A Randomised Double-Blinded Placebo-Controlled Trial to Assess the Efficacy and Safety of Scopolamine Compared to Placebo in Individuals With Bipolar Disorder Who Are Experiencing a Depressive Episode
Phase: PHASE2
Conditions: Bipolar Disorder Depression
Sponsor: Dr. Brian Hallahan

••• 
NUIG-2017-002 
Page 1 of62 
Title Page 
A Randomised Double-Blinded Placebo-Controlled Trial to Assess the Efficacy and Safety of 
Scopolamine Compared to Placebo in Individuals with Bipolar Disorder who are Experiencing a 
Depressive Episode {SCOPE-BO) 
Protocol Version no: 
Test Drug: 
Clinical Phase: 
EudraCT number: 
Sponsor Number: 
Chief Investigator: 
Co-ordinating Centre: 
Sponsor: 
3 
Scopolamine 
llb 
2017-003112-39 
NUIG-2017-002 
Dr. Brian Hallahan 
Department of Psychiatry 
Clinical Science Institute 
Date: 181h December 2020 
National University of Ireland, Galway 
Galway, Ireland 
brian. hallahan@nuiqalway.ie 
(091) 494162 
HRB, Clinical Research Facility, Galway 
National University of Ireland, Galway 
University Hospital Galway 
Newcastle Road 
Galway, Ireland 
(091) 495 964 
Prof. Lokesh Joshi 
(Vice President of Research) 
National University of Ireland Galway 
University Road 
Galway 
(091) 495 678 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization - Good Clinical Practice (ICH-GCP) and any applicable regulatory requirements. 
Confidential 
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. 
Version 3 Dated 18-Dec-2020 
Confidential 
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1. (I) Sponsor Protocol AgnMment Pav-
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Page 3 of62 
1. (ii) Chief Investigator Agreement 
I, the undersigned, agree to the content of the final clinical trial protocol, as presented. 
Signed: 
Chief Investigator 
Signature 
Version 3 Dated 18-Dec-2020 
Print name 
CRFG 
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Date 
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Page 4 of 62 
2. Site Investigator Agreeement 
I, the undersigned, am responsible for the conduct of the trial at this site and agree to the 
following: 
I understand and will conduct the trial according to the protocol, any approved protocol 
amendments, ICH GCP and all applicable regulatory authority requirements and national laws. 
I will not deviate from the protocol without prior written approval from the HPRA and the Ethics 
Committee, except where necessary to prevent any immediate danger to the participant. 
I have sufficient time to properly conduct and complete the trial within the agreed trial period, 
and I have available an adequate number of qualified staff and adequate facilities for the 
foreseen duration of the trial to conduct the trial properly and safely. I will ensure that any staff 
at my site(s) who are involved in the trial conduct are adequately trained regarding the protocol 
and their responsibilities. 
Signed: 
Pr6flesi-~ 
Signature 
Version 3 Dated 18-Dec-2020 
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NUIG-2017-002 
TABLE OF CONTENTS 
1. 
2. 
3. 
4. 
5. 
6. 
(i) Sponsor Protocol Agreement Page 
Site Investigator Agreeement 
Document History 
Synopsis 
Abbreviations 
Introduction 
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4 
9 
12 
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6.1 
Background information 
19 
6.1.1 What is Bipolar disorder? 
19 
6.1.2 Scopolamine trials and putative antidepressant effect 
19 
6.1.3 Population, including sample size and power calculation 
20 
6.2 
Rationale for the study 
22 
6.2.1 Muscarinic Cholinergic Receptors (CHRMs) 
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6.2.2 Cholinergic System and Mood Disorders 
22 
6.2.3 Other proposed mechanisms for Scopolamine's putative antidepressant effect 
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6.2.4 Scopolamine administration in study 
23 
7. 
Study Objectives 
23 
7.1 
Primary Objective 
23 
7.2 
Secondary Objectives 
7.3 
Primary and Secondary/exploaratory endpoints/outcome measures 
7 .3 .1 Primary Endpoint 
7 .3 .2 Secondary Endpoints 
8. 
Trial Design 
8.1 
Design Summary 
8.1.1 Treatment Group 
8.1.2 Placebo Group 
8.1.3 Placebo run-in 
8.2 
Selection of study population 
8.2.1 Population 
8.2.2 Inclusion criteria 
8.2.3 Exclusion criteria 
8.3 
Recruitment, Study visits and procedures 
8.3.1 Treatment duration 
8.3.2 Identification and Recruitment 
8.3.3 Screening Assessments (Visit I) 
8.3.4 Visit 2 Assessments 
8.3.5 Treatment (Visit 3, Visit 4 and Visit 5) 
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8.3.6 Follow up visits (Visit 6 and 7) 
8.4 
Description of Study Procedures 
8.4.1 fufonned Consent 
8.4.2 Medical and Surgical History 
8.4.3 Demographics 
8.4.4 Physical Examination 
8.4.4.1 
Vital signs 
8.4.4.2 
ECG Test 
8.4.5 Laboratory Tests 
8.4.6 Current Medications 
8.4. 7 Pregnancy and contraception Advice 
8.5 
Psychometric fustruments 
8.6 
Randomisation 
8.7 
Discontinuing/Stopping fufusions 
8.8 
Blinding 
8.9 
Definition of end-of-trial 
8.10 
Premature tennination of the study 
8.11 
Discontinuation/withdrawal of participants from study protocol 
8.12 
Outcome measures 
8.12.1 Effectiveness Assessment 
8.12.1.1 
Primary outcome measure 
8.12.1.2 
Secondary outcome measure 
9. 
Treatment of Trial Participants 
9.1 
Description of study treatment(s) 
9 .2 
Fonnulation, packaging and handling 
9.3 
Storage and disposition of study treatment(s) 
9.4 
Preparation/Reconstitution of Dosage Fonn 
9.5 
Accountaibility of the study treatment(s) 
9 .6 
Assessment of compliance 
9. 7 
Overdose of Study treatment 
9.8 
Prior and concomitant therapy 
9 .8.1 Pennitted medications/non-investigational medicinal products 
9.8.2 Prohibited medications 
10. 
Safety reporting 
10.1 
Definitions 
10.1.1 Adverse event (AE) 
10.1.2 Adverse Reaction (AR) 
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NUIG-2017-002 
10.1.3 Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
10.1.4 Suspected unexpected serious adverse reactions (SUSAR) 
10.1.5 Servere Adverse Event 
10.2 Evaluation of AEs and SAEs 
10.2.1 Events exempt from reporting 
10.2.1.1 
Canulation related 
10.2.1.2 
10.2.1.3 
10.2.1.4 
Scopolamine infusion related 
Change in depressive or (hypo )manic symptoms 
Psychotropic medications 
10.2.1.5 
Psychometric measures 
10.2.2 Assessment of seriousness 
10.2.3 Assessment of causality 
10 .2.4 Assessment of severity 
10.2.5 Assessment of expectedness 
10.3 Reporting responsibilities of the investigator 
10.3.l Adverse events/serious adverse events 
10.3.2 Timelines for reporting 
10.3.2.1 
Adverse events 
10.3.2.2 
Serious adverse events 
10.4 Responsibilities of the Sponsor 
10.4.1 Regulatory Authorities 
10.4.2 Safety Reports 
10.4.3 Annual Reports 
10.4.4 Pregnancy 
10.5 
Data Safety Monitoring Board (DSMB) 
10.6 Trial Steering Committee {TSC) 
11. 
Statistics 
11.l 
General considerations 
11.2 Determination of sample size 
11.3 Analysis sets 
11.4 Demographic and baseline disease characteristics 
11.5 
Effectiveness analysis 
11.5 .1 Primary effectiveness analysis 
11.5.2 Secondary effectiveness analysis 
11.6 Safety analysis 
11. 7 The level of statistical significance 
11.8 Procedure for accounting for missing, unused and spurious data 
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NUIG-2017-002 
11.9 Procedure for reporting any deviation(s) from the original statistical plan 
12. 
Direct Access to Source Data/Documents 
13. 
Data handling and record keeping 
13.1 Data collection, source documens and case report forms 
13.2 Data reporting 
14. 
Retention of essential documents 
15. 
Quality control and quality assurance procedures 
16. 
Audits and inspections 
17. 
Ethics 
17. I 
Declaration of Helsinki 
17.2 
Good Clinical Practise 
17 .3 
Approvals 
17.4 
Scopolamine benefits and risks assessment 
17.4.1 Physical Risks 
17.4.1.1 
Tolerability and Adverse Effects ofIV Scopolamine 
17.4.1.2 
Risks secondary to Phlebotomy 
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17.4.1.3 
Risks and hazards secondary to peripheral venous cannulation and intravenous 
administration of investigative medicinal product (e.g. Scopolamine and IOOmls of normal saline or 
IOOmls of normal saline) 
57 
17.4.1.4 
17.4.1.5 
Risks and hazards secondary to IV Scopolamine infusion 
Psychological risks 
17.4.1.6 
Psychosocial risks 
17 .5 
Participant confidentiality 
17.6 
Other Ethical considerations 
18. 
Financing and insurance/indemnity 
19. 
Clinical study report and publication policy 
20. 
References 
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NUIG-2017-002 
3. Document History 
Document 
Date of Issue 
1.0 
03-Sept-2019 
2 
11-0ct-2019 
Version 3 Dated 18-Dec-2020 
,l)B ~ch 
M' Board 
Page 9of62 
Summary of Change 
NIA-first release of document. 
• 
Date/version number updated. 
• 
Table of contents/page numbers updated. 
• 
Minor changes to format and spacing. 
• 
The word "subject" has been updated to 
"participant" 
throughout 
the 
protocol 
for 
consistency. 
• 
Abbreviations 
edited 
to 
remove 
RNA 
Ribonucleic Acid and ROI Republic of Ireland. 
• 
Section 9.1 Description of study treatments, 
updated to reference that the placebo will be 
an authorised product, commercially sourced 
through 
the 
Galway 
University 
Hospital 
pharmacy. 
• 
Exclusion criterion 12 updated to include acute 
porphyria. 
Section 
8. 11, 
Discontinuation/withdrawal of participants from 
study protocol has additionally been updated to 
account for this. 
• 
Exclusion criterion 13 updated to provide 
clarification that patients on anticholinergic 
medications will be excluded from enrolling in 
the study. 
• 
Reference 
to 
Buprenorphine 
has 
been 
removed due to its lack of anti-cholinergic 
activity (exclusion criterion 13, section 8.11 
(Discontinuation/withdrawal 
of 
participants 
from study protocol) and 9.8.2 (Prohibited 
medications) updated. 
• 
Additional exclusion criterion 20 added stating 
that any disorder, unwillingness or inability, not 
covered by any of the other exclusion criteria, 
which in the investigator's opinion, might 
jeopardise 
the 
participant's 
safety 
or 
compliance with the protocol. 
• 
Section 8.4.2, Medical and Surgical History, 
updated 
to 
align 
to 
SmPc information, 
warnings and precautions that, medical history 
of prostatic hypertrophy, asthma, hepatic or 
renal impairment, gastrointestinal obstruction, 
epilepsy and thyrotoxicosis should be sought. 
• 
Section 8.4.4.1, Vital signs has been updated 
to indicate that Clinical support includes ready 
access to resuscitation equipment and clinical 
expertise 
and 
participant 
should 
be 
asymptomatic 
of 
potential 
IMP 
related 
symptoms as well as having satisfactory vital 
signs before discharge post infusion. 
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Version 3 Dated 18-Dec-2020 
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Page 10 of 62 
• 
Section 9.8.1 has been updated to replace 
reference to section 9.7.2 with section 9.8.2. 
• 
To align with the SmPC warnings and 
precautions, blood tests for U&Es, LFTs and 
TFTs are required to be within acceptable 
ranges in the previous 4 months at screening 
(visit 1 ). If necessary blood tests will be 
performed at Visit 1 or Visit 2 and confirmed as 
acceptable prior to first infusion. Updates to 
inclusion criteria, abbreviations, Table 2 (table 
and 
footnote), 
section 
8.3.3 
& 
8.3.4 
(assessments) and 8.4.5 (Laboratory tests) 
have been made. 
• 
Duplicated paragraph in section 8.6 removed 
and HORS score agreed at <23. 
• 
Vital signs included as part of Visit 1 
assessments in protocol version 2. Updates 
made to Table 2 and section 8.3.3 Screening 
assessments. 
• 
Vital signs have been removed from placebo 
run-in exclusion criteria at randomisation visit. 
Updates made to Exclusion criteria, section 
8.3.5 (Psychometric instruments). 
• 
The version of SCIO questionnaire has been 
updated to SCIO-RV from the DSM-V Axis I 
disorder. The following sections updated to 
account for this: Section 6.1.3, 8.3.3, 8.5, 
inclusion criterion 1, Table 2 (table and 
footnote). 
• 
The WAIS questionnaire is replacing the WASI 
questionnaire in protocol Version 2. The 
following sections updated to account for this: 
Section 8.3.4, 8.3.5, 8.3.6, 8.5, abbreviations, 
and Table 2 (table and footnote). 
• 
A pregnancy urine dipstick test has been 
introduced to confirm pregnancy status at Visit 
2, 3, 4, 5 prior to each infusion. This test is in 
addition to serum pregnancy test, at Visit 2 but 
for which the results are not immediately 
available and will confirm pregnancy status 
prior to infusion at Visit 3. The following 
sections 
updated 
to 
incorporate 
these 
changes: Section 8.4.5 (Laboratory Tests), 
exclusion criterion 18, Table 2 (Table and 
footnote), section 8.3.4, 8.3.5, 8.4.7. 
• 
Table 2, Visit 3 column heading, * beside 
Randomisation removed. 
• 
Reference section updated for version 2 to 
remove references no longer required and 
additional references added. 
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18-Dec-2020 
Page 11of62 
• 
Update in Investigative Medicinal Product from 
400micrograms/ml 
to 
600micrograms/ml 
(section 9.1), product supplier and dose to 
participant remaining the same 
• 
Deletion of section 10.2.6, replication of 
section 10.2.5 
• 
Section 8.4.2, Medical and Surgical History, 
updated to align to Sm PC information 
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4. Synopsis 
Title of study 
Name of sponsor 
Phase of development 
Objectives 
Trial design 
Version 3 Dated 18-Dec-2020 
Page 12 of 62 
A Randomised Double-Blinded Placebo-Controlled Trial to 
Assess the Efficacy and Safety of Scopolamine Compared 
to Placebo in Individuals with Bipolar Disorder who are 
ExperiencinQ a Depressive Episode (SCOPE-BO) 
Prof. Lokesh Joshi 
(Vice President of Research) 
National University of Ireland Galway 
University Road 
Galway 
Phase I lb Trial 
Primary Objective: 
1. The primary objective is to investigate the efficacy and 
safety of IV Scopolamine, compared to placebo, in 
reducing severity of depression in individuals with 
bipolar disorder who are experiencing a depressive 
episode of at least moderate severity. 
Secondary objectives: 
1. To investigate if IV Scopolamine compared to placebo 
improves mood, cognition and functioning as measured 
on a number of objective and subjective psychometric 
instruments 
in 
individuals 
with 
bipolar 
disorder 
experiencing a depressive episode of at least moderate 
severity. 
2. To investigate the safety and tolerability of repeated (x3) 
IV Scopolamine versus placebo in individuals with 
bipolar disorder experiencing a depressive episode of at 
least moderate severity. 
This is a single-site, randomised, double-blind, placebo-
controlled, parallel, phase llb clinical trial. The trial will be 
sponsored by the National University of Ireland (NUI) 
Galway and the sponsorship role coordinated by the HRB-
Clinical Research facility Galway (CRFG). 
The site will be University Hospital Galway, Galway and the 
site activities will also be coordinated by the CRFG. 
Participants will be attending the Galway-Roscommon 
Mental Health Services, including a specialised bipolar clinic 
in Galway and referred due to experiencing a depressive 
episode by their treating clinical team; or patients who have 
previously attended NUI Galway/HRB-CRFG with an 
interest to participate/or have participated in research and 
have indicated a willingness to engage in future research; 
or patients who approach the research group directly 
requesting participation. 
Once participants have consented to the trial they will be 
reviewed for eligibility, with inclusion and exclusion criteria 
at the screeninQ visit (Visit 1 ). 
