Community-based Transcranial Direct Current Stimulation Treatment for Bipolar Depression
Phase: NA
Conditions: Depression, Bipolar, Bipolar Disorder, Mood Disorders, Mental Disorder
Sponsor: University of East London

 
 
1 
 
 
Trial Name:  
 
Community-based transcranial direct current stimulation treatment for bipolar depression 
 
 
Document date:  
 
17/07/2023  
 
Principal Investigator 
Professor Cynthia H.Y. Fu, University of East London, Water 
Lane, London, E15 4LZ 
 
Protocol contributors  
Professor Allan H. Young, Centre for Affective Disorders, 
Institute of Psychiatry, Psychology and Neuroscience, King’s 
College London 
Professor Michael Bauer, Technische Universität Dresden, 
Germany  
Dr. Philipp Ritter, Technische Universität Dresden, Germany  
Professor Elvira Bramon, University College London 
Clinicaltrials.gov ID 
NCT05436613 
Funders 
Milken Institute (financial support) 
Flow Neuroscience (provision of Flow tDCS device) 
 
 
 
 
Contents 
TRIAL SUMMARY ......................................................................................................................... 2 
1 
RATIONALE ...................................................................................................................... 5 
2 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ............................................. 5 
3 
TRIAL DESIGN .................................................................................................................. 7 
4 
TRIAL SETTING ................................................................................................................ 7 
5 
PARTICIPANT ELIGIBILITY CRITERIA ............................................................................ 7 
6 
TRIAL PROCEDURES ...................................................................................................... 8 
7 
TRIAL TREATMENTS ..................................................................................................... 10 
8 
RECORDING AND REPORTING OF ADVERSE EVENTS ............................................ 11 
9 
STATISTICAL ANALYSIS PLAN ..................................................................................... 14 
10 
REFERENCES ................................................................................................................. 17 
11 
SCHEDULE OF EVENTS ................................................................................................. 18 
 
 
 

 
 
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TRIAL SUMMARY 
Trial Title: 
Community-based transcranial direct current stimulation 
treatment for bipolar depression 
Short Title: 
Transcranial direct current stimulation therapy for bipolar 
depression (b-DEP) 
Trial Design: 
Pilot, open-label, single arm design 
Trial Participants: 
Participants will have a diagnosis of Bipolar disorder, in a 
current depressive episode of moderate severity, receiving 
pharmacological or psychological treatment, ages minimum 
18 years, community-dwelling. 
Total number of participants planned: 
50  
Treatment duration: 
6 weeks 
Additional follow up duration: 
3 months 
Total trial duration per participant: 
5 months 
Estimated total trial duration: 
1 year 
Planned trial sites: 
Multi-site 
 
Objectives 
Outcome Measures 
Primary Objective: 
 
To assess the efficacy of 
tDCS treatment 
clinical response as 
measured by MADRS score 
improvement of >= 50% 
following the course of tDCS 
treatment 
Secondary Objective: 
 
To assess acceptability and 
safety of the intervention. 
 
 
 
Participant retention at the 
end of the treatment who 
have completed a minimum 
of 15 tDCS sessions. 
Participant acceptability 
questionnaire scales 
tDCS Adverse Events 
Questionnaire at each 
session 
Formulation, Dose, Route of 
Administration 
Transcranial direct current stimulation (tDCS) device with a 
bifrontal montage at left dorsolateral prefrontal cortex 
(DLPFC) and cathode at right DLPFC (EEG positions F3 and 
F4, respectively). Stimulation is 2 mA, and electrode area is is 
35 cm2. 
The intervention consists of a 6-week course of active tDCS, 
consisting of 5 sessions per week for the first 3 weeks 
followed by 2 sessions per week for 3 weeks, for a total of 21 
tDCS sessions. The duration of each session is 30 minutes. 
 
 
 

 
 
3 
 
ii. LIST OF ABBREVIATIONS 
Define all unusual or ‘technical’ terms related to the trial.  Add or delete as appropriate to your trial.  
Maintain alphabetical order for ease of reference. 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CE 
Conformité Européene (European Conformity) 
CI 
Chief Investigator 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP  
Clinical Trial of Investigational Medicinal Product  
CTU 
Clinical Trials Unit  
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EEG 
electroencephalogram 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
GP 
General Practitioner 
HAMA 
Hamilton Anxiety Scale 
HRSD 
Hamilton Rating Scale for Depression 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use. 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File (This forms part of the TMF) 
ISRCTN 
International Standard Randomised Controlled Trials  
Number 
MA 
Marketing Authorisation 
MADRS 
Montgomery–Åsberg Depression Rating Scale 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MINI 
Mini-International Neuropsychiatric Interview 
MS 
Member State 
NHS R&D 
National Health Service Research & Development   
NIMP 
Non-Investigational Medicinal Product 
NIHR 
National Institute for Health Research 
PHQ-9 
Patient Health Questionnaire 
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
Q-LES-Q 
Quality of Life Enjoyment and Satisfaction Questionnaire 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person  
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 

 
 
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SAR 
Serious Adverse Reaction 
SDS 
Sheehan Disability Scale 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
tbc 
to be confirmed 
tDCS 
transcranial direct current stimulation 
tDCS AEQ 
tDCS Adverse Events Questionnaire 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UK 
United Kingdom 
YMRS 
Young Mania Rating Scale 
 
 

 
 
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1 
RATIONALE  
While there has been some demonstrated efficacy for tDCS as a first-line treatment for depression, 
the studies to date have investigated tDCS that is provided in the clinic. This is a problem because the 
treatment requires daily clinic visits for several weeks which could limit its accessibility and uptake 
among patients. As tDCS is a portable and safe treatment, it could be provided at home.  
The present study is a proof-of-concept trial to assess the efficacy, acceptability and safety of tDCS 
treatment for bipolar depression within a community-based setting. 
The findings from the present study will be applied to the design of a multi-site, randomised sham-
controlled trial of community-based tDCS treatment for bipolar depression. 
The present study will also investigate EEG and neuropsychological correlates and potential 
predictors of clinical response.  
1.1 
Assessment and management of risk 
Noninvasive transcranial direct current stimulation (tDCS) has been used in human for decades. 
These noninvasive current stimulation techniques use battery-powered current generator devices that 
have a built-in circuitry to limit the current above a certain level, typically 2 mA.  
The most common adverse events are mild skin redness (54%) at the site of the electrodes, which 
resolves following stimulation, itching (39%) and tingling (22%), followed by headache (16%), 
discomfort (13%) and burning sensation (10%) (Brunoni et al., 2011, Sampaio-Junior et al., 2018). 
There is no significant difference in rates between active and sham tDCS, except for skin redness 
which is more common with active (54%) relative to sham tDCS (19%) (Sampaio-Junior et al., 2018). 
Participants have been unable to distinguish whether they were receiving active or sham tDCS 
though, and there have been no differences in the discontinuation rates for active and sham 
treatments, mean rates 10% and 12%, respectively (Meron et al., 2015). In our recent pilot study in 
unipolar depression, the discontinuation rate has been 7.6% (2 out of 26 enrolled participants).  
The risk of treatment-emergent mania or hypomania is estimated to be around 4% with a course of 
active tDCS and 0.5% with sham tDCS, with no statistical difference between active and sham tDCS 
(Brunoni et al., 2017; Sampaio-Junior et al., 2018). While the rate is lower than the 5-9% risk 
associated with antidepressant medication, it might be higher than the risk of <1% associated with 
repetitive transcranial magnetic stimulation (Xia et al., 2008).  
Protocols in human trials (≤ 40 min, ≤ 4 milliamperes, ≤ 7.2 Coulombs) have not produced any reports 
of serious adverse effect or irreversible injury with over 33,200 sessions and 1,000 participants with 
repeated sessions (Bikson et al., 2016).  
 
2 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
The aim of the present project is to investigate the efficacy, acceptability and safety of community-
based tDCS treatment for bipolar depression  
2.1 
Primary objective 
The primary objective is to assess efficacy as measured by clinical response following a course of 
tDCS treatment.  
2.2 
Secondary objectives 
The secondary objectives are to assess the acceptability and safety of the tDCS sessions.  
2.3 
Outcome measures/endpoints 
Clinical response as measured by clinician-rated MADRS score improvement of >= 50% following the 
course of tDCS treatment.  

 
 
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2.4 
Primary endpoint/outcome 
Clinical response as measured by clinician-rated MADRS score improvement of >= 50% following the 
course of tDCS treatment.  
2.5 
Secondary endpoints/outcomes 
1) 
Participant retention at the end of the treatment who have completed a minimum of 15 tDCS 
sessions 
2) 
Participant acceptability questionnaire scales 
3) 
tDCS Adverse Events Questionnaire at each session (Brunoni et al., 2011)  
2.6 
Exploratory endpoints/outcomes  
Exploratory measures: 
i. 
Trained rater measure of depressive symptoms: Montgomery–Åsberg Depression Rating Scale 
(MADRS) remission rate 
ii. 
Self-report measure of depressive symptoms: Patient Health Questionnaire (PHQ-9) 
iii. 
Trained rater measure of anxiety symptoms: Hamilton Anxiety Scale (HAMA) 
iv. 
Trained rater measure of manic symptoms: Young Mania Rating Scale (YMRS) 
v. 
Self-report measure of disability and impairment: Sheehan Disability Scale (SDS) 
vi. 
Self-report Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) 
vii. 
Self-report acceptability of tDCS from healthy controls. 
viii. 
EEG recordings will be acquired during an eyes-closed resting state for 10 minutes and eyes 
open resting state for 10 minutes using a mobile EEG device in participants’ homes (Muse 
EEG; https://choosemuse.com/) (Hashemi et al., 2016). Resting state EEG will be acquired at 
baseline for healthy controls and at 2 timepoints for participants with bipolar depression: 1) at 
baseline, and 2) at the end of the 6-week course of treatment. EEG coherence, a measure of 
neural connectivity, will be examined as a potential surrogate outcome measure (Miniussi et 
al., 2012). 
ix. 
Neuropsychological measures: verbal learning (Rey Auditory Verbal Learning Test (RAVLT)) 
and information processing speed (Symbol-Digit Modalities Test (SDMT)) will be assessed in 
participants’ homes. Neuropsychological assessments will be delivered to participants and 
administered by a research team member via video call. Our pilot data indicates feasibility and 
acceptance of the neuropsychological assessments as all participants had completed the 
assessments (26 out of 26 participants). The measures will be acquired at baseline for healthy 
controls, and at 2 timepoints for participants with bipolar depression: 1) at baseline, and 2) at 
the end of the 6-week course of treatment.  
Exploratory outcomes: 
1) MADRS score <= 9 following the course of tDCS 
2) Improvement in self-reported depressive symptoms as measured by PHQ-9 
3) Improvement in anxiety symptoms as measured by HAMA  
4) No significant increase in manic symptoms as measured by YMRS score >13 
5) Improvement in disability experience as measured by SDS 
6) Improvement in quality of life as measured by Q-LES-Q 
7) Healthy control participant baseline acceptability questionnaire. 
8) We hypothesize that increased functional connectivity in the resting state default mode network is 
linked with an improvement in depressive symptoms at the end of treatment.  
9) We will apply machine learning analysis to examine the potential of resting state EEG coherence 
to predict clinical response (Al-Kaysi et al., 2016).  
10) Effects on cognitive functioning as measured by neuropsychological tasks.  
 
 
 

 
 
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2.7  
Table of endpoints/outcomes 
Objectives 
Outcome Measures  
Timepoint of evaluation of 
this outcome measure 
Primary Objective 
To assess the efficacy of tDCS 
treatment. 
 
Clinical response as measured by 
MADRS score improvement of >= 
50% following the course of tDCS 
treatment  
 
End of tDCS sessions (visit 
21)  
Secondary Objectives 
To assess the acceptability 
and safety of the intervention 
 
 
Participant retention at the end of the 
treatment who have completed a 
minimum of 15 tDCS sessions 
Participant acceptability questionnaire 
scales 
tDCS Adverse Events Questionnaire  
 
End of tDCS sessions (visit 
21) 
 
 
 
At each session 
 
3 
TRIAL DESIGN 
The present study is a proof-of-concept trial to assess the efficacy, acceptability and safety of tDCS 
treatment for bipolar depression within a community-based setting. 
4 
TRIAL SETTING 
School of Psychology, University of East London  
5 
PARTICIPANT ELIGIBILITY CRITERIA 
 
5.1 
Bipolar depression sample 
5.1.1 Inclusion criteria 
• 
participants capable of giving informed consent 
• 
male and female 
• 
minimum of 18 years of age 
• 
diagnosis of bipolar disorder based on DSM-5 criteria, with a current depressive episode of at 
least a moderate severity 
• 
diagnosis will be confirmed by the Mini-International Neuropsychiatric Interview 
• 
Depressive symptoms severity will be assessed using the Montgomery–Åsberg Depression 
Rating Scale (MADRS) with a minimum score of 18, indicating at least a moderate severity of 
symptoms.  
• 
Being on a stable dosage of mood stabilising medication for a minimum of two weeks or not 
taking any medications for a minimum of two weeks. We would like to emphasize that we 
would not ask participants to stop their medications in order to take part in the study  
 
5.1.2 Exclusion criteria 
• 
any concurrent psychiatric disorder, including obsessive compulsive disorder 
• 
having a significant risk of suicide 
• 
score greater than 8 in the Young Mania Rating Scale 
• 
exclusion criteria for tDCS, including having a scalp or skin condition (e.g. psoriasis or 
eczema); if contact with the scalp is not possible; having metallic implants, including 
intracranial electrodes, surgical clips, shrapnel or a pacemaker 

 
 
8 
 
• 
history of epilepsy 
• 
history of a seizure which resulted in a loss of consciousness 
• 
neurological disorder or history of migraines 
 
5.2 
Healthy control sample 
 
 
5.2.1 Inclusion criteria 
• 
participants capable of giving informed consent 
• 
male and female 
• 
minimum of 18 years of age 
 
5.2.2 Exclusion criteria 
• 
any concurrent psychiatric disorder, including obsessive compulsive disorder 
• 
having a significant risk of suicide 
• 
score greater than 8 in the Young Mania Rating Scale 
 
 
6 
TRIAL PROCEDURES  
The Schedule of Events is presented in table format in Appendix 2. 
6.1 
Recruitment 
Based on an effect size of d = 0.70 (Meron et al., 2015; Mutz et al., 2018) following a 6-week course of 
tDCS treatment (consisting of 15-21 sessions) with 90% power, we will enrol 50 participants to 
achieve a sample size of 45 participants with bipolar depression who will complete the course of 
treatment, based on a 10% attrition rate.  
We will enrol 35 healthy controls to complete baseline activities. 
Our participants have a wide ethnic diversity. In our pilot study, 38% of participants were of non-White 
ethnicity i.e. 12% Black/African Caribbean, 4% Pakistani, 4% Chinese, 16% Mixed ethnic background, 
and 62% English or any White background. Recruitment will be from primary care, consulting 
psychiatrists, print and social media advertisements.  
6.1.1    Participant identification 
Potential participants will be referred by their GPs and psychiatrists as well as recruited by publicity, 
leaflets and websites. 
Only a member of the patient’s existing clinical care team will have access to patient records without 
explicit consent in order to identify potential participants, to check whether they meet the inclusion 
criteria and to make the initial approach to patients. 
Participants will be identified by their responsible physician or will be identified by self-referral. All 
participants will be required to be under the care of a GP for study participation.  
6.1.2 Screening 
The screen assessment for participants with bipolar depression requires a DSM-5 diagnosis of major 
depressive disorder by a MINI interview assessment and a minimum score of 18 on the MADRS. The 
maximum duration between screening and recruitment is 20 days. 
6.1.3  Payment  
Participants with bipolar depression will be reimbursed for their participation in the study: $66. (£50. GBP) 
and for the EEG assessments: $44. (£30. GBP).  
Healthy control participants will be reimbursed £20 for their participation in the study. 

 
 
9 
 
Participants that travel to the research centre will be reimbursed for their travel expenses, up to a total of 
£20 per visit. 
After the trial, participants will be able to keep the tDCS device if they would like to and will be provided 
with NICE tDCS for Depression most recent Interventional Procedures Guidance, published 26 August 
2015 (https://www.nice.org.uk/guidance/ipg530). 
 
6.2   Consent  
The Chief Investigator (PI) retains overall responsibility for the conduct of research which includes the 
taking of informed consent of participants at their site. The PI will ensure that any person delegated 
responsibility to participate in the informed consent process is duly authorised, trained and competent 
to participate according to the ethically approved protocol, principles of Good Clinical Practice (GCP) 
and Declaration of Helsinki.  
Informed consent will be obtained prior to the participant undergoing procedures that are specifically 
for the purposes of the trial and are out-with standard routine care at the participating site. 
The right of a participant to refuse participation without giving reasons will be respected.   
The participant will remain free to withdraw at any time from the trial without giving reasons and 
without prejudicing his/her further treatment and will be provided with a contact point where he/she 
may obtain further information about the trial. Data and samples collected up to the point of withdrawal 
will only be used after withdrawal if the participant has consented for this. Any intention to utilise such 
data is outlined in the consent literature. Where a participant is required to re-consent or new 
information is required to be provided to a participant, the PI will ensure this is done in a timely 
manner.  
The PI takes responsibility for ensuring that all vulnerable participants are protected and participate 
voluntarily in an environment free from coercion or undue influence. 
The potential participant will discuss with an individual knowledgeable about the research about the 
nature and objectives of the trial and possible risks associated with their participation. The potential 
participant will have the opportunity to ask questions. 
The written material (information leaflet and consent document) is approved by the REC and id in 
compliance with GCP, local regulatory requirements and legal requirements 
All participants will be capable of giving consent for themselves:  
• 
understand the purpose and nature of the research  
• 
understand what the research involves, its benefits (or lack of benefits), risks and burdens  
• 
understand the alternatives to taking part  
• 
be able to retain the information long enough to make an effective decision. 
• 
be able to make a free choice  
• 
be capable of making this particular decision at the time it needs to be made  
 
6.2.1 Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies, if applicable: N/A 
6.3 
The randomisation scheme: N/A  
6.3.1 Method of implementing the randomisation/allocation sequence: N/A 
6.4 
Blinding: N/A 
6.5 
Emergency Unblinding: N/A 

 
 
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6.6 
Baseline data 
The baseline data consist of: MADRS, tDCS AEQ, Acceptability questionnaire, PHQ-9, HAMA, YMRS, 
SDS, Q-LES-Q, EEG, AVLT, SDMT (Appendix 2). 
6.7 
Trial assessments 
Trial assessments are described in Appendix 2. 
6.8 
Long term follow-up assessments 
Long term follow-up assessments will be acquired at 3 months following the final treatment visit 
(Appendix 2). 
Participants who do not respond to repeated attempts at contact will be identified as ‘lost to follow-up’. 
6.9 
Qualitative assessments  
At the final tDCS session, participants will complete the acceptability questionnaire and provide 
feedback on their experience of the study. 
6.10 
Withdrawal criteria  
Participants will be withdrawn from the trial if they do not comply with the intervention, namely if they 
are unable to have a minimum of 50% of the tDCS session (10 out of 21 sessions), or if they develop 
serious adverse effects from any part of the study. Recording of the reasons for withdrawal will be 
made. Should a participant lose capacity to consent during the study then they would be withdrawn 
from the study, and that their identifiable data already collected with consent would be retained for 
use, and that no further data collection would take place. Their GP will be informed about their 
withdrawal, and there will have a telephone follow up at 1 month following their withdrawal. 
6.11 
Storage and analysis of clinical samples: N/A  
6.12 
End of trial: N/A 
7 
TRIAL TREATMENTS 
 
7.1 
Name and description of intervention(s) under investigation 
 We will use the Flow Neuroscience Flow tDCS device (Figure 1). 
The tDCS device consists of two electrodes through which the 
stimulation is applied (anode electrode) and through which the 
stimulation is returned (cathode electrode), which creates a circuit.   
The Flow tDCS device consists of an adjustable headset with the 
tDCS electrodes built in. 
7.2 
Regulatory status of the drug (if applicable): N/A  
7.3 
Product Characteristics:  
The Flow tDCS device has CE mark approval for the treatment of 
major depression. The device is portable and commercially 
available. The device can be programmed to provide the specific 
stimulation parameters for the study.  
The Soterix tDCS device is a similar device which has CE mark 
approval for the treatment of major depression (Figure 3). 
Figure 2. Flow tDCS device  
Figure 3.  Soterix tDCS device  

 
 
11 
 
7.4 
Drug storage and supply (if applicable): N/A  
7.5  
Preparation and labelling of Investigational Medicinal Product (if applicable): N/A 
7.6 
Dosage schedules: 
The Flow Neuroscience tDCS headset will be delivered to the participant’s home. The device is 
designed and approved (CE) to be used at home without supervision. 
6-week course of active tDCS treatment, consisting of 5 sessions per week for the first 3 weeks 
followed by 2 sessions per week for 3 weeks, for a total of 21 tDCS sessions. Duration of each 
session is 30 minutes. We will use the Flow Neuroscience tDCS device (Figure 1) with a bifrontal 
montage: anode at left dorsolateral prefrontal cortex (DLPFC) and cathode at right DLPFC (EEG 
positions F3 and F4, respectively). Stimulation is 2 mA, and electrode area is 35 cm2. During each 
session, participant will be seated comfortably with their eyes open, and research assistant will 
provide a discreet presence without interacting with the participant by video call.  
 
tDCS parameters are based on meta-analyses (Meron et al., 2015; Dondé et al., 2017; Mutz et al., 
2018) indicating that effects are greatest at 2 mA current of 30-minute stimulus. The tDCS equipment 
records the duration of each session, and there is an automatic shut-off to prevent unsafe use.  
7.7 
Dosage modifications: N/A  
7.8 
Known drug reactions and interaction with other therapies: N/A 
7.9 
Concomitant medication 
Participants who wish to begin another antidepressant treatment while taking part in the study will be able 
to continue in the trial.  
7.10 
Trial restrictions  
There are no known contraindications whilst on the active phase of the trial including dietary 
requirements or restrictions. 
7.11 
Assessment of compliance with treatment  
The tDCS device records the duration of each session, and there is an automatic shut-off to prevent 
unsafe use. The equipment will be programmed to provide only the type of stimulation, intensity and 
session length that are specified in the protocol. The placement is determined by the location of the 
electrodes which are fitted to the headset. The research assistant will be present at each session, in 
person or via video link, in order to aid in the initial positioning and to monitor for any adverse events.  
7.12 
Name and description of each Non-Investigational Medicinal Product (NIMP): N/A 
8 
RECORDING AND REPORTING OF ADVERSE EVENTS 
8.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom an 
intervention has been administered, including occurrences which are 
not necessarily caused by or related to the intervention. 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to an 
intervention which is related to any dose administered to that 
participant. 

12 
The phrase "response to an intervention" means that a causal 
relationship between an intervention 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 intervention qualify as adverse reactions.  
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
•
results in death
•
is life-threatening
•
requires inpatient hospitalisation or prolongation of existing
hospitalisation
•
results in persistent or significant disability/incapacity
•
consists of a congenital anomaly or birth defect
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" 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. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to the trial intervention, based on the information provided. 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the intervention. 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and 
“severe”, the following note of clarification is provided: “Severe” is often used to describe intensity of a 
specific event, which may be of relatively minor medical significance. “Seriousness” is the regulatory 
definition supplied above. 
Detailed guidance can be found here: 
 http://ec.europa.eu/health/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf 
8.2 
Operational definitions for (S)AEs  
An SAE is any AE from this study that results in one of the following outcomes: 
death 
initial or prolonged inpatient hospitalization 
a life-threatening experience (that is, immediate risk of dying) 
persistent or significant disability/incapacity 
congenital anomaly/birth defect 
considered significant by the investigator for any other reason 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious adverse events when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. 

 
 
13 
 
In all cases AEs and / or laboratory abnormalities that are critical to the safety evaluation of the 
participant must be reported to the Sponsor; these may be volunteered by the participant, discovered 
by the investigator questioning or detected through laboratory test or other investigation. Where 
certain AEs are not required to be reported to the Sponsor, these will still be recorded in the 
participant’s medical records. 
8.3 
Recording and reporting of SAEs, SARs AND SUSARs  
All serious adverse events will be recorded in the CRF as well as in the trial database, from which a 
line listing of SAEs can be extracted for review. The line-listing of SAEs will be reported to the Sponsor 
once per year. 
All SAEs must be recorded on a serious adverse event (SAE) form. The CI/PI or designated individual 
will complete the Sponsor’s SAE form and the form will be preferably emailed to the Sponsor within 5 
working days of becoming aware of the event. The Chief or Principal Investigator will respond to any 
SAE queries raised by the Sponsor as soon as possible.  
Where the event is unexpected and thought to be related to the intervention, this must be reported by 
the Investigator to the Health Research Authority within 15 days. 
For each SAEs the following information will be collected: 
• 
full details in medical terms and case description 
• 
event duration (start and end dates, if applicable) 
• 
action taken 
• 
outcome 
• 
seriousness criteria 
• 
causality (i.e. relatedness to intervention), in the opinion of the investigator 
• 
whether the event would be considered anticipated 
8.4 
Responsibilities 
Principal Investigator (PI):  
Checking for AEs and ARs when participants attend for tDCS sessions and at follow up. 
1. Using medical judgement in assigning seriousness and causality and providing an 
opinion on whether the event/reaction was anticipated.  
2. Ensuring that all SAEs are recorded and reported to the Sponsor.  
3. Ensuring that AEs and ARs are recorded and reported to the Sponsor in line with the 
requirements of the protocol.  
Chief Investigator (CI) / delegate: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning the SAEs seriousness, causality and whether the 
event was anticipated where it has not been possible to obtain local medical 
assessment. 
3. Immediate review of all SUSARs.  
4. Review of specific SAEs and SARs in accordance with the trial risk assessment and 
protocol. 
Sponsor: (NB where relevant these can be delegated to CI) 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs 
according to the trial protocol onto a database.  
2. Reporting safety information to the CI, delegate or independent clinical reviewer for the 
ongoing assessment of the risk / benefit. 

 
 
14 
 
3. Notifying Investigators of SUSARs that occur within the trial. 
8.5 
Notification of deaths  
All deaths, including deaths deemed unrelated to the study, will be reported to the Sponsor within 24 
hours of notification. 
8.6 
Pregnancy reporting  
All pregnancies within the trial (either the trial participant or the participant’s partner, with participants 
consent) will be reported to the Principal Investigator and the Sponsor. 
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for the 
mother or child/foetus. If the outcome meets the serious criteria, this would be considered an SAE. 
8.7 
Overdose: N/A  
8.8 
Reporting urgent safety measures  
If any urgent safety measures are taken the Sponsor shall immediately and in any event no later than 
3 days from the date the measures are taken, give written notice to the relevant REC of the measures 
taken and the circumstances giving rise to those measures. 
8.9 
The type and duration of the follow-up of participants after adverse reactions. 
For 3 months after the last tDCS to the participants, adverse events and reactions be recorded and 
reported.  
Any SUSAR will need to be reported to the Sponