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  


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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 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 effect 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 
- 
is deemed to be an important medical events** 
 
*Regarding a life-threatening event, this refers to an event in which the subject was at risk of death at 


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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. 
 
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. 
 


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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 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 


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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 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 IMB 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 IMB 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. 
 


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14.5 Data safety monitoring board (DSMB) 
 
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.  
 
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. 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 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 who become pregnant while participating in the study. Follow 
up of participants’ partner’s pregnancy is not relevant to this trial.  
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 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).  


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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. A 95% confidence interval will also be determined for the 
difference between ketamine and midazolam groups in treatment response. 
 
As this is a pilot trial and insufficiently powered to achieve statistical significance, there will be no 
formal comparison of the two treatment groups. However, we will determine a 95% confidence 
interval between the two groups at various timepoints (baseline, before and after each infusion and at 
6 and 12 weeks post final infusion) during the trial. 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.  
 
15.3 Analysis sets 
 
Pilot trial data will be analysed on an intention-to-treat basis for all 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 


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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 
 
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 
change in score of the objectively rated 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. 
 
 
15.5.2 
Secondary efficacy endpoints 
 
(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 MoCA. 
(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 (MoCA), 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 a 95% confidence 
interval will be determined for the difference between ketamine and midazolam groups in treatment 
response. 
 
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.  


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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 
 
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.  
 


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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.  
 
 
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. 


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(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.  
 
 
 
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 


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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  
 
This study may further the understanding of depression, a major public health issue, and provide 
further information about a potential adjunctive therapy to routine care to help accelerate recovery 
in patients with severe depression admitted to hospital. 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 accelerating their recovery, 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. 
(i) 
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 MDD. 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. 
Birth control methods which may be considered as highly effective are methods that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. 
Such methods include combined (estrogen and progestogen containing) hormonal 
contraception  associated with inhibition of ovulation, progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device (IUD), 
intrauterine hormone-releasing system ( IUS), bilateral tubal occlusion, vasectomised 
partner and sexual abstinence. 
 
21.6 Subject confidentiality 


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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 an active comparator group. There is no evidence to suggest that 
subjects who are randomised to the active comparator 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 discrepancy between midazolam 
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 Mater Misericordiae Hospitals 
Group. 
 
Please see Appendix, “St Patrick’s Mental Health Services Indemnity Policy”. 
 
 
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. 
 


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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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