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Key inclusion criteria 
Version 3 Dated 18-Dec-2020 
Page 13 of 62 
At the next visit, Visit 2, all participants will receive placebo 
run-in (100mls of Saline IV). 
The maximum time between screening (Visit 1) and Visit 2 
is 14 days. The screening visit and Visit 2 can be completed 
on the same day. 
Within 7 days of Visit 2, participants will be assessed against 
the placebo run-in criteria and if these criteria are met they 
will be randomised (visit 3) to receive either placebo (n=25) 
or 4 µg/kg Scopolamine (n=25) IV in 100mls of Saline over 
15 minutes at 
• 
Visit 3 (Day 0), 
• 
Visit 4 (days 2-6) and 
• 
Visit 5 (days 6-10), 
At least two days will elapse between IV infusions (Visits 2-
5). 
Two follow-up visits (Visits 6 and 7) will occur at days 15 (+/-
5 days) and days 29 (+/- 7 days). At least two days will 
elapse between Visits 5 and 6. 
To be eligible each participant must meet all of the following 
eligibility criteria at Screening (Visit 1) and must continue to 
fulfil these criteria at Visit 2 to take part in the trial: 
1. Diagnosis of Bipolar Disorder according to Diagnostic 
Statistics Manual (DSM)-V criteria 
2. Experiencing an episode of depression of at least 
moderate severity at Visit 1 (Screening) and Visit 2 
based on clinical interview by a trained clinician and a 
Hamilton Depression Rating Scale (HORS) score~ 14. 
3. 
~ 18 years old at Visit 2 (male or female) 
4. In the opinion of the Principal Investigator or Sub 
Investigator's, be able and willing to provide written 
informed consent and to comply with the requirements 
of this study protocol. 
5. Written informed consent prior to participating in the 
study 
6. U&Es, LFTs and TFTs laboratory tests within acceptable 
ranges in the previous 4 months of the Screening 'Visit 
(Visit 1 ). 
Placebo run-in inclusion criteria at Randomisation visit 
(Visit 3): 
7. In addition to above participants must be experiencing 
an episode of depression of at least mild severity (having 
previously experienced an episode of moderate depression 
at Visit 2 with HORS ~ 14), based on clinical interview by a 
trained clinician and a HDRS score of~ 8. 
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NUIG-2017-002 
Key exclusion criteria 
Version 3 Dated 18-Dec-2020 
Page 14 of62 
Participants who meet any one or more of the following 
exclusion criteria at Screening (Visit 1) or Visit 2 will not be 
eligible to take part in the trial: 
1. History of other Axis I diagnosis (including Recurrent 
Depressive Disorder or Psychotic Disorders such as 
schizo-affective disorder, conditions that can also 
present with depressive episodes) 
2. History in the three months prior to Visit 2 of alcohol 
dependence syndrome or substance dependence 
syndrome. 
3. Current use of oral steroid at Visit 1 
4. A confirmed diagnosis of dementia 
5. A diagnosis of intellectual disability (IQ < 70) 
6. Participants with bipolar disorder that are euthymic in the 
investigator's opinion, at screening or Visit 2. 
7. Participants with bipolar disorder that are hypomanic or 
manic (Young Mania Rating Scale (YMRS) > 6) at 
screening or Visit 2. 
8. Presence of an established neurological disorder or 
other serious demyelinating conditions as determined by 
the treating physician (e.g. space occupying lesion, 
multiple sclerosis) 
9. Current involuntary detention under the Mental Health 
Act (MHA) 2001 in an acute psychiatric inpatient unit 
10. Severity of Bipolar Disorder is such that participation in 
a clinical trial is not appropriate because of the risk of 
imminent self-harm (based on clinical note review and 
review at screening visit by experienced clinician) 
11. A history of an allergic reaction or sensitivity to 
Scopolamine (Hyoscine Hydrobromide). Participants will 
be asked at· the screening visit about any previous 
treatment with scopolamine (Hyoscine Hydrobromide) to 
ascertain any previous allergic reaction or sensitivity to 
this agent. 
12. A clinical diagnosis of narrow angle glaucoma, 
myasthenia gravis, paralytic ileus, pyloric stenosis, toxic 
megacolon and acute porphyria. 
13. Individuals will be excluded from the study if currently 
prescribed 
anticholinergic 
medications 
including 
Physostigmine, Biperiden and Procyclidine. Individuals 
will additionally be excluded if currently prescribed 
Tricyclic Antidepressants which are associated with 
significant anticholinergic properties (e.g. Amitriptyline 
and Nortriptyline) that are currently causing the 
participant to experience anticholinergic side effects 
(e.g. blurred vision, constipation, urinary retention, 
cognitive 
difficulties). 
No 
individuals 
will 
have 
anticholinergic medications stopped to allow them enter 
the trial. 
14. Bradycardia < 50 bpm, tachycardia > 100bpm or 
hypotension (systolic BP <90 and I or diastolic BP < 60) 
prior to IV administration of placebo or Scopolamine 
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Number of participants 
Test Drug 
Dose 
Mode of administration 
Version 3 Dated 18-Dec-2020 
Page 15 of 62 
15. A recent history in the last 6 months of symptomatic 
orthostatic hypotension or syncope. 
16. Previous participation in this trial. Participation is defined 
as randomised. Participation in another trial within 3 
months prior to Visit 1. Receipt of any investigational 
medicinal product (IMP) within 3 months prior to Visit 1. 
17. Participants 
concurrently 
being 
administered 
Electroconvulsive Therapy (ECT). 
18. Pregnancy, as determined by a positive urine dipstick at 
Visits 2, 3, 4, 5, positive blood serum result executed at 
Visit 2 and confirmed prior to infusion at Visit 3 or 
participants who are actively breastfeeding (female 
only). 
19. Women of child-bearing potential are defined as all 
women physiologically capable of becoming pregnant, 
unless they are using highly effective methods of 
contraception during dosing of study treatment. Highly 
effective contraception methods include: 
• Female 
sterilization 
(have 
had 
surgical 
bilateral 
oophorectomy with or without hysterectomy) or tubal 
ligation at least six weeks before taking study treatment. 
• Male partner sterilization 
• Combination of any two of the following: 
a. 
Barrier methods of contraception e.g. Condom 
b. 
Use of oral, injected or implanted hormonal methods 
of 
contraception 
or 
other 
forms 
of 
hormonal 
contraception 
c. 
Placement of an intrauterine device (IUD) or 
intrauterine system (IUS) 
• Women who are considered post-menopausal i.e. 
amenorrhea 
at 
least 
12 
months 
or undergone 
hysterectomy/bilateral oophorectomy 
20. Any disorder, unwillingness or inability, not covered by 
any of the other exclusion criteria, which in the 
investigator's opinion, might jeopardise the participant's 
safety or compliance with the protocol 
Placebo run-in exclusion criteria at Randomisation visit 
(Visit 3): 
21. In addition to having completed Visit 2, participants must 
not be experiencing a hypomanic, or manic episode 
(YMRS >6). 
22. A Serious Adverse Event (SAE) experienced during 
infusion which 
required medical intervention and 
whereby attending physician deemed it inappropriate for 
the participant to engage in future infusions. 
The total sample size of patients randomised is 50 
participants, with 25 individuals in each arm. 
Scopolamine (Hyoscine Hydrobromide) 
4µg/kg in 1 OOml Saline 
15 minutes IV infusion 
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Placebo 
Dose 
Mode of administration 
Duration of treatment 
Primary endpoint 
Secondary endpoints 
Statistical methods 
Sample size 
Version 3 Dated 18-Dec-2020 
Page 16 of62 
Saline (Sodium Chloride 0.9%) 
100 ml 
15 minutes IV infusion 
Run-in period will be a maximum 21 days. The treatment 
period will be a maximum 10 days and the maximum 
number of days for follow up is 28 days 
The primary endpoint will be the change in severity of 
objective depressive symptoms as measured by change in 
HORS score from pre-randomisation (pre-IV infusion at Visit 
3) compared to Visit 6. 
These include change in severity of depressive symptoms 
at study Visits 3, 4, 5, 6 and 7 and changes in cognitive 
scores at Visit 6 
The primary analysis of the primary outcome will estimate 
the difference in change in HORS score between groups 
from pre-randomisation (pre-IV on Visit 3) to Visit 6 (with 
treating scores as continuous variables). 
Secondary outcomes will be analysed as appropriate to the 
distribution of each outcome, comparing the difference 
between groups at the specified follow-up visits. 
Pre-randomisation variables predictive of each outcome; 
and stratifying variables will be included in ANCOVA or 
generalised linear models of outcome variables. 
Inverse probability weighting will be used to account for 
missing outcome data and loss to follow-up at a given 
follow-up visit. 
The primary outcome in this study is the Hamilton 
Depression Rating Scale score (HORS). A decrease of 50% 
or more in the HORS score between randomisation and Visit 
6 is considered clinically meaningful, and sufficient to 
consider a patient to have experienced a response. We 
anticipate that the average HORS score in the proposed 
population pre-randomisation will be 24 units and that this 
outcome variable will be approximately normal. Based on a 
review of the literature, it is estimated that a range of 
plausible values for the standard deviation is between 5 to 
13 units. Using this information, a sample of 44 participants 
(22 in each group) will have 85% power to detect a 
difference of 12 units in mean score change between the 
treatment and control arms, i.e. an expected HORS mean 
score of 12 in the treatment group vs. an expected HORS 
mean score of 24 in the control group after Visit 6. The 
sample size is based on a 2-sample t-test (two-sided) with 
a standard deviation of 13 units (conservative approach) 
and a significant level of 0.05. Allocating 25 participants to 
each arm will ensure power >=85% when loss to follow-up 
is <12% (6 participants missing at Visit 6 follow up). 
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5. 
Abbreviations 
Ach 
AE 
AMPA 
APA 
AR 
AUDIT 
BAI 
BDI 
BP 
BPD 
bpm 
CA 
CANT AB 
CDMS 
CGl-1 
CGl-S 
CHRMs 
Cl 
CRA 
CRF 
CRO 
CT 
CTA 
DMF 
DMP 
DSM 
DSMB 
ECG 
ECT 
EU 
GAF 
GCP 
GDPR 
GP 
HORS 
HPRA 
HR 
HRB-CRFG 
HSE 
ICF 
ICH 
IEC 
IL 
IMP 
IMPD 
IQ 
IV 
LFTs 
MAD RS 
MDD 
MEHi 
MHA 
Acetylcholine 
Adverse event 
a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
American Psychiatric Association 
Adverse reaction 
Alcohol Use Disorder Identification Test 
Beck Anxiety Inventory 
Beck Depression Inventory 
Blood Pressure 
Bipolar Disorder 
beats per minute 
Competent authority 
Cambridge Neuropsychological Test Automated Battery 
Clinical Data Management System 
Clinical Global Impression-Improvement 
Clinical Global Impression-Severity 
Muscarinic cholinergic receptors 
Chief investigator/Co-ordinating investigator 
Clinical research associate 
Case report form 
Contract research organisation 
Clinical trial 
Clinical trial authorisation 
Data Management File 
Data Management Plan 
Diagnostic Statistics Manual 
Drug Safety Monitoring Board 
Electrocardiogram 
Electroconvulsive Therapy 
European Union 
Global Assessment of Functioning 
Good Clinical Practice 
General Data Protection Regulation 
General Practitioner 
Hamilton Depression Rating Scale 
Health Products Regulatory Authority 
Heart Rate 
Health Research Board - Clinical Research Facility Galway 
Health Service Executive 
Informed consent form 
International Conference on Harmonisation 
Independent Ethics Committee 
Interleukin 
lnvestigational medicinal products 
lnvestigational medicinal product dossier 
Intelligence Quotient 
Intravenous 
Liver Function Tests 
Montgomery and Asberg Depression Scale 
Major Depressive Disorder 
Modified Edinburgh Handedness Inventory 
Mental Health Act 
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mTOR 
NCHD 
NEO Pl-FFI 
NMDA 
NUI Galway 
PAL 
Pl 
PIL 
POMS 
PRISE 
REC 
ROI 
RR 
SAE 
SAR 
SCIO 
Sm PC 
SMRI 
soc 
SOP 
SU SAR 
TFTs 
TNF 
TSC 
t1/2 
U&Es 
VAS 
WAIS 
WHO 
YMRS 
mammalian Target of Rapamycin 
Non-Consultant Hospital Doctor 
NEO Personality Inventory-Five Factor Inventory 
N-methyl-D-aspartate 
National University of Ireland Galway 
Paired Associates Learning 
Principal Investigator 
PatienUparticipant information leaflet 
Profile of Mood States 
Patient Rated Inventory of Side Effects 
Research Ethics Committee 
Republic of Ireland 
Respiratory Rate 
Serious adverse event 
Serious adverse reaction 
Structured Clinical Interview for DSM 
Summary of product characteristics 
Stanley Medical Research Institute 
System Organ Class 
Standard operating procedure 
Suspected unexpected serious adverse reaction 
Thyroid Function Tests 
Tumor Necrosis Factor 
Trial Steering Committee 
Half-life 
Urea and Electrolytes 
Visual Analogue Scale 
Wechsler Adult Intelligence Scale 
World Health Organisation 
Young Mania Rating Scale 
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6. 
Introduction 
6.1 
Background information 
6.1.1 What is Bipolar disorder? 
Bipolar disorder is a chronic disabling psychiatric disorder characterized by recurrent episodes 
of mania or hypomania and depression. Bipolar disorder can be separated into bipolar 1 and 
bipolar 2 disorders with bipolar 1 disorder characterizing individuals who have episodes of 
mania and depression, and bipolar 2 disorder characterizing individuals who have episodes 
of depression with periods of hypomania, but not mania (DSM-IV; APA, 1995). Bipolar disorder 
has an estimated prevalence of approximately 1 % and a roughly equal gender ratio (Belmaker, 
2004). Bipolar disorder is one of the top 20 leading causes of disability worldwide, with a 
similar disability adjusted life year rate (138.3 per 100,000) to more prevalent conditions such 
as asthma (147.9 per 100,000) and Alzheimer's disease (108.5 per 100,000) (Ferrari et al., 
2016). 
Current pharmacological treatments for bipolar disorder and in particular for the management 
of depressive episodes in bipolar disorder remain sub-optimal, with pharmacological 
strategies employed to date often only partially effective (Fournier et al., 2010; Yildiz et al., 
2011 ). In addition to the time duration for treatment response, multiple treatment trials are also 
often required, thus increasing patient discomfort and distress (lnsel and Wang, 2009). 
Consequently, 
pharmacological 
mechanisms 
that 
potentially 
alleviate 
depressive 
symptomatology in bipolar disorder and ameliorate patient functioning could present an 
additional pharmacological strategy for the management of bipolar disorder. A number of 
recent studies have suggested that Scopolamine, a pan muscarinic (M) receptor antagonist 
can elicit a rapid anti-depressant response in both major depressive disorder (MOD) and 
bipolar disorder (Ellis et al., 2014; Furey et al., 2006; Drevets et al., 2010) and thus may 
present a novel therapeutic strategy, particularly for the management of bipolar disorder, in 
individuals experiencing depressive episodes (Janowsky, 2011 ). No significant adverse 
effects were noted with treatment with Scopolamine (intravenously) in the above-named 
studies. 
6.1.2 Scopolamine trials and putative antidepressant effect 
A number of double-blind placebo-controlled trials of Intravenous (IV) Scopolamine, have 
been associated with a rapid-acting anti-depressant effect in MOD or bipolar disorder (Drevets 
and Furey, 2006; Furey and Drevets, 2010; Furey et al., 2010; Ellis et al., 2014), but other 
trials have not reported a significant treatment effect (Newhouse et al., 1988; Gillin et al., 1991) 
(See Table 1 ). Of note, those clinical trials where efficacy has been demonstrated have been 
undertaken in the same centre (Mood and Anxieties Disorder Program at the National Institute 
of Mental Health in Bethesda, MD) with the more recent trials of larger numbers from that 
centre including individuals that participated in the previous clinical trials. Although beneficial 
effects have been noted for depressive episodes in both MOD and bipolar disorder, the actual 
numbers of participants with bipolar disorder has been limited with only 14 participants 
experiencing a depressive episode included in these studies described to date (Ellis et al., 
2014; Furey et al., 201 O; Furey and Drevets, 2006). Fewer studies have utilised other potential 
modes of administration for Scopolamine. A previous study of intramuscular scopolamine 
demonstrated no antidepressant effect (Gillin et al., 1991 ), whilst one trial of oral scopolamine 
as an augmentation agent demonstrated an antidepressant effect, albeit this study did not 
demonstrate a rapid-acting effect as demonstrated in the studies of IV Scopolamine and did 
not include individuals with bipolar disorder (Khajavi et al., 2012). In addition, oral Scopolamine 
has very limited bioavailability of -4 %).Trials relating to administration of Scopolamine 
utilising a transdermal patch for the management of depressive episodes have yet to be 
published. 
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Compared to clinical studies, few non-clinical animal model studies have been conducted. 
However, both mouse and rat models (Helpless Mouse and Flinders Sensitive Rat) that 
demonstrate behavioural phenotypes consistent with a model of depression have noted 
associations with reduced activity with cholinergic agonism (Daws & Overstreet, 1999; Popa 
et al., 2006). 
Thus, a putative effect of scopolamine is suggested from animal studies and clinical trials in 
humans, with a suggestion that the effect was most evident with IV administration of 
scopolamine. However, studies of IV scopolamine as a treatment agent for depressive 
episodes to date have had limited numbers of participants and have included heterogeneous 
populations. This study will be the first to exclusively examine depressive episodes in bipolar 
disorder to ascertain if a rapid antidepressant effect is demonstrated. 
6.1.3 Population, including sample size and power calculation 
Trial participants will be adults (both male and female) who have bipolar disorder and are 
experiencing a depressive episode of at least moderate severity. 
A diagnosis of bipolar disorder (bipolar 1 or 2 disorder) will be determined by interview with 
the Structured Clinical Interview for DSM-V (SCIO-RV) with severity of the depressive episode 
assessed using the Hamilton Depression Rating Scale (HORS) (HORS ;;:14 for study inclusion) 
at screening. Participants will all be required to provide informed consent and will fulfil the 
inclusion and exclusion criteria as detailed in Section 8.2.2 and section 8.2.3. 
Participants will be attending the Galway-Roscommon Mental Health Services for the 
management of bipolar disorder or will be participants who have previously engaged in 
research into bipolar disorder at NUI Galway and expressed a preference to be contacted 
again in relation to future research projects. 
The primary outcome in this study is the change in severity of depressive symptoms as 
measured on the Hamilton Depression Rating Scale score (HORS). Allocating 25 participants 
to each arm will ensure power <::85% to detect a 50% lower score on the Hamilton Depression 
Rating Scale score (HORS) in the Scopolamine group compared to placebo group. This 
assumes a loss to follow-up of :512%. It is also anticipated that approximately 60 participants 
will need to be recruited to ensure 50 participants are eligible for randomisation after a placebo 
run-in. Further details of this sample size calculation are given in section 11 .2 . 
T bl 1 S 
a e 
t. I f 
d 
copo amine ria s or 
. d 
. BPD 
d MOD 
epress1ve eo1so es in 
an 
Author 
Agent and Diagnosis 
N 
Assessment 
Trial fin~in gs 
Newhouse 
0.1, 0.25, 0.5mg IV, 
9=MDD 
et al., 1988 
placebo, 1 mg lorazepam 
-
given 2 days apart 
Cross-over study 
Baseline HORS= 29 (SD 
= 7) 
Poland et 
4.5mcg/kg IV x2 given 
14 =MOD 
al., 1989 
one week apart (at night-
16 =past 
time) 
MDE (now 
asymptomatic) 
18 = HC 
Gillin et al., 
0.4mg IM 
10 = MDD 
1991 
10= HC 
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No effect of any dose of 
Scopolamine on depressive 
symptoms 
Mood effects not measured 
Scopolamine increased REM 
sleep latency, reduced REM 
density and activity in all 
orouos 
No effect on depressive 
symptoms 
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Author 
Agent and Diaanosis 
N 
Furey and 
Depressive Episode: 
9= MDD 
Drevets, 
MADRS mean = 32 (SD = 
9 = BPD 
2006 
6) 
Unmedicated > 3 weeks 
7 IV sessions 3-5 days 
apart 
Single-blind lead in 
4ug/kg IV or placebo x 3 
Cross-over design 
Interview 3-5 days post 
last session 
Sessions every 3-5 days 
Sessions every 3-5 days 
Drevets and 
Depressive Episode 
22 =MOD 
Furey, 
Unmedicated > 3 weeks 
2010* 
7 IV sessions 3-5 days 
apart 
Single-blind lead in 
4ug/kg IV or placebo x 3 
Cross-over design 
Interview 3-5 days post 
last session 
Sessions everv 3-5 days 
Furey et al., 
Depressive Episode: 
38 =MOD 
2010* 
MADRS BPAD baseline 
14 = BPD 
=30, SD=9, MDD = 30, 
SD= 8) 
Female= 31, Male =21 
Unmedicated > 3 weeks 
7 IV sessions 3-5 days 
apart 
Single-blind lead in 
4ug/kg IV or placebo x 3 
Cross-over design 
Interview 3-5 days post 
last session 
Sessions everv 3-5 days 
Khajavi et 
1 mg oral x 6 weeks 
40 = MDD 
al., 2012 
Patients treated with 
citalopram 
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Assessment 
Trial findinas 
MAD RS, 
56% remission rate, 61 % 
HARS, YMRS, 
response rate 
CGI 
Effect persisted for 2/52 
Self-Report 
No elation 
VAS and 
BPAD, MDD groups -
similar 
POMS during 
response rates 
session 20, 
60, 120, 150 
minutes 
MAD RS, 
50% remission and 64% 
HARS, YMRS, 
response 
CGI 
Antidepressant effect within 3-
Self-Report 
4 days of Scopolamine 
VAS and 
administration 
POMS during 
session 20, 
60, 120, 150 
minutes 
MADRS, 
58% remission and 71 % 
HARS, YMRS, 
response in females, 28% 
CGI 
remission and 42% response 
Self-Report 
in males 
VAS and 
No effect of diagnosis (BD v 
POMS during 
MOD) 
session 20, 
60, 120, 150 
minutes 
HORS 
Antidepressant effect (65% 
remission and response rate 
with Scopolamine compared 
to 30% and 20% in placebo 
group) 
No improvement in speed of 
onset of antidepressant effect 
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Author 
Agent and Diag nosis 
N 
Assessment 
Trial findings 
Ellis et al., 
Treatment na"ive (MDD = 
62 = MDD 
MAD RS 
Both treatment na"ive(58% 
2014** 
31; BPD = 4) (MADRS 
13=BPD(1= 
response, 29% remission) and 
31, SD = 5), Treatment 
BPD1) 
treatment resistant (42% 
resistant (MDD = 31; 
response, 19% remission) 
BPAD = 9) (MADRS = 33, 
SD= 4). 
7 IV sessions 3-5 days 
apart 
Single-blind lead in 
0.4mcg IV or placebo x 3 
cross-over 
Interview 3-5 days post 
last session 
Sessions every 3-5 days 
Unmedicated for > 2 
weeks 
BDI = Beck Depression Inventory; BPD = Bipolar Disorder; EEG = Electroencephalogram; 
HARS = Hamilton Anxiety Rating Scale; HORS = Hamilton Depression Rating Scale; 
MADRS = Montgomery and Asberg Depression Rating Scale; MDD = Major Depressive 
Disorder; MDE =Major Depressive Episode; POMS =Profile of Mood States; REM= Rapid 
Eye movement; SD = Standard Deviation; VAS =Visual Analogue Scale 
*Included participants from Furey & Drevets (2006) 
**Included participants from Furey & Drevets (2006), Furey et al., (2010) and Drevets & 
Furey (2010) 
6.2 
Rationale for the study 
6.2.1 Muscarinic Cholinergic Receptors (CHRMs) 
Muscarinic cholinergic receptors (CHRMs) are a family of seven-transmembrane domain 
receptors consisting of five receptor subtypes (M1-5) and are associated with heterotrimeric 
G-proteins to translate a transduction cascade (Bonner et al., 1987, Hulme et al., 1990). M1 
and 3 receptors act as postsynaptic receptors in the central nervous system (CNS), where 
they are mainly localized in the cortex and hippocampus and play an important role in cognitive 
function (Porter et al., 2002). M2 and M4 receptors have been demonstrated to act as 
presynaptic autoreceptors in the cerebral cortex (Lai et al., 2001), basal ganglia and 
hippocampus (Lai et al., 2001; Dean et al., 2000; Scarr et al., 2007), having an inhibitory effect 
on the release of acetylcholine (Ach). MS receptors are predominantly distributed in the 
hippocampus and substantia nigra and have been demonstrated to have a role in the 
modulation of dopamine release (Vilaro et al., 1990; Weiner et al., 1990). 
6.2.2 Cholinergic System and Mood Disorders 
Despite the paucity of human studies targeting the cholinergic system in mood disorders, this 
system has long been implicated as a contributory factor in their aetiology. In 1950, the 
organophosphorus insecticide disopropyl-fluorophosphate (DFP), a cholinesterase inhibitor 
(increasing synaptic ACh) was demonstrated to have a depressive effect on healthy controls 
and individuals with mania (Rowntree et al., 1950), with these findings also noted by other 
authors (Gershon and Shaw, 1961 ). Physostigmine, a cholinesterase inhibitor (and thus an 
opposite effect to Scopolamine) has been demonstrated to exacerbate depressive 
symptomatology in individuals with bipolar disorder (Davis et al., 1978; Janowsky et al., 1972). 
These, and other observations, have led to the hypothesis that an imbalance between central 
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cholinergic and adrenergic neurotransmitter activity, released from the cholinergic nerves in 
the parasympathetic, and adrenergic nerves in the sympathetic systems could induce mania 
and depression (Janowsky et al., 1972). Thus, over-activity and oversensitivity of the 
cholinergic system has been associated with depressive symptomatology, with a reduction in 
M2 receptors demonstrated in vivo during depression (Cannon et al., 2006), partially explained 
by variation in the M2 gene (Cannon et al., 2011). M2 antagonism by Scopolamine (a 
cholinergic antagonist} may potentially regulate activity of this system and therefore reduce 
the oversensitivity associated with depression. 
6.2.3 other proposed mechanisms for Scopolamine's putative antidepressant effect 
In addition to modulation of the cholinergic system, several other potential mechanisms have 
been considered to explain the observed antidepressant effect of Scopolamine. This is likely 
given the persistence of the antidepressant effect beyond the plasma half-life of Scopolamine 
(t1/2 = - 3 hours) (Drevets and Furey, 2010). These include modulation of N-methyl-D-
aspartate (NMDA} receptor activity, with increased NMDA receptor gene expression and 
reduced mRNA concentrations of NMDA receptors 1A and 2A in rodents' brain (Liu et al., 
2004) resulting in reduced neuronal damage in the hippocampus secondary to glutamate 
medicated neurotoxicity (Rami et al., 1997). Further evidence for modulation of the 
glutamatergic system is derived from the enhancement of extracellular glutamate 
concentrations in the striatum in rodents with Scopolamine administration (Rawls and 
McGinty, 1988) which may additionally activate synaptic plastic pathways. Activation of 
synaptic plasticity has been proposed as an underlying biological effect for "scopolamine's 
rapid antidepressant activity, with scopolamine rapidly increasing mammalian target of 
rapamycin (mTOR} signalling and synaptogenesis (Voleti et al., 2013), with pre-treatment with 
mTOR and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA} antagonists in 
animal trials (Voleti et al., 2013) blocking "Scopolamine's antidepressant effects. The mTOR 
pathway has similarly been implicated in the rapid antidepressant effects of ketamine (Dwyer 
et al., 2012). 
6.2.4 Scopolamine administration in study 
At Visit 2, all participants will receive placebo run-in (1 OOmls of Saline IV} (see section 8.1.3 
for rationale). The screening visit (Visit 1) and Visit 2 may occur on the same day. Within 7 
days of Visit 2, participants will be randomised (Visit 3) to receive either placebo (n=25} or 4 
µg/kg Scopolamine (n=25) IV in 100mls of Saline over 15 minutes at Visits 3 (day 0), 4 (days 
2-6) and 5 (days 6-10), with at least 2 days between IV infusions (Visits 2, 3, 4 and 5). Two 
follow-up visits (Visits 6 and 7) will occur at day 15 (+/-5 days) and day 29 (+/- 7 days). There 
will be at least 2 days between Visits 5 and 6 and 3 days between Visits 6 and 7. 
7. 
Study Objectives 
7 .1 Primary Objective 
The primary objective is to investigate the efficacy and safety of IV Scopolamine, compared 
to placebo, in reducing severity of depression in individuals with bipolar disorder who are 
experiencing a depressive episode of at least moderate severity. 
7.2 Secondary Objectives 
There are a number of secondary objectives. 
1. To investigate if IV Scopolamine compared to placebo improves mood, cognition and 
functioning as measured on a number of objective and subjective psychometric 
instruments in individuals with bipolar disorder experiencing a depressive episode of 
at least moderate severity. 
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2. To investigate the safety and tolerability of repeated (x3) IV Scopolamine versus 
placebo in individuals with bipolar disorder experiencing a depressive episode of at 
least moderate severity. 
7.3 Primary and Secondary/exploaratory endpoints/outcome measures 
7.3.1 Primary Endpoint 
The primary endpoint will be the change in severity of objective depressive symptoms as 
measured by change in HORS score from pre-randomisation (pre-IV infusion on Visit 3) 
compared to Visit 6. 
7.3.2 Secondary Endpoints 
1. 
Remission of depressive episode measured with the HDRS at Visit 6 compared to Visit 3. 
2. 
Response to a depressive episode measured with the HORS at Visit 6 compared to Visit 
3. 
3. 
Reduction of depressive symptoms (MADRS) at Visit 6 compared to Visit 3. 
4. 
Improvement in objectively measured overall functioning (GAF) at Visit 6 compared to 
Visit 3. 
5. 
Reduction in depressive symptoms as measured using the POMS after all IV infusion 
visits compared to before IV infusions at the same visit (Visits 2, 3, 4, 5). 
6. 
Response and remission data measured with the HDRS at Visit 7 compared to pre-
randomisation HORS scores at Visit 3. 
7. 
Reduction in subjectively measured mood symptoms using the POMS at follow-up visits 
(Visits 6 and 7) compared to pre-randomisation. 
8. 
Reduction in depressive symptoms, measured with the MADRS at Visit 7 compared to 
MADRS scores at Visit 3. 
9. 
Improvement in global functioning, measured with the GAF at Visit 7 compared to pre-
infusion GAF scores at Visit 3. 
10. Psychiatric inpatient admissions due to depressive episodes over the duration of the 
study. 
11. Antidepressant medication usage or change in antidepressant medication dose due to 
depressive episodes over the duration of the study. 
12. Adverse events over the duration of the study. 
13. Post infusion side effects at all 3 IV treatment visits: Bradycardia, Hypotension, Dizziness 
and Sedation (Visits 3, 4 and 5) 
14. Occurrence of a hypo (manic) episode over the duration of the study. 
15. Improvement in motor processing, visual and spatial memory at Visit 6 compared to initial 
scores measured at Visit 2 or Visit 3 as measured on CANT AB. 
8. 
Trial Design 
8.1 Design Summary 
This is a single-site, randomised, double-blind, placebo-controlled, parallel, phase llb clinical 
trial. The trial will be sponsored by the National University of Ireland (NUI) Galway and the 
sponsorship role coordinated by the HRS-Clinical Research facility Galway (CRFG). 
The site will be University Hospital Galway, Galway and the site activities will also be 
coordinated by the CRFG. Participants will be attending the Galway-Roscommon Mental 
Health Services, including a specialised bipolar clinic in Galway and referred due to 
experiencing a depressive episode by their treating clinical team; or patients who have 
previously attended NUI Galway/HRB-CRFG with an interest to participate/or have 
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participated in research and have indicated a willingness to engage in future research; or 
patients who approach the research group directly requesting participation. 
Once participants have consented to the trial they will be reviewed against the inclusion and 
exclusion criteria at the screening visit (Visit 1 ). Eligible participants will be randomised to one 
of two groups; treatment group (n - 25) or placebo group (n - 25). Participants will receive 
Scopolamine or placebo in addition to their current treatment regimen. 
At the next visit, Visit 2, all participants will receive placebo run-in (100mls of Saline IV). This 
has been utilised in other IV Scopolamine treatment studies (Furey & Drevets, 2006; Drevets 
and Furey, 2010; Furey et al., 2010; Ellis et al., 2014) and has the advantage of reducing the 
subsequent placebo effect (when receiving active intervention) noted between groups and 
reducing the loss to follow-up rate post-randomisation (Davis et al., 1995; Rosenkranz, 2016). 
The maximum time between screening (Visit 1) and Visit 2 is 14 days. The screening visit and 
Visit 2 can occur on the same day and thus some data attained on the 'screening visit' will not 
require replication on the same day including a review of inclusion and exclusion criteria, the 
Hamilton Depression Rating Scale (HORS) and the Young Mania Rating Scale (YMRS) and 
pre-infusion vital signs. 
Within 7 days of Visit 2, participants will be assessed against the placebo run-in criteria and if 
these criteria are met they will be randomised (visit 3) to receive either placebo (n=25) or 4 
µg/kg Scopolamine (n=25) IV in 100mls of Saline over 15 minutes at: 
• 
Visit 3 (Day 0), 
• 
Visit 4 (days 2-6) and 
• 
Visit 5 (days 6-10), 
At least two days will elapse between IV infusions (Visits 2-5). 
Two follow-up visits (Visits 6 and 7) will occur at days 15 (+/-5 days) and days 29 (+/- 7 days). 
At least two days will elapse between Visits 5 and 6. 
8.1.1 Treatment Group 
Participants randomised to the scopolamine group will receive one 15-minute infusion of IV 
Scopolamine in 1 OOml saline, repeated over 3 visits (Visit 3, 4 & 5). 
8.1.2 Placebo Group 
Participants randomised to the placebo group will receive one 15-minute infusion of IV saline, 
repeated over 3 visits (Visit 3, 4 & 5). 
8.1.3 Placebo run-in 
All participants will receive placebo at Visit 2, known as a placebo run-in. In addition, at Visit 
3 pre-randomisation, participants must ensure they continue to fulfil placebo run-in inclusion 
criteria. 
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Figure 1: CONSORT Trial Flow Diagram: A Randomised Double-Blind Placebo-Controlled 
Trial of Scopolamine in Bipolar Disorder 
I 
I 
ENROLMENT 
Sampling Frame 
• Attending the Galway-Roscommon Mental Health 
Services, including a specialised bipolar clinic in Galway 
who are referred due to experiencing a depressive 
episode 
• Previously attended HRB-CRFG with an interest to 
participate/or have participated in research and 
indicated a willingness to engage in future research: 
• Approach the research group directly requesting 
participation. 
I 
Visit 1: Screening& Informed 
Consent (n-60) 
I 
Visit 2: IV Placebo 
(100mls of saline over 15 minutes) 
I 
Drop-out or 
ineligible (n - 10) 
I 
I 
Visit 3: Assessment 
I 
I 
I 
I n=25 I I Visit 3: Randomisation (n=50) 
I n=25 ! 
I 
I 
I 
Visit 3-5 
Visit 3-5 
Allocated IV Scopolamine 
Allocated to IV placebo 
(4 µg/kg over 15 minutes in 1 OOmls of 
(1 OOmls of Saline over 15 minutes) 
Saline) 
-j 
Drop-out (n - 6) r-
• Visit 3: Scopolamine Day 0 
• Visit 3: Placebo Day O 
• Visit 4: Scopolamine Day 2-6 
• Visit 4: Placebo Day 2-6 
• Visit 5: Scopolamine Day 6-10 
• Visit 5: Placebo Day 6-10 
I 
I 
Follow-Up 
Follow-Up 
• Visit 6: Day 15 ( +/-5) 
• Visit6: Day15(+/-5) 
• Visit 7: Day 29 (+/-7) 
• Visit 7: Day 29 (+/-7) 
Note timeline between visits: 
Visit 1 and 2: :<;14 days. Can also occur on the same day and thus data does from screening visit does not need to be replicated at Visit 2. 
Visit 2 and 3: 2:2 days and s7 days 
Visit 3 and Visit 4 and Visit 5 and Visit 6: 2:2 days 
Visit 6 and Visit 7: 2:3 days 
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8.2 Selection of study population 
8.2.1 Population 
Page 27 of 62 
There will be 50 adult trial participants (both male and female) who have bipolar disorder 
(bipolar disorder 1 or 2) and are experiencing a depressive episode of at least moderate 
severity as measured by a HORS of 2: 14 at Visit 2; with 25 participants randomised to receive 
Scopolamine and 25 randomised to receive placebo. It is anticipated that approximately 60 
individuals will be recruited into the study at Visit 2, and that approximately 10 individuals will 
withdraw prior to study randomisation. Thus, the target for recruitment is approximately 60 
patients with 50 patients to be randomised into the trial. 
8.2.2 Inclusion criteria 
To be eligible for inclusion, each participant must meet all of the following inclusion criteria at 
Screening (Visit 1) and must continue to fulfil these criteria at Visit 2 to take part in the trial: 
1. Diagnosis of Bipolar Disorder according to Diagnostic Statistics Manual (DSM)-V 
criteria 
2. Experiencing an episode of depression of at least moderate severity at Visit 1 
(Screening) and Visit 2 based on clinical interview by a trained clinician and a 
Hamilton Depression Rating Scale (HORS) score 2: 14. 
3. 
2: 18 years old at Visit 2 (male or female) 
4. In the opinion of the Principal Investigator or Sub Investigator's, be able and willing 
to provide written informed consent and to comply with the requirements of this 
study protocol. 
5. Written informed consent prior to participating in the study 
6. U&Es, LFTs and TFTs laboratory tests within acceptable ranges in the previous 4 
months of the Screening Visit (Visit 1). 
Placebo run-in inclusion criteria at Randomisation visit (Visit 3): 
7. In addition to above, participants must be experiencing an episode of depression of 
at least mild severity (having previously experienced an episode of moderate 
depression at Visit 2 with HORS 2:14), based on clinical interview by a trained 
clinician and a HORS score of 2: 8. 
8.2.3 Exclusion criteria 
Participants who meet any one or more of the following exclusion criteria at Screening (Visit 
1) or the Visit 2 will not be eligible to take part in the trial: 
1. History of other Axis I diagnosis (including Recurrent Depressive Disorder or Psychotic 
Disorders such as schizo-affective disorder, conditions that can also present with 
depressive episodes) 
2. History in the three months prior to Visit 2 of alcohol dependence syndrome or 
substance dependence syndrome. 
3. Current use of oral steroid at Visit 1 
4. A confirmed diagnosis of dementia 
5. A diagnosis of intellectual disability (IQ < 70) 
6. Participants with bipolar disorder that are euthymic in the investigators opinion at 
screening or Visit 2. 
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7. Participants with bipolar disorder that are hypomanic or manic (Young Mania Rating 
Scale (YMRS) > 6) at screening or Visit 2. 
8. Presence of an established neurological disorder or other serious demyelinating 
conditions as determined by the treating physician (e.g. space occupying lesion, 
multiple sclerosis) 
9. Current involuntary detention under the Mental Health Act (MHA) 2001 in an acute 
psychiatric inpatient unit 
10. Severity of Bipolar Disorder is such that participation in a clinical trial is not appropriate 
because of the risk of imminent self-harm (based on clinical note review and review at 
screening visit by experienced clinician) 
11. A history of an allergic reaction or sensitivity to Scopolamine (Hyoscine Hydrobromide). 
Participants will be asked at the screening visit about any previous treatment with 
scopolamine (Hyoscine Hydrobromide) to ascertain any previous allergic reaction or 
sensitivity to this agent. 
12. A clinical diagnosis of narrow angle glaucoma, myasthenia gravis, paralytic ileus, 
pyloric stenosis, toxic megacolon and acute porphyria. 
13. Individuals will be excluded from the study if currently prescribed anticholinergic 
medications, including Physostigmine, Biperiden and Procyclidine. Individuals will 
additionally be excluded if currently prescribed Tricyclic Antidepressants which are 
associated with 
significant anticholinergic properties (e.g. 
Amitriptyline and 
Nortriptyline) that are currently causing the participant to experience anticholinergic 
side effects (e.g. blurred vision, constipation, urinary retention, cognitive difficulties). 
No individuals will have anticholinergic medications stopped to allow them enter the 
trial. 
14. Bradycardia < 50 bpm, tachycardia> 100bpm or hypotension (systolic BP <90 and I 
or diastolic BP < 60) prior to IV administration of placebo or Scopolamine 
15. A recent history in the last 6 months of symptomatic orthostatic hypotension or 
syncope. 
16. Previous participation in this trial. Participation is defined as randomised. Participation 
in another trial within 3 months prior to Visit 1. Receipt of any investigational medicinal 
product (IMP) within 3 months prior to Visit 1. 
17. Participants concurrently being administered Electroconvulsive Therapy (ECT). 
18. Pregnancy, as determined by a positive urine dipstick at Visits 2, 3, 4, 5, positive blood 
serum result executed at Visit 2 and confirmed prior to infusion at Visit 3 or participants 
who are actively breastfeeding (female only). 
19. Women of child-bearing potential are defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of study treatment. Highly effective contraception methods include: 
• 
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least six weeks before taking 
study treatment. 
• 
Male partner sterilization 
• 
Combination of any two of the following: 
a. Barrier methods of contraception e.g. Condom 
b. Use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception 
c. Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
• 
Women who are considered post-menopausal i.e. amenorrhea at least 
12 months or undergone hysterectomy/bilateral oophorectomy 
20. Any disorder, unwillingness or inability, not covered by any of the other exclusion 
criteria, which in the investigator's opinion, might jeopardise the participant's safety or 
compliance with the protocol 
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Placebo run-in exclusion criteria at Randomisation visit (Visit 3): 
21. In addition to having completed Visit 2, participants must not be experiencing a 
hypomanic, or manic episode (YMRS >6). 
22. A Serious Adverse Event (SAE) experienced during infusion which required medical 
intervention and whereby attending physician deemed it inappropriate for the 
participant to engage in future infusions. 
8.3 Recruitment, Study visits and procedures 
8.3.1 Treatment duration 
Run-in period will be a maximum 21 days. The treatment period will be a maximum 10 days 
and the maximum number of days for follow up is 28 days 
8.3.2 Identification and Recruitment 
Potential participants for this study will be identified as follows: 
1. Patients currently attending the Galway-Roscommon Mental Health Services, 
including a specialised bipolar clinic in Galway who are referred due to experiencing a 
depressive episode by their treating clinical team; or, 
Or, 
2. Patients who have previously attended NUI Galway/HRB-CRFG with an interest to 
participate/or have participated in research and indicated a willingness to engage in 
future research: 
Or, 
3. Patients who approach the research group directly requesting participation. 
Informed written consent will be obtained prior to any study related procedures being 
undertaken. 
8.3.3 Screening Assessments (Visit 1) 
• 
Informed consent 
• 
Review of inclusion/exclusion criteria 
• 
Demographic Data (Gender, Age, Race) 
• 
Handedness MEHi questionnaire 
• 
Review of relevant medical and surgical history 
• 
Review clinical history of bipolar disorder 
• 
Recording of current medications 
• 
Vital Signs recorded (BP, HR, RR) 
• 
U&Es, LFTs and TFTs blood tests (if required) 
• 
Completion of SCIO-RV for DSM-V Disorders 
• 
Completion of HORS questionnaire 
• 
Completion of YMRS questionnaire 
• 
AUDIT screening for alcohol use 
• 
Verbal confirmation received from female participants that they are not pregnant. 
• 
Adequate contraception advice given to female and male participants (see 8.4. 7) 
The maximum amount of time between screening and Visit 2 will be 14 days, inclusive of 
weekend days and bank holidays. The screening visit and the Visit 2 may occur on the same 
day and thus case data for screening visit does not need to be replicated for the Visit 2. 
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8.3.4 Visit 2 Assessments 
The following pre-treatment assessments will be performed at Visit 2. 
• 
Confirmation of eligibility (review inclusion/exclusion criteria) 
• 
Confirmation of pregnancy status (pregnancy tests) and contraception advice 
• 
U&Es, LFTs and TFTs blood tests (if required) 
• 
Review of current medications, including changes in medications since Visit 1 
• 
Physical measurements (height and weight) 
• 
Vital Signs recorded (BP, HR, RR) (pre-infusion but post cannulation) 
• 
ECG to be undertaken 
• 
Completion of HDRS (pre-infusion) 
• 
Completion of the YMRS (pre-infusion) 
• 
Completion by participant of the POMS (pre-infusion) (optional) 
• 
Completion of CGl-S (pre-infusion) 
• 
Completion of Fagerstrom (pre-infusion) 
• 
Completion of MADRS questionnaire (pre-infusion) 
• 
Completion by participant of a VAS (pre-infusion) 
• 
Cannulation site check (pre-infusion) 
• 
IV cannulation 
The following post-treatment assessments will be performed at Visit 2: 
• 
Cannulation site check (post-infusion) 
• 
15-minute infusion of IV placebo (100ml saline) 
• 
Completion by participant of the POMS (minimum 15 minutes post infusion) (optional) 
• 
Completion of WAIS (post-infusion) 
• 
Completion of NEO (post-infusion) 
• 
Completion by participant of a VAS (minimum 15 minutes post-infusion) 
• 
Undertake CANTAB tests (post-infusion) (may occur at Visit 3 either) 
• 
Vital Signs recorded (BP, HR, RR) within 15 minutes of when infusion stopped and 
50 to 90 minutes post-infusion 
• 
Completion of PRISE questionnaire by participant (post-infusion, optional) 
• 
Assessment for other adverse effects (see section 10.1) (pre, during and post infusion) 
8.3.5 Treatment (Visit 3, Visit 4 and Visit 5) 
At Visit 3, after assessment, participants will be randomised to placebo (n=25) (100mls IV 
Saline) or 4 µg/kg Scopolamine (n=25) IV in 100mls of Saline over 15 minutes and receive 
further infusions at Visits 4 (days 2-6) and 5 (days 6-10), with at least 2 days between IV 
infusions (see Table 2). 
Assessments at Visits 3 prior to randomisation to ensure trial eligibility 
• 
As per inclusion criterion 7 and exclusion criteria 21 and 22. 
• 
HDRS ~ 8 (indicating depressed mood of at least mild severity 
• 
YMRS <6 (indicating patient is not (hypo)manic) 
• 
Medication review to ensure no participants have been prescribed medications which 
would exclude the participant from the trial between Visit 2 and Randomisation. 
• 
Confirmation of pregnancy serum result (females only) 
Randomisation via Interactive Web Response System (IWRS) (Visit 3 only) 
Assessments at Visits 3, 4 and 5 are: 
• 
Review of any medication changes 
• 
Vital Signs recorded (BP, HR, RR) (pre-infusion but post cannulation) 
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• 
Dispensing via IWRS (Visit 3, 4, and 5) 
• 
Completion of HORS questionnaire (Visit 3 (completed as part of eligibility 
assessment), Visit 4, and 5, pre-infusion) 
• 
Completion of MADRS questionnaire (Visits 3, 4 and 5, pre-infusion) 
• 
Completion of YMRS (Visit 3 (completed as part of eligibility assessment), Visit 4, 
and 5, pre-infusion) 
• 
Confirmation of pregnancy status (Urine dipstick) and contraception advice (Visit 3, 4 
and 5, pre-infusion) 
• 
Completion by participant of VAS (Visit 3, 4, and 5, pre-infusion) 
• 
Completion by participant of the POMS (Visit 3, 4, and 5, pre-infusion) (optional) 
• 
Completion of GAF questionnaire (Visits 3 and 5, pre-infusion) 
• 
Completion of CGl-S (Visit 3, 4 and 5, pre-infusion) 
• 
Completion of CGl-1 (Visits3, 4 and 5, pre-infusion) 
• 
IV cannulation 
• 
Cannulation site check (pre-infusion and post-infusion) 
• 
Completion by participant of the POMS (minimum 15 minutes post-infusion (optional) 
• 
Completion by participant of VAS (minimum 15 minutes post-infusion) 
• 
Completion by participant of CANTAB subscales (Visit 3, post-infusion) (optional) 
• 
Completion of WAIS (post infusion at Visit 3,4, or 5) (optional) 
• 
Completion of NEOPl-FFI (post infusion at Visit 3,4, or 5) (optional) 
• 
Vital Signs recorded (BP, HR, RR) (within 15 minutes of infusion stopping and 50 to 
90 minutes post-infusion) 
• 
Completion by participant of the PRISE questionnaire (post-infusion at Visit 3, 4 or 5 
optional) 
• 
Assessment for other adverse effects (see section 10.1) (pre, during and post 
infusion) 
· 
8.3.6 Follow up visits (Visit 6 and 7) 
Visits 6 [15 (+/-5 Days)] and 7 [29(+/-7)] have no treatment component. There will be at least 
2 days between Visit 5 and 6 and 3 days between Visits 6 and 7. 
Assessments at Visit 6 and 7 are: 
• 
Review of any medication changes 
• 
Completion of HORS questionnaire 
• 
Completion of YMRS questionnaire 
• 
Completion by participant of the POMS questionnaire (optional) 
• 
Completion of CGl-S 
• 
Completion of CGl-1 
• 
Completion by participant of CANTAB subscales (Visit 6) (optional) 
• 
Completion of MADRS questionnaire 
• 
Completion of GAF questionnaire 
• 
Completion of WAIS (optional) 
• 
Completion of NEOPl-FFI (optional) 
• 
Adverse event assessment (see section 10.1) 
• 
Participant assessment of treatment group (IV Scopolamine or IV Saline) (Visit 7) 
Visits 6 and 7 maybe conducted over the telephone if necessary but only in limited 
circumstance such as participant withdrawn or unwilling /unable to attend clinic for scheduled 
visit. 
An outline of scheduled study assessments and procedures are outlined below in table 2. 
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Table 2: Schedule of Assessments 
Procedures 
Sioned informed consent 
Inclusion/Exclusion 
Randomisation 
IWRS 
Demoqraphy 
MEHi 
Medical/Surgical 
Historv/ Historv BPD 
Current Medication 
Vital Si ans - HR, BP & RR 
SCID-RV 
HDRS 
YMRS 
AUDIT 
Preonancv Discussion 
Contraception Advice 
Serum Preonancv Test! 
Preqnancv urine di cstic~ 
U&Es, LFTs, TFTs 0 
Faoerstrom 
CGl-S 
CGH 
VAS 
MA DRS 
GAF 
ECG 
Heioht Ccml & Weicht (kc) 
IV Cannulation 
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Visit 1 
Screening 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pre 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
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Visit 3 
Visit4 
Visit 5 
Visit6 
Visit 7 
Randomisation 
Day 15 
Day 29 
Dayo 
Day 4 (± 2 Days) 
Day 8 (± 2 Days) 
(± 5 Days) 
(± 7 Days) 
Scop0lamine or Placebo 
Scooolamine or Placebo 
Scooolamine or Placebo 
Follow-Up 
Follow-Up 
IV Infusion 
IV Infusion 
IV Infusion 
Post 
Pre 
During 
Post 
Pre 
Durinq 
Post 
Pre 
Durinq 
Post 
X*** 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
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Visit 1 
Visit 2 
Visit3 
Visit4 
Visits 
Visit& 
Visit 7 
Procedures 
Screening 
Randomisation 
Day 15 
Day29 
DayO 
Day 4 (± 2 Days) 
Day 8 (± 2 Days) 
(± 5 Days) 
(± 7 Days) 
PLACEBO 
Scopclamine or Placebo 
Scopclamine or Placebo 
Scopolamine or Placebo 
Follow-Up 
Follow-Up 
IV Infusion 
IV Infusion 
IV Infusion 
IV Infusion 
Pre 
Durina 
Post 
Pre 
Durina 
Post 
Pre 
Durina 
Post 
Pre 
Durina 
Post 
Infusion administration 
x 
x 
x 
x 
Adverse Events 
. x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Cannulation Site Check 
x 
x 
x 
x 
x 
x 
x 
x 
POMS (Optional) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CANTAB •• (O otional) 
x 
x 
x 
WAIS * (Optional) 
x• 
x• 
x• 
x• 
x• 
x• 
NEO-Pl-FFI *(Optional) 
x• 
x• 
x• 
x· 
x• 
x• 
PRISE (Optional) 
x 
x 
x 
x 
Subiective Assessment 
x 
Randomisation will only occur at Visit 3 after HORS is demonstrated to be ~ 8 and YMRS < 6. These measures will be conducted pre-randomisation (and 
consequently also pre-infusion). 
Pre-infusion vital signs should be taken post cannulation. Post-infusion vital signs within 15 minutes of infusion stopping and 50 to 90 minutes post-infusion. 
Visit 6 and 7 can be conducted by telephone in limited circumstances if a participant has withdrawn or is unwilling/unable to attend clinic at the scheduled time. 
* Can be undertaken at any of the marked visit 
** These include Paired Associates Learning (PAL), Spatial recognition, Delayed Match to Sample, ID-ED Shift, motor screening and Eyes of the Mind tests. 
***Only inclusion criterion 7 and exclusion criteria 21 and 22 are required to be met for randomisation at Visit 3 only 
ti Pregnancy test (serum pregnancy test and pregnancy urine dipstick), when required, for female participants only. Serum result confirmed prior to Visit 3. 
0 Blood tests for U&Es (Urine and Electrolytes), LFTs (liver Function Tests) and TFTs (Thyroid Function Tests) should be confirmed within acceptable ranges 
in the previous 4 months of the Screening (Visit 1 ). Can be performed if required at Visit 1 or 2 (results must be confirmed as acceptable prior to infusion). 
AUDIT= Alcohol Use Disorder Identification Test; BP= Blood Pressure; CANTAB =Cambridge Neuropsychological Test Automated Battery, CGl-1 =Clinical Global Impression- Improvement, CGl-
S= Clinical Global Impression- Severity, ECG= Electrocardiograph; Fagerstrom: Test for Nicotine Dependence, GAF= Global Assessment of Functioning; HORS= Hamilton Depression Rating Scale; 
HR = Heart Rate; IV = Intravenous; IWRS = Interactive Web Response System; MAORS = Montgomery and Asberg Depression Rating Scale; MEHi = Modified Edinburgh Handedness Inventory; 
NEO Pl-FFI = NEO Personality Inventory-Five Factor Inventory; POMS = Profile of Mood States; PRISE= Patient Rated Inventory of Side Effects; RR = Respiratory Rate; SCIO-RV = Structured 
Clinical Interview for DSM; VAS= Visual Analogue Scale; YMRS =Young Mania Rating Scale; WAIS= Wechsler Adult Intelligence Scale. 
Note timeftne between visits: 
Visit 1 and 2: ,; 14 days. Can also occur on the same day and thus data does from screening visit does not need to be replicated at Visit 2. 
Visit 2 and 3: ;,2 days and s 7 days 
Visit 3 and Visit4 and Visit 5 and Visit 6: ;>:2 days 
Visit 6 and Visit 7: ;,3 days 
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8.4 Description of Study Procedures 
8.4.1 Informed Consent 
Page 34 of 62 
Eligible participants may only be included in the trial after providing written informed consent. 
Informed consent must be obtained prior to conducting any trial specific procedures and the 
process for obtaining informed consent must be fully documented in the patient's medical 
records. 
The central ethics committee (EC) approved Patient Information Leaflet and Informed Consent 
Form (PIL and ICF) will be provided to potential participants, which the member of the research 
team, Principal Investigator and/or Sub Investigator's will explain and discuss the nature of 
the study. Potential participants will have ample time to ask and have answered any questions 
prior to making a decision regarding participation. 
When the participant is ready to do so, the ICF will be initialled, signed and dated by the 
participant, and the Principal Investigator and/or Sub-Investigators who administered the 
informed consent form. The complete original ICF will be filed by the site in the site file, a copy 
of the ICF will be given to the participant and a copy will be filed in the participant's notes. 
8.4.2 Medical and Surgical History 
Details of current and previous relevant diagnoses and treatments will be recorded as deemed 
relevant by Pl I Sub Pl or research team. In particular, medical history of cardiovascular 
disease, prostatic hypertrophy, asthma, hepatic or renal impairment, gastrointestinal 
obstruction, epilepsy and thyrotoxicosis should be sought. 
8.4.3 Demographics 
The date of birth, gender, race and handedness will be recorded. Handedness will be 
accurately measured utilising the Modified Edinburgh Handedness Inventory (MEHi, Oldfield, 
1971; Tan, 1988). 
8.4.4 Physical Examination 
Height (cm) and weight (kg) will be recorded at Visit 2. The weight at Visit 2 will be used for 
the duration of the study to inform dose calculations. 
8.4.4.1 Vital signs 
Vital signs will be recorded for all participants and will include: blood pressure (BP), heart rate 
(HR) (beats per minute (bpm)), and respiratory rate (RR) (respirations per minute). These will 
be recorded at screening, Visit 2 and at Visits 3, 4 and 5. Patients will rest for 5 minutes before 
measurements are obtained. Vital signs will be recorded prior to infusions and post infusions. 
Prior to infusion vital signs should be obtained post cannulation. 
For post infusion vital signs will be taken within 15 minutes post-infusion administration and 
fifty to 90 minutes post-infusion, resting HR and BP will be measured, with a requirement for 
a HR ~50bpm, and BP ~90mm Hg Systolic and ~60mm Hg diastolic prior to visit completion. 
Clinical support is present to support and advise research staff and participants in relation to 
the management or treatment strategies that are required if the participants HR is < 50 bpm 
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or > 1 OObpm or if participant is hypotensive (BP < 90/60). Clinical support includes ready 
access to resuscitation equipment and clinical expertise. 
Where BP and I or HR are abnormal when measured post-infusion the participants respiratory 
rate will additionally be recorded, and this information will be provided to an on-site clinician. 
All participants will be required to remain in the HRB-CRFG for a period of observation by trial 
staff for a minimum of 90 minutes post infusion. Participants should be asymptomatic of 
potential IMP related symptoms as well as having satisfactory vital signs before discharge 
post infusion. 
8.4.4.2 ECG Test 
An ECG will be performed at Visit 2. Abnormal findings will be noted for clinical significance 
and the report will be signed by the investigator. If deemed required by the treating physician, 
additional input will be obtained by an additional registered medical practitioner prior to 
continuation in the study. 
8.4.5 Laboratory Tests 
Prior to engagement in the clinical study, trial participants will demonstrate no renal/hepatic 
impairment and no evidence of thyrotoxicosis. This will be based on an evaluation of medical 
history and blood tests including Urea and Electrolytes (U&Es), Liver Function Tests (LFTs) 
and Thyroid Function Tests (TFTs). The most recent U&Es, LFTs and TFTs baseline must be 
demonstrated to be within acceptable range in the previous 4 months of the Screening visit 
(visit 1 ). If no blood tests have been completed within the last 4 months, these will be 
performed at Visit 1 or Visit 2 and confirmed as acceptable prior to first infusion. Where results 
are obtained that are outside the laboratory stated normal range, this will be discussed with 
the Pl and where required, the Pl will further liaise with clinical colleagues to ensure that any 
findings are not clinically significant and are acceptable prior to administration of IMP or 
placebo. If clinically significant, in the opinion of the investigator, the participant will not receive 
IMP or placebo. 
Women of child-bearing potential must have a negative pregnancy test. A urine pregnancy 
dipstick test will confirm pregnancy status at Visits 2, 3, 4 and 5 prior to each infusion. A serum 
pregnancy blood test will additionally be conducted at Visit 2 and this will confirm pregnancy 
status prior to infusion at Visit 3 (placebo/Scopolamine). 
8.4.6 Current Medications 
All medications will be recorded and changes in psychotropic medication recorded at each 
study visit. All over-the-counter or prescription medication, vitamins, and/or herbal 
supplements will be recorded in the patients notes. The indication for treatments will be 
recorded. Psychotropic medications prescribed over the previous 6 months will additionally be 
recorded. 
8.4.7 Pregnancy and contraception Advice 
Women of childbearing potential can only be included in the study if they have a negative urine 
dipstick test at Visits 2, 3, 4, 5 prior to infusions and a negative blood serum pregnancy test 
executed at Visit 2 and confirmed prior to infusion at Visit 3. 
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Women of child-bearing potential are defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing of study treatment (Visits 1-5). Highly effective contraception methods include: 
• 
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least six weeks before taking 
study treatment. 
• 
Male partner sterilization 
• 
Combination of any two of the following (advice will be provided to all 
appropriate female participants): 
a. Barrier methods of contraception e.g. Condom 
b. Use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception 
c. Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
• 
Women who are considered post-menopausal i.e. amenorrhea at least 
12 months or undergone hysterectomy/bilateral oophorectomy 
• 
All males participating in this study should similarly be provided with 
adequate contraception advice as detailed above. 
8.5 Psychometric Instruments 
The timings of administration of the below questionnaires is provided in Table 2. The SCID-
RV, HORS, YMRS, MADRS, GAF, AUDIT, Fagerstrom and VAS should be completed on all 
participants. The other listed psychometric instruments are desirable but not compulsory and 
are indicated as optional (POMS, CANTAB, PRISE, WAIS, NEO-Pl-FFI). The POMS and VAS 
should be completed a minimum of 15 minutes post-infusion. The WAIS and NEO-Pl-FFI can 
be completed at any of the scheduled visits. Details of each psychometric instrument is 
provided below: 
• 
Alcohol Use Disorder Identification Test (AUDIT, Baber et al., 2001). A 10-item 
questionnaire to identify harmful use or dependence on alcohol. 
• 
The Cambridge Neuropsychological Test Automated Battery (CANTAB; Owen et al., 
1995; Sahakian et al., 1988) will be undertaken with participants. Tests conducted from 
this battery will entail the Paired Associates Learning, Spatial recognition, ID-ED shift, 
delated match to sample, motor screening and eyes to mind test. These tests will be 
used to evaluate visual, new and spatial memory, motor speed and social cognition. 
• 
Clinical Global Impression (CGI, Guy, 1976). A rating scale that measures illness 
severity (CGl-S) (1-7), and global improvement (CGl-1) (1-7)) and has an efficacy index 
(which relates therapeutic effect to adverse effects) (1-4). 
• 
Fagerstrom Test for Nicotine Dependence (Heatherton et al., 1991 ). A 6-item 
questionnaire examining nicotine dependence. 
• 
Global Assessment of Functioning (GAF, Hall, 1995). A rating scale from 1-100 that 
measures an individuals' functioning and is observer rated. 
• 
Hamilton Depression Rating Scale (HORS, Hamilton, 1960). A 21-item observer rated 
instrument that measures symptoms of depression. 
• 
Montgomery and Asberg Depression Rating Scale (MADRS, Montgomery & Asberg, 
1979). A 10-item observer rated scale that measures symptoms of depression. 
• 
NEO Personality Inventory-Five Factor Inventory (NEO Pl-FFI, Costa & Mccrae, 
1992). This 60 item personality inventory measures personality traits in five dimensions 
(neuroticism, 
extraversion, 
openness 
to 
experience, 
agreeableness 
and 
conscientiousness). 
• 
Patient Rated Inventory of Side Effects (PRISE). A 9 item self-report instrument 
measuring adverse effects associated with the gastrointestinal, genitourinary, nervous, 
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cardiac systems, sense organs, skin, sexual functioning, sleep and other general 
adverse effects. 
• 
Profile of Mood State (POMS, McNair et al., 1971). A rating scale where 65 adjectives 
are rated by participants on a 5-point Likert scale. Six factors are derived from these 
adjectives (tension, depression, anger, fatigue, vigour and confusion). 
• 
Structured Clinical Interview for DSM-V Axis I Disorders (SCIO-RV, First et al., 2015). 
This is a semi-structured interview that evaluates pathology and has a demographic 
section followed by nine diagnostic modules, including two that examine mood 
disorders. 
• 
Visual Analog Scale (VAS). A series of scales will be created to indicate on a 10-point 
Likert how participants feel they are on the following items (happy, restless, sad, 
anxious, anger, drowsiness and alertness). These items are consistent with that used 
by Furey et al. (2012) in their study of Scopolamine in mood disorders. 
• 
Wechsler Adult Intelligence Scale (WAIS, Wechsler, 1955) is a structured instrument 
to estimate IQ. 
• 
Young Mania Rating Scale (YMRS, Young et al., 1978). An 11-item observer rated 
instrument that measures symptoms of mania. 
8.6 Randomisation 
Participants will be randomly assigned to receive either scopolamine or placebo in a 1: 1 ratio. 
Randomly permuted blocks of sizes 4 and 6 will be used to ensure similar numbers of 
participants in each arm of the trial. 
Randomisation will be stratified by the HORS score at trial entry (a score of <23 indicating a 
mild-moderate depressive episode and a score <:!23 indicating a severe depressive episode) 
to ensure greater balance between arms in the final trial sample and increase the efficiency of 
our treatment effect estimates. 
A validated randomisation system will be used at Visit 3, (after HORS and YMRS are 
completed) to randomise patients to either arm. This centralised system will ensure allocation 
concealment; preventing blinded trial staff from knowing which treatment group will be 
allocated. Blocks of randomly varying length will also reduce the predictability of the allocation 
sequence. 
8.7 Discontinuing/Stopping Infusions 
If a trial participant requires medical intervention during or post infusion, the treating physician 
must assess if it is appropriate to proceed with the current and/or future infusions. If infusions 
are not completed participants would be asked to complete all other aspects of scheduled visits. 
8.8 Blinding 
This trial will be conducted in a double-blind fashion with placebo control identical to 
Scopolamine solution to avoid bias in the assessment of outcomes. 
Site Investigators, site personnel, participants, and outcome assessors will be blinded to 
treatment allocation. Placebo infusion must be prepared, labelled and administered to match 
procedures for Scopolamine (hyoscine hydrobromide) infusion in order to maintain the blind. 
Placebo and Scopolamine are identical, colourless solutions and infusions are identical once 
prepared. Blinding will be maintained as per the process steps and controls outlined in the 
study specific lnvestigational Medicinal Product (IMP) Handling Manual. The unblinded study 
member will be unblinded throughout the length of the study and will not be involved in any 
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patient assessments or data analysis. Study personnel who administer the infusions to the 
participants must remain blinded. Discussions regarding treatments between the unblinded 
team member and the blinded team member must be avoided where possible. 
Unblinding will be as per the instructions outlined in the study specific procedure provided to 
site by the sponsor. 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 participant, a caring physician may 
unblind a single participant. Any breaking of the blind, whether intentional or unintentional will 
be recorded and reported to the sponsor as soon as possible. Unblinding will be recorded and 
justified in the final report. 
Circumstances in which unblinding for multiple or all participants may take place include 
SUSARs, reporting for multiple SAEs or SARs, or if there is new information regarding the 
safety of the IMP as determined by the caring physician. 
8.9 Definition of end-of-trial 
The end of trial will be the date of the last visit of the last participant (5Q1h randomised 
participant). The Sponsor, the funder (Stanley Medical Research Institute (SMRI) and/or Data 
safety and monitoring board (DSMB) /Trial steering committee (TSC} have the right at any 
time to terminate the study for clinical or administrative reasons. The end of the study will be 
reported to the approving EC and HPRA within 90 days of the end of the clinical trial, or within 
15 days if the study is terminated prematurely by the Sponsor or the Sponsors representative. 
The EU Declaration of the End of Trial form must be used for this. The investigators will inform 
participants and ensure that the appropriate follow-up is arranged for all involved. A summary 
report of the study will be provided to the REC and HPRA within 1 year of the end of the study. 
8.10 Premature termination of the study 
The trial may be terminated prematurely if: 
• 
new information about safety or efficacy becomes available 
• 
there is unsatisfactory progress of the study, including unsatisfactory progress in 
relation to participant recruitment. 
• 
if deemed necessary by the Sponsor, Chief investigator, DSMB, TSC, and I or SMRI 
If the trial ends prematurely then the HPRA and the approving EC will need to be informed as 
required. 
8.11 Discontinuation/withdrawal of participants from study protocol 
Study participants 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 participant from study treatment or withdraw a 
participant from the study at any time if it is in the best interest of the participant. In this 
instance, participants must discontinue the investigational medicinal product (Scopolamine) 
and be withdrawn from the study. Reasons for investigator to discontinue a participant from 
study treatment include but are not limited to: 
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• 
Pregnancy, 
• 
Involuntary detention under the MHA 2001 in an acute psychiatric inpatient unit 
• 
Treatment with ECT 
• 
Severity of symptoms such that participation in a clinical trial is not appropriate 
because of the risk of imminent self-harm (based on review by clinician at study 
visit} 
• 
Development in the study of narrow angle glaucoma, myasthenia gravis, paralytic 
ileus, pyloric stenosis, toxic megacolon and acute porphyria. 
• 
Development post-infusion of bradycardia (HR < 50 bpm), tachycardia (HR > 
100bpm) or hypotension (Systolic BP <90mm HG or Diastolic BP <60mm Hg} that 
required clinical treatment (e.g. administration of additional medications, review in 
Emergency Department} 
• 
Treatment at day of infusion with anticholinergic medications (e.g. Physostigmine, 
Biperiden, Procyclidine) 
If a participant withdraws before completing the study, the reason for withdrawal must be 
documented in their medical notes. Participants who request to have no further infusions, will 
be invited to complete pre-infusion questionnaires for remaining treatment visits. Ideally, all 
participants who discontinue the study should comply with specified follow-up procedures 
(days 15 +/-5, days 29 +/-7) as detailed in this protocol (i.e. assessments via interview 
compromising psychometric instruments, discussion of adverse effects and medication and 
phlebotomy - Table 2, Section 8.3). If the participant is unable to attend for follow-up 
procedures, a telephone interview will be offered to attain relevant study data. The only 
exception to this requirement is when a participant withdraws consent for all study procedures. 
If a study participant withdraws consent after just receiving or during an infusion, monitoring 
for 50-90 minutes post infusion for bradycardia, hypotension, dizziness and sedation must 
occur, with the study specific Adverse Event Form completed. 
If a participant withdraws due to an adverse event, the investigator will arrange for follow-up 
visits until the adverse event has resolved or stabilised. 
8.12 Outcome measures 
8.12.1 Effectiveness Assessment 
8.12.1.1 
Primary outcome measure 
The primary outcome measure will be the change from Visit 2 in severity of objective 
depressive symptoms after the final scheduled treatment as measured by change in the HDRS 
depression score from Visit 3 (pre-infusion and randomisation} to Visit 6. 
8.12.1.2 
Secondary outcome measure 
1. Remission of depressive episode after the last IV treatment (measured objectively at 
Visit 6), and is defined as occurring when an individual has: 
(i} a HDRS score 'S.7 
(ii} a MADRS score <6 
2. Remission of depressive episode at follow-up (measured objectively at Visit 7) 
(i) a HDRS score S7 
(ii} a MADRS score <6 
3. Response to a depressive episode after the last IV treatment (measured at Visit 6) is 
defined as: 
(i) a 50% reduction in MADRS score at Visit 6 compared to Visit 3 
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4. Response to a depressive episode at follow-up (measured objectively at Visit 7) 
(i) a 50% reduction in MADRS score at Visit 6 compared to Visit 3 
5. Improvement in mood symptoms measured with the HORS and MADRS at visits 5, 6 
and 7 compared to Visit 3. 
6. Improvement in objectively measured overall functioning, measured with the GAF at 
Visit 5, 6 and at follow-up at Visit 7 compared to Visit 3 
7. Improvement in objectively rated illness severity, measured with the CGl-S at visits 4, 
5, 6 and 7 compared to Visit 3 and CGl-1 at visits 4, 5, 6 and 7 compared to Visit 3. 
8. Changing subjective measured depressive symptoms with the POMS and VAS 
(i) a reduction in POMS score post-infusion compared to pre-infusion at visits 2, 
3, 4 and 5 across the six different factors of the POMS (tension, depression, 
anger, fatigue, vigour and confusion). 
(ii) a reduction in VAS scores post-infusion compared to pre-infusion at visits 2, 3, 
4 and 5 across 8 items (happy, restless, sad, anxious, anger, drowsiness and 
alertness). 
9. A change in subjectively measured depressive symptoms at Visit 6 compared to Visit 
3 as measured with the POMS and VAS. 
10. A reduction in subjectively measured depressive symptoms at follow-up (Visit 7) 
compared to Visit 3 as measured with the POMS and VAS. 
11. Psychiatric inpatient admission of a participant due to depressive episodes between 
Visit 2 and Visit 7. 
12. Antidepressants medication use or change by a participant due to depressive episodes 
over the duration of the study (Visit 2 to Visit 7): 
(i) Introduction of a new antidepressant (yes I no) 
(ii) Increase in dose of an existing antidepressant (yes I no) 
13. Change in motor processing, visual and spatial memory (3 categorical variables) at 
Visit 6 compared to Visit 2 based on the CANTAB battery of tests. 
14. Occurrence of a hypo (manic) episodes at visits 3, 4, 5, 6 or 7, as defined by a score 
of >6 on the YMRS. 
15. Occurrence of other adverse effects as observed on monitoring of vital signs, reported 
by participants or measured utilising the PRISE questionnaire 
9. 
Treatment of Trial Participants 
9.1 Description of study treatment(s) 
Investigative Medicinal Product: (Active treatment): Scopolamine (Hyoscine Hydrobromide 
600 micrograms/ml, 1 ml) Dosage = 4µg/kg in 100mls of Saline administered intravenously 
over 15 minutes via pulsed infusion. The Scopolamine dose is µg of drug per kg weight of the 
participant. 
Scopolamine supplier: Martindale Pharmaceuticals, Essex, UK. 
Placebo: Commercially available 0.9% sodium chloride 100ml infusion bag will be used as the 
placebo control in this trial. It will be administered intravenously over 15 minutes via pulsed 
infusion. The volume addition of active drug (hyoscine hydrobromide) will on average be less 
than 1 ml (1 OOkg patient or less) for each infusion bag, therefore no volume addition is required 
for the preparation of the placebo infusion bag as the volume difference to the active treatment 
infusion will be negligible to the total volume to be infused (100mls +volume overage in each 
bag) and will not be noticeable to personnel administering the infusion, thereby maintaining 
the blind. 
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Placebo supplier: Commercially available 0.9% Sodium Chloride 100ml infusion bag. 
This is an authorised product which will be approved stock sourced through the Galway 
University Hospital pharmacy. The details will be outlined in the IMP handling manual and the 
product number and batch number will be recorded for the duration of the trial. 
9.2 Formulation, packaging and handling 
Both placebo (0.9% sodium chloride) and Scopolamine are clear, colourless solutions and 
infusions are identical once prepared. The pharmacist will dispense the study drug to an 
unblinded research healthcare professional who will prepare the Scopolamine infusion as per 
the IMP handling manual (the unblinded healthcare professional will not be involved in 
assessments or data analysis). Blinding will be maintained as per the process steps and 
controls outlined in the study specific lnvestigational Medicinal Product (IMP) Handling 
Manual. 
The Clinical Trials Pharmacy Unit at the HRB-CRFG, will label commercial stock of 
Scopolamine as per Annex 13 and per approved study instructions. Labels will indicate: 
(i) 
Use of the treatment in this trial 
(ii) 
Name of sponsor and Cl 
(iii) 
Trial reference code allowing identification of the trial, site, investigator and 
participant number 
(iv) 
The product is 'For Clinical Trial Use Only' 
These labels will be added by pharmacy staff on receipt of delivery of the IMP to the HRB-
CRFG in accordance with Annex 13 (EU Guidelines to Good Manufacturing Practice, 
lnvestigational Medicinal Products). 
9.3 Storage and disposition of study treatment(s) 
Scopolamine (and placebo) will be stored securely at the HRB-CRFG as per manufacturer's 
guidelines. Scopolamine (hyoscine hydrobromide) will be stored in Pharmacy Clinical Trials 
Unit (PCTU) as per manufactures storage instructions. Placebo will be stored in clinical area 
as per manufactures instructions. Active and control treatments will be prepared into infusions 
by an appropriately trained and delegated unblinded site team healthcare professional based 
in the HRB-CRFG as per institutions guidelines/applicable SOPs in a separate clinical area 
away from the blinded study personnel and participant treatment area. The unblinded staff 
member will not be involved in any patient assessments or data analysis. Infusions should be 
administered to the participant immediately with minimal delay. The entire contents of the 
infusion bag must be administered to the participant. Empty infusion bags and any unused 
product will be disposed of according to institutions guidelines/applicable SOPs 
An accurate and timely record of IMP & placebo inventory must be maintained through the 
duration of the trial (including receipt, dispensing, return if applicable and destruction of 
unused product). A temperature log must be maintained for documentation of appropriately 
IMP and placebo storage areas. 
9.4 Preparation/Reconstitution of Dosage Form 
Administration instructions and dose preparation instructions will be provided as per the IMP 
handling manual. 
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9.5 Accountaibility of the study treatment(s) 
The study medication will be supplied by Martindale Pharmaceuticals, UK. Upon delivery, 
receipt of the products will be recorded by pharmacy staff and labels applied as described in 
IMP Handling Manual with products then transferred to the secure storage area. Unopened 
products which are unused by end-of-trial will be destroyed on site as per site destruction 
policies. 
9.6 Assessment of compliance 
In this study, interventions will be administered intravenously by the research team and thus 
treatment non-compliance will be low-risk. Non-compliance may result however from 
participants refusing further infusions after attaining an initial infusion(s), or asking for an 
infusion to be discontinued during an infusion. 
The investigator is responsible for ensuring that the study treatment is administered in 
compliance with the protocol. Participant compliance will be assessed by maintaining 
dispensing records. 
9. 7 Overdose of Study treatment 
It is deemed unlikely that an overdose will occur in this study, given the safeguards in place 
with careful preparation of each infusion. The Scopolamine drug will be prepared by approved 
study specific instructions as per the IMP Handling Manual to ensure appropriate preparation 
of the drug and accuracy of calculations performed as part of drug preparation. In the very 
improbable event of an overdose, the study participant will be monitored for any change in 
vital signs by the research team members. If adverse symptoms arise secondary to an 
overdose, local site policy will be followed in relation to management of any medical 
emergency. Infusions will be administered over a 15 minute period, with this controlled by use 
of a calibrated IV infusion pump. Thus, it is unlikely that an infusion will be administered in a 
time-frame of less than 15 minutes, however if this occurs and adverse symptoms arise, local 
policy will similarly be followed in relation to the management of a medical emergency. 
9.8 Prior and concomitant therapy 
All current medication, in addition to the study medication taken during the study will be 
recorded in the patient's notes. Medications will be documented at the point of consent, at 
Visit 2 with changes in treatment notes at every assessment appointment thereafter. 
Psychotropic medications prescribed over the previous six months will also be documented. 
9.8.1 Permitted medications/non-investigational medicinal products 
All medications including herbal treatments aside from those listed in section 9.8.2 are 
permitted. Standard of care will continue for all participants during this study. 
9.8.2 Prohibited medications 
The following medications are contraindicated during the randomised treatment period as they 
may potentially alter the pharmacokinetics of Scopolamine and any participants newly 
prescribed these medications at randomisation visit will be excluded from the trial prior to any 
infusion being administered. 
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• 
Physostigmine 
• 
Biperiden 
• 
Procyclidine 
• 
Tricyclic Antidepressants with significant anticholinergic properties (e.g. Amitriptyline 
and Nortriptyline) that are causing the participant to experience anticholinergic side 
effects (e.g. blurred vision, constipation, urinary retention, cognitive difficulties). 
Participants prescribed any of the above agents during the trial will not receive any further 
intervention (infusions of Scopolamine or placebo), however will be followed up for the 
remainder of the trial with data collected included in intention-to-treat analyses if one infusion 
and one follow-up assessment have been completed. 
Participants cannot participate in any other IMP studies while participating in this study (Visits 
2-7). 
10. 
Safety reporting 
Adverse events will be captured for all study participants from the time of consent for the 
duration of their participation in the study i.e. from the time of consent to their final study visit. 
A full AE review at each study visit will ensure that a complete evaluation of the safety and 
tolerability of the IMP is conducted. 
All participants will have their heart rate and blood pressure measured prior to infusion and 
post-infusion to measure haemodynamic changes, with normal results (see section 8.4.4.1) 
required post-infusion prior to the participant completing their visit (minimum 90 min monitoring 
period). 
If the readings have not returned to normal within this required 90-minute monitoring period a 
further period of monitoring will be conducted. A treating investigator must assess and decide 
if medical intervention is required based on their clinical judgement. Additionally, the PRISE 
questionnaire (this is optional for participants) will be used where participants agree to 
document other adverse effects prior to participants completing their clinical visits 2, 3, 4, and 
5 (see Section 8.5). All adverse events will be reported to the Sponsor on the AE case report. 
10.1 Definitions 
10.1.1 Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical trial participant 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. 
Each individual unintended sign, symptom or disease is considered a separate adverse event 
unless an overarching diagnosis can be made for a collection of signs or symptoms that are 
clinically linked and temporally related. The overarching diagnosis should be as specific as 
possible, using all available clinical data. 
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All events must undergo an assessment to determine if any of the seriousness criteria are met 
and each event must be reported to the Sponsor. 
10.1.2 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. 
10.1.3 Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
Any untoward medical occurrence or affect that at any dose meets one or more of the following 
criteria: 
• results in death, 
• is life-threatening*, 
• requires hospitalisation (defined as >24 hour hospital stay or admission to inpatient 
hospital area) or prolongation of existing hospitalisation, 
• results in persistent or significant disability or incapacity, 
• is a congenital anomaly or birth defect 
• is medically important** 
* This refers to an event in which the participant was at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death if it were more 
severe. 
-
Some medical events may jeopardise the participant 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. 
10.1.4 Suspected unexpected serious adverse reactions (SUSAR) 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (i.e. section 4.8 of the summary of product characteristics). 
10.1.5 Servere Adverse Event 
The term 'severity' is used here to describe the intensity of a specific event. This has to be 
distinguished from the term 'serious'. 
10.2 Evaluation of AEs and SAEs 
The investigator or delegate will report all AEs and SAEs to the Sponsor as outlined in section 
10.3, except for those identified as outcomes identified below. 
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10.2.1 Events exempt from reporting 
10.2.1.1 
Canulation related 
The following commonly experienced events related to cannulation are exempt from AE 
reporting if they are reported at the site of cannulation and are deemed non-clinically 
significant by a study investigator. 
(a) Discomfort 
(b) Small haematoma 
(c) Bruising 
(d) Transient light headedness 
(e) Irritation to plaster/dressing used over or around cannulation site. 
If the nature or severity of the event exceeds what is commonly experienced or if the event is 
deemed clinically significant by the investigator the event should then be reported as an AE. 
Events related to cannulation must be reported as SAEs/SARs if they meet one or more of the 
seriousness criteria as defined above. 
10.2.1.2 
Scopolamine infusion related 
The following events are considered expected, transient side effects of scopolamine therapy 
and are therefore exempt from safety reporting if they occur in the 90 minutes post IMP 
infusion (visit 3, visit 4 or visit 5). These events will be captured on a study outcome form. 
(a) Drowsiness 
(b) Blurred vision 
(c) Dry mouth 
(d) Thirst 
(e) Urinary retention 
The above occurrences are considered Adverse events and therefore reportable if any of the 
following occur: 
• 
medical intervention or treatment 
• 
prolonged monitoring in addition to the 90 minutes post infusion required by the 
protocol 
• 
deemed medically significant by an investigator 
• 
cessation of the study drug (current or subsequent infusions) 
These events must be reported as SAEs/SARs if they meet one or more of the seriousness 
criteria. 
10.2.1.3 
Change in depressive or {hypo)manic symptoms 
Change of baseline depressive symptoms or development of (hypo)manic symptoms based 
on clinical review are exempt from safety reporting unless they: 
(a) are associated with self-harm 
(b) are associated with uncharacteristic erratic behaviour 
(c) meet any one or more of the seriousness criteria 
These events are collected on case report forms. 
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10.2.1.4 
Psychotropic medications 
Changes in psychotropic medications are exempt from safety reporting. These changes are 
collected on case report forms. 
10.2.1.5 
Psychometric measures 
Variations in psychometric assessments captured on HORS, YMRS, CGl-S, CGl-1, VAS, 
MADRS, GAF and POMS are exempt from safety reporting. Psychometric assessments are 
collected on case report forms. 
10.2.2 Assessment of seriousness 
An appropriately qualified, delegated member of the site team should make an assessment of 
seriousness as defined in section 10.1.3. 
10.2.3 Assessment of causality 
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 investigator 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. 
• 
Unlikely: where a temporal relationship to the study medication makes a relationship 
improbable (but not impossible} and disease or other drugs provide plausible 
explanations. 
• 
Possible: 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. 
• 
Probable: The temporal relationship and absence of a more likely explanation suggest 
the event could be related to the study medication. 
• 
Definite: Plausible temporal relationship and cannot be explained by disease or other 
drugs. 
All AEs/SAEs judged as having a reasonable suspected causal relationship (e.g. definite, 
possible, probable} 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. 
The causality assessment provided by the investigator will also be reviewed by the sponsor. 
The investigator causality assessment should not be downgraded by the sponsor. 
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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10.2.4 Assessment of severity 
The investigator will make an assessment of severity for each AE/SAE and record this on the 
AE case report form according to one of the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities. 
• 
Severe or medically significant: An event that prevents normal everyday activities. 
• 
Life threatening: An event that has life-threatening consequences 
Note: the term 'severe', should not be confused with 'serious' which is a regulatory definition 
based on participant/event outcome or action criteria. 
10.2.5 Assessment of expectedness 
An expectedness assessment will be carried out by the sponsor for each serious adverse 
reaction to the IMP. The expectedness of a serious adverse reaction will be determined by the 
sponsor according to the reference safety information (RSI) as contained within section 4.8 of 
the Sm PC for scopolamine. 
10.3 Reporting responsibilities of the investigator 
10.3.1 Adverse events/serious adverse events 
Any AE whose onset occurred between the time of informed consent and the last completed 
visit, observed by the investigator or reported by the participant, whether or not attributed to 
the study medication, will be recorded on the AE case report form. The Site Investigator or 
delegate will follow AE's and SAE's reported during the treatment period until resolved, 
considered stable, or completion of patient participation in the Scopolamine trial (i.e. final 
follow up Visit). Follow up information will be sought and submitted as it becomes available. 
All SAEs will be followed up until resolution or they are clearly determined to be due to a 
participant's stable or chronic condition or intercurrent illness( es). 
The following information will be recorded in the adverse event form: Adverse event term, 
description, date of onset, outcome, date of resolution, seriousness, severity, assessment of 
relatedness to the study medication, and action taken with study drug. The Site Investigator is 
responsible for the assessment of severity (intensity) and causality/relatedness to IMP for all 
AEs and SAEs. A SAE should also be substantiated by a source document(s). 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 up until the event is considered stable. All related AEs that result in a 
participant's withdrawal from the study or are present post-infusion will be followed up until a 
satisfactory resolution occurs. Participants will continue to be monitored for AEs throughout 
the study period up to and including visit 7. 
It will be left to the investigator's clinical judgment whether or not an AE is of sufficient severity 
to require the participant's removal from treatment. A participant may also voluntarily withdraw 
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from treatment due to what he or she perceives as an intolerable AE. If either of these occurs, 
the participant must undergo an end-of-study assessment and be given appropriate care 
under medical supervision until symptoms cease or the condition becomes stable. 
Any pregnancy occurring during the clinical study and the outcome of the pregnancy should 
be recorded and followed-up for congenital anomaly or birth defect. 
Any SAE in a participant that the investigator becomes aware of occurring after they have 
finished the study follow up period, which are deemed by the investigator to be causally related 
to the IMP should be forwarded to saereport@nuigalway.ie. 
10.3.2 Timelines for reporting 
10.3.2.1 
Adverse events 
Adverse event information will be reported by site personnel in a timely fashion from the time 
the site becomes aware of the event. 
10.3.2.2 
Serious adverse events 
An appropriately qualified member of the site team will report all serious adverse events 
(SAEs) to the sponsor immediately but no later than 24 hours after site awareness of the SAE. 
The site team are considered aware of an adverse event from the time of first notification of 
the first member of the Scopolamine site team, as per the Site Delegation Log. All SAE's will 
be submitted by the site by completing the required fields on the AE eCRF within 24 hours of 
site awareness of the event. If the eCRF is unavailable a paper copy of the eCRF should be 
completed and submitted to HRB-CRFG within 24 hours of site awareness of the event. A 
valid SAE report must include all of the following: 
• 
Adverse event term (based on what is known at the time of reporting) 
• 
Seriousness criteria 
• 
Severity 
• 
Causality assessments (for Scopolamine/placebo) 
• 
Investigator sign-off 
The immediate report will be followed by detailed, written reports. The immediate and follow-
up reports will identify participants by unique code numbers assigned to the latter. 
All SAE information must be recorded on an SAE forms submitted to sponsor. Additional 
information received for an event (follow-up or corrections to the original event) should be 
detailed and submitted to the sponsor in an expedited manner. 
The Site Investigator or delegate will follow AEs and SAEs reported during participation in the 
trial until resolved, considered stable or completion of participation in the Scopolamine trial. 
Follow up information will be sought and submitted as it becomes available. All SAEs should 
be followed up until resolution or they are clearly determined to be due to a participant's stable 
or chronic condition or intercurrent illness( es). 
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10.4 Responsibilities of the Sponsor 
10.4.1 Regulatory Authorities 
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The sponsor will keep detailed records of all adverse events which are reported to them by 
the investigator or investigators. The sponsor will report all SUSARs to the competent authority 
(HPRA) or EudraVigilance (as required), the approving ethics committees concerned, and all 
principal investigators. Fatal or life-threatening SUSARs must be reported within 7 days. 
If the initial report is incomplete, e.g. all the information/assessment has not been provided; 
the sponsor will submit a completed follow up report within an additional eight days. 
SUSARs which are not fatal or life-threatening are to be reported within 15 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. 
10.4.2 Safety Reports 
The sponsor will distribute masked expedited SUSAR reports, to each participating Site 
Investigator, as appropriate. SUSARs of which the treatment allocation of the participant is un-
blinded should be reported by the sponsor to the national competent authority or 
EudraVigilance (as required) and the approving EC. 
10.4.3 Annual Reports 
In addition to the expedited reporting above, the sponsor shall submit annually throughout the 
clinical trial or on request, a Development Safety Update Report to the competent authority 
(HPRA) and ethics committees. The annual safety report will be presented in the DSUR format 
as per the requirements of ICH-GCP and applicable regulatory, HPRA and internal sponsor 
requirements. 
10.4.4 Pregnancy 
Pregnancy is not considered an AE or SAE however the investigator must collect pregnancy 
information for female trial participants or female partners of male trial participants who 
become pregnant while participating in a study to determine the outcome of the pregnancy. If 
a congenital anomaly or birth defect is recorded following a pregnancy which occurred during 
the study the congenital anomaly or birth defect will be reported as a SAE. In some 
circumstances, it may be necessary to monitor the development of the new-born for an 
appropriate period post-delivery. The investigator will record the information and submit this 
to the sponsor. 
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10.5 Data Safety Monitoring Board (DSMB) 
A DSMB is established and members will serve in an individual capacity and provide their 
expertise and recommendations. The primary responsibilities of the DSMB will be to: 
1. Become familiar with the research protocol and the procedures for data 
safety/monitoring. 
2. Review interim analyses of outcome data/adverse event reports. 
3. Make written recommendations to the TSC concerning the continuation, modification, 
or termination of the trial. 
4. Consider any requests for release of interim trial data and make recommendations to 
the TSC or TWG on the advisability of this. 
5. Review major proposed modifications to the study prior to their implementation (e.g., 
termination, increasing target sample size). 
6. Maintain confidentiality during all phases of DSMB review and deliberations. 
7. Review SAEs and SUSARs as appropriate 
The responsibilities of the DSMB are outlined further in the DSMB charter. The membership 
of the DSMB reflects the professions necessary to interpret the data and results from the study 
and to evaluate participant safety fully. 
10.6 Trial Steering Committee (TSC) 
The purpose of the TSC is to provide strategic oversight for the overall direction and strategy 
for a clinical trial. The primary responsibilities of the TSC are: 
1. To contribute to the design of the study 
2. Increase information exchange at an early stage of trial development 
3. Increase the efficiency of clinical trial collaboration 
4. To monitor and review a) Recruitment progress, b) Quality control, c) Ethical amendments, 
d) Financial aspects, and e) Publications 
5. To determine action points to facilitate the satisfactory progress of the Scopolamine study. 
This committee includes investigators, other experts not otherwise involved in the trial, and 
representative of the sponsor. 
11. 
Statistics 
11.1 
General considerations 
Descriptive statistics, graphs and tables will be used to summarise baseline variables, follow-
up outcome variables, and operational variables including rates of recruitment, willingness to 
be randomised, willingness to complete assessments, adherence to allocated treatments and 
follow-up and reasons for drop-out between groups. 
Suitable numerical and graphical summaries will be generated to for patient characteristics. 
Continuous variables will be summarized by mean, median, standard deviation (SD), minimum 
and maximum. Categorical variables will be summarized by counts and percentages. 
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Data analyses will be performed blinded to allocation. Full specification of the statistical 
analysis to be conducted and its rationale will be given in the statistical analysis plan, along 
with detailed tables, listings and graphs will be provided separately. This plan will be finalized 
prior to the end of enrolment. 
11.2 Determination of sample size 
The primary outcome in this study is the Hamilton Depression Rating Scale score (HORS). It 
is judged that a decrease of 50% or more in the HORS score between randomisation and Visit 
6 will be sufficient to consider a patient to have experienced a response. We anticipate that 
the average HORS score in the proposed population pre-randomisation will be 24 units and 
that this outcome variable will be approximately normal. Based on results from the literature, 
it is estimated that a range of plausible values for the standard deviation is between 5 to 13 
units. Using this information, a sample of 44 participants (22 in each group) will have 85% 
power to detect a difference of 12 units between the treatment and control arms, i.e. an 
expected HORS mean score of 12 in the treatment group vs. an expected HORS mean score 
of 24 in the control group after Visit 6. The sample size is based on a 2-sample t-test (two-
sided) with a standard deviation of 13 units (conservative approach) and a significant level of 
0.05. Allocating 25 participants to each arm will ensure power >=85% when loss to follow-up 
is <12% (6 participants missing at Visit 6 follow up). 
11.3 Analysis sets 
Effectiveness outcomes will be analysed on an intention-to-treat basis for all participants 
randomised and with available follow-up data as per their randomised allocation. 
A per-protocol dataset is not well-defined under multiple treatments, here it could reasonably 
be defined as those participants who either received at least 1, at least 2 or all 3 IV treatments 
after randomisation. Sensitivity analyses will thus be performed on the primary outcome to 
assess efficacy of the treatment compared to placebo by incorporating the original allocation 
of participants and their level of adherence to treatment. This will involve examining the short 
term-effect of treatment in a longitudinal model and the overall effect of number of IV 
treatments received at follow-up visits after the final IV treatment. 
11.4 Demographic and baseline disease characteristics 
Demographic, baseline outcome variables (primary and secondary), and additional baseline 
disease characteristic data will be summarized for each treatment group using descriptive 
statistics. 
11.5 Effectiveness analysis 
11.5.1 Primary effectiveness analysis 
For the primary effectiveness analysis of the primary outcome, it is expected that pre-
randomisation measurements of the HORS score will be correlated with the scores obtained 
at Visit 6 of treatment. The mean scores at Visit 6 will be compared across the study arms 
using an ANCOVA model. The response variable will be the change in HORS score from Visit 
3 to HORS at Visit 6 including the HORS score at Visit 3 as a covariate in the model. The 
addition of stratifying variables and other variables as covariates will be considered as 
appropriate and specified in the statistical analysis plan. This analysis will increase the power 
to detect significant differences between the groups. 
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Inverse probability weighting will be applied to the primary outcome analysis. These weights 
will be derived based on the inverse of the probability of a patient's data being missing given 
their pre-randomisation measurements. This will ensure the estimate and inference is more 
representative of all patients randomised, reducing bias in the estimation of the treatment 
effect due to participants lost to follow-up and missing data. 
Inference regarding the treatment effectiveness will focus on the point estimate, confidence 
interval and p-value for hypothesis confirmation. 
11.5.2 Secondary effectiveness analysis 
Secondary outcomes will be analysed as appropriate (according to the distribution of each 
outcome), comparing the difference between groups at the specified follow-up visit and relative 
to baseline value (where specified/measured). Baseline variables predictive of each outcome 
(the measure at baseline where available), and stratifying variables will be included in 
ANCOVA or generalised linear models of outcome variables. The statistical analysis plan will 
give complete specification of these models. 
For secondary outcomes, the focus will be on the point estimates and confidence intervals for 
hypothesis generation. 
Additional analysis of the primary outcome will compare the time course of HORS under 
placebo and treatment using a mixed-effects model including fixed-effects terms for time since 
randomisation/study visit, trial arm and their interactions, and a random effect to account for 
correlation of multiple observations per participant. 
11.6 Safety analysis 
The results of clinical monitoring including blood pressure or heart rate changes, and AEs 
secondary to phlebotomy or cannulation will be examined between the groups. Adverse 
events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence of treatment-emergent adverse events will be summarized by system organ 
class (SOC) and preferred term. 
Safety data will be presented primarily in a descriptive fashion. The small sample size and 
likely low adverse event rates will mean any inference is likely underpowered to detect a range 
of meaningful differences. 
Blinded data will be presented to the DSMB for safety evaluation to coincide with scheduled 
DSMB meetings. 
11.7 The level of statistical significance 
The level of statistical significance will be set at p < 0.05, relating only to the primary analysis 
of effectiveness. Inference for the treatment effect estimate other outcomes will focus on the 
point estimate and the confidence interval. 
11.8 
Procedure for accounting for missing, unused and spurious data 
Any missing data which occurs will be summarised and reasons given. As per the statistical 
analysis specification, an inverse probability weighting will be performed in the primary 
outcome analysis (weights based on the inverse probability of a patient's data being missing 
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given their pre-randomisation measurements). This will ensure the estimate and inference is 
more representative of all patients randomised. 
11.9 Procedure for reporting any deviation(s) from the original statistical plan 
Deviations from the original statistical plan will be recorded and justified in the final report. 
12. 
Direct Access to Source Data/Documents 
Direct access will be granted to authorised representatives from the sponsor, and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. Consent from 
patients/legal representatives for direct access to data will also be obtained. The patients' 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
13. Data handling and record keeping 
Data will be entered, handled and stored at the HRB-CRFG. It will be pseudo-anonymised and 
then processed by members of the research team at the HRB-CRFG. Data will also be 
submitted to a data repository at the National Institute of Mental Health (NIMH) based in 
Maryland, Bethseda, USA on a twice-yearly basis to house data on behalf of SMRI. 
13.1 Data collection, source documens and case report forms 
Source documents for this study will include hospital records and procedure reports and data 
collection forms. These documents will be used to enter data on the case report forms. Once 
registered to a trial the patient will be provided with a unique, study-specific participant 
identifier and this and their initials will be the only way the patient will be identified in the 
database. Data will be directly entered into the Clinical Data Management System (CDMS) by 
the site staff. Data entry is by single data entry. Data queries will be generated within the 
CDMS for the investigational site as required to clarify data discrepancies or request missing 
information. The designated site staff will be required to respond to these queries and these 
responses with be reviewed by the Data Management Team. Any amendments to the data 
will be tracked within the audit trail of the CDMS. 
Data reported on the case report forms 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 confidential conditions. On all study-specific documents other than the 
signed consent, the participant will be referred to by the study participant identification 
number/code. 
Patient identification on the CRF and questionnaires will be through participant initials and 
their unique trial identifier allocated at the time of enrolment. No names or other identifying 
details will be recorded on the CRF or in any other format. 
13.2 Data reporting 
Central data management will be performed by the Data Management Centre at the HRB-
CRFG. The Lead Data Manager will develop a Data Management Plan (DMP) which will detail 
all activities relating to the management of the clinical data. All project specific data 
management documentation will be filed in a Data Management File (DMF). The Data 
management team will also develop a CDMS to store the clinical data. This will be developed 
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following the relevant Data Management SOPs and adhering to regulatory and appropriate 
legislative requirements. 
Local user access to the electronic CRF will be controlled via assigned usernames and 
passwords, approved by the study Data Manager based at NUIG. Access to the central study 
database will be governed by HRB-CRFG standard operating procedures (SOP)s and signed 
off by the Lead Site Investigator. Audit trails will log all transactions of data into and out of the 
system including time, date, user ID and the records involved. All external electronic 
communication with the central database will be protected by using Secure Socket Layer 
technology. The main database will be hosted in a secure enterprise scale data centre. 
The research team will take every precaution to respect privacy in accordance with relevant 
legislation and EU Directives on protection of individuals with regard to the processing of 
personal data. 
The data in the study database will be pseudo-anonymised, so that a number will be assigned 
to each patient which will be mapped to identifiable patient details at each hospital site only. 
This means that the data in the database is non-identifiable but will permit re-identification by 
the local site investigator in case of emergencies and requirement to follow up the patient. 
The data for this study may be transferred within and/or outside the EU in line with reporting 
requirements. For data transferred outside the EU, the data controller must be assured of the 
legality and privacy safeguards of the transfer and ensure adherence to all other applicable 
legislative and regulatory requirements including GDPR and Clinical Trial legislation pertaining 
to such data transfer. 
14. Retention of essential documents 
The investigator will maintain all trial records according to GCP and the applicable regulatory 
requirements. The trial master file (TMF) will be established at the beginning of the trial by 
the sponsor. The investigator site files will be maintained at the investigators site. These will 
contain the essential documents in line with ICH-GCP. On completion of the trial the essential 
documents will be maintained by the investigator for a period of at least 15 years or as 
otherwise specified in the regulations. 
Following confirmation, the sponsor will notify the investigator when they are no longer 
required to maintain the files. If the investigator withdraws from the responsibility of keeping 
the trial records, custody must be transferred to a person willing to accept responsibility and 
this must be documented in writing to the sponsor. 
15. 
Quality control and quality assurance procedures 
This study will be conducted in accordance with the current approved protocol, International 
Conference on Harmonisation Good Clinical Practice (GCP), relevant regulations and SOPs. 
15.1 Protocol compliance 
The investigators will conduct the study in compliance with the protocol given 
approval/favourable opinion by the Ethics Committee and the appropriate regulatory authority 
and as per investigator responsibilities outlined in ICH-GCP E6 R2. Substantial changes to 
the protocol will require HPRA authority and ethics committee approval/favourable opinion 
prior to implementation, except when modification is needed to eliminate an immediate 
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hazard(s) to patients. All protocol modifications will be submitted to the competent 
authority/research ethics committees for review in accordance with the governing regulations. 
Site investigator should report any trial-related deviations, violations or serious breaches of 
GCP and/or the trial protocol to the sponsor/delegate. The Pis will report any serious breaches 
of GCP to the sponsor immediately after becoming aware of them. 
15.2 
Monitoring arrangements 
The sponsor will be responsible for trial monitoring. The frequency and type of monitoring will 
be detailed in the monitoring plan and agreed by the trial sponsor/sponsor delegate. Protocol 
compliance will be monitored by a monitor who will undertake site visits in accordance with 
the study monitoring plan to ensure that the protocol is adhered to. The monitor will check the 
completeness of patient records, the accuracy of entries on CRFs, the adherence to the 
protocol, SOPs and GCP, and the progress of patient recruitment. The Principal Investigator 
should ensure that access to all investigation related documents including source documents 
to confirm their consistency with CRF entries) are available during monitoring visits. The extent 
of source data verification (SDV) will be documented in the monitoring plan. Any deviations 
from the protocol will be reported to a sponsor representative as per the process and timelines 
communicated to site during investigator site initiation visit training. 
16. 
Audits and inspections 
This trial may be subject to internal or external auditing or inspection procedures to ensure 
adherence to GCP. Access to all trial-related documents will be given at that time. 
17. 
Ethics 
17.1 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. 
17.2 Good Clinical Practise 
The trial will be carried out in accordance with the principles of the International Conference 
on Harmonisation Good Clinical Practice (ICH-GCP) guidelines. 
17 .3 Approvals 
Required documents including the protocol, informed consent form, participant information 
leaflet, and any other required documents will be submitted to a recognised research ethics 
committee (REC) (Galway University Hospitals Research Ethics Committee) and the HPRA 
for written approval, as per submission requirements. 
The sponsor will submit and obtain approval from the above parties for substantial 
amendments to the original approved documents. 
17.4 Scopolamine benefits and risks assessment 
Bipolar disorder is one of the top 20 leading causes of disability worldwide, with a similar 
disability adjusted life year rate (138.3 per 100,000) to more prevalent conditions such as 
asthma (147.9 per 100,000) and Alzheimer's disease (108.5 per 100,000) (Ferrari et al., 
2016).Current pharmacological treatments for bipolar disorder and in particular for the 
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management of depressive episodes in bipolar disorder remain sub-optimal, with 
pharmacological strategies employed to date often only partially effective (Fournier et al., 
201 O; Yildiz et al., 2011 ). In addition to the time duration for treatment response, multiple 
treatment trials are also often required, thus increasing patient discomfort and distress (lnsel 
and Wang, 2009). Consequently, pharmacological mechanisms that potentially alleviate 
depressive symptomatology in bipolar disorder and ameliorate patient functioning could 
present an additional pharmacological strategy for the management of bipolar disorder. A 
number of recent studies have suggested that scopolamine, the agent being investigated in 
this study (a pan muscarinic (M) receptor antagonist) can elicit a rapid anti-depressant 
response in both major depressive disorder and bipolar disorder (Ellis et al., 2014; Furey et 
al., 2006; Drevets et al., 2010) and thus may present a novel therapeutic strategy, particularly 
for the management of BPD, in individuals experiencing depressive episodes (Janowsky, 
2011). 
It is envisaged that the potential burden of the study will be less than the potential value of this 
research, but there are no guaranteed direct benefits. Participants may benefit indirectly from 
participation in terms of increased awareness of mental health issues. Some participants may 
benefit from scopolamine administration in attaining a rapid treatment for their depressive 
episode. 
This study will not include incapacitated adults or children (<18 years of age). Issues regarding 
specific vulnerable populations are addressed individually below. 
(i) The study requires inclusion of adults with mental illness to address the research 
question. Only those who have the capacity to provide valid informed consent will be 
invited to participate. Where there is concern expressed about the capacity of a person 
to make a decision regarding treatment, a capacity assessment will be performed by 
the principal investigator or sub-investigator to ensure that participants are able to 
provide written informed consent. 
(ii) Women of childbearing age are defined by the Irish Central Statistics Office as 
women of ages 15-49 years (Census 2011, This is Ireland (Part 1)- 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 (1% of all women) 
experience bipolar disorder with this disorder usually have its onset in individuals aged 
20-45 years of age. Bipolar disorder is equally common in men and women (Kroon et 
al., 2013) and thus the primary study objective cannot be accurately achieved without 
including women of childbearing age. At screening visit, precautions will be taken, as 
detailed in section 8.4.7, in relation to advice on adequate contraception use between 
Visit 1 to Visit 5. 
17.4.1 
Physical Risks 
17.4.1.1 
Tolerability and Adverse Effects of IV Scopolamine 
Pulsed IV infusion (4 µg/kg over 15 minutes) has to date been well tolerated with no significant 
adverse effects (AEs) encountered in other studies that have administered this agent on a 
similar time regime and at a similar dose to the proposed study (Fury and Drevets, 2010, Fury 
et al., 2012) 
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17.4.1.2 
Risks secondary to Phlebotomy 
Phlebotomy is rarely associated with serious adverse effects and will be performed in this 
study by experienced delegated staff member of the HRB Clinical Research Facility with 
phlebotomy experience. Serious side effects such as loss of consciousness and seizures and 
injury to adjacent structures are rare and vasovagal attacks may occur occasionally. Bruising 
and small haematoma may occur in approximately 12% of individuals (WHO, 2010). All efforts 
will be made to reduce the likelihood of adverse events due to phlebotomy, however 
discomfort during the procedure is common. 
17.4.1.3 
Risks and hazards secondary to peripheral venous cannulation and 
intravenous administration of investigative medicinal product (e.g. 
Scopolamine and 100mls of nonnal saline or 100mls of normal saline) 
Complications that can potentially arise following the procedure of cannulation include 
infiltration, extravasation, venous spasm, phlebitis, thrombophlebitis, large haematoma, nerve 
injury, arterial puncture, embolism and needle stick injury (HSE, 2013). In this study, peripheral 
venous cannulation will be performed using aseptic technique and in accordance with local 
venous cannulation policy. Cannulation will be utilized for a 15 minute infusion, via a calibrated 
infusion pump, and be removed prior to discharge from the clinical research facility. The 
cannulation site will be monitored during the infusion and after cannula removal. Discomfort is 
common during the insertion of a peripheral venous cannula, however every effort will be 
made to minimize pain or discomfort, including the use of topical anaesthetics, where 
indicated. 
17.4.1.4 
Risks and hazards secondary to IV Scopolamine infusion 
AEs that have occurred have been transient in nature (<3 hours) and have included light 
headedness, sedation, a transiently reduced heart rate and blood pressure (requiring no 
intervention) and the recognised anticholinergic adverse effects of dry mouth and blurred 
vision (Drevets and Furey, 201 O; Furey and Zarate, 2013). 
Pulsed IV administration has not been associated to date with potential AEs noted with high 
oral dosages including delirium, (hypo)mania, psychosis or disorientation (Furey and Zarate, 
2013). 
17.4.1.5 
Psychological risks 
Distress 
Some participants may find questionnaires distressing or anxiety-provoking. This is difficult to 
predict, however researchers will be vigilant for possible negative psychological effects and 
seek to minimise these wherever possible. Most participants will have experience in answering 
questions similar to those on the questionnaires and many will previously have completed 
similar questionnaires. Researchers are all experienced in conducting clinical trials and in 
research with individuals with bipolar disorder and other major mental illnesses. If participants 
are distressed, they will be supported and given time out from completion of the 
questionnaires. If the distress continues, they will be advised that any remaining 
questionnaires are not required. Where significant distress is present, the clinical team of the 
participant will be informed by the research team, so that additional support after the clinical 
visit can be provided. 
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Psychosocial risks 
Inconvenience 
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Attending for assessments or interventions may cause inconvenience to participants. It is 
anticipated that participants will predominantly reside in Galway or close to Galway. Participant 
visits will be organised so they will not have to wait prior to review by the researcher. 
17.5 Participant confidentiality 
The trial staff will ensure that the participants' anonymity is maintained. The participants will 
be pseudo-anonymised and identified by initials and a participant's identification number on 
the CRF and any database. All documents will be stored securely. The study will comply with 
the Data Protection Act and the General Data Protection Regulation (GDPR). 
17.6 Other Ethical considerations 
The vulnerability of this study group is fully appreciated, and every effort will be undertaken to 
protect their safety and well-being. During their time on the trial, participants will continue usual 
care, as recommended by their responsible clinical team. In line with the applicable regulatory 
requirements, consenting processes will be standardised and a robust SOP for consenting 
participants will be adhered to. 
18. 
Financing and insurance/indemnity 
Indemnity is provided by indemnity cover for research in place from NUI Galway/State Claims 
agency (Clinical Indemnity scheme) once the trial is approved by a Clinical Research Ethics 
Committee and regulatory authority. 
Funding has been attained from the Stanley Medical Research Institute (SMRI) -Treatment 
Trials. The SMRI is a non-profit organisation supporting research in the cause of, and 
treatments for, schizophrenia and bipolar disorder based in the United States of America. 
19. 
Clinical study report and publication policy 
The publication policy involves formal presentation of study findings at national and 
international neuroscience and psychiatry meetings including potentially the College of 
Psychiatrists of Ireland Winter Conference, Biological Psychiatry annual conference and the 
International Society for Bipolar Disorder annual conference, following consultation with the 
sponsor and the HRB-CRFG. 
Final findings will be submitted for peer-review and publication in relevant high-impact 
scientific journals and upon publication may be further publicised in national and international 
print and electronic media though public relations departments and the NUI Galway website. 
Further knowledge dissemination will include registering the trial in the EudraCT database and 
publication of the trial protocol in a peer-reviewed journal. 
Research progress and developments will be presented at in-house research meetings with 
the Department of Psychiatry at Galway University Hospitals and at the HRB-CRFG. 
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20. 
References 
• 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(5th Edn) (DSM-V). Arlington, VA APA, 2013. 
• 
Babor TF, Higgins-Biddle, JC, Saunders JB, Monteiro, MG. The Alcohol Use Disorders 
Identification Test (2nd edition). World Health Organization (2001) 
• 
Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch 
Gen Psychiatry 1961; 4: 561-571. 
• 
Beck AT, Steer RA. Beck Anxiety Inventory Manual, San Antonio, Tx. Psychological 
Corporation. 1993. 
• 
Belmaker, RH. Bipolar Disorder. NEJM 2004; 351: 476-486. 
• 
Bonner Tl, Buckley NJ, Young AC, Brann MR. Identification of a family of muscarinic 
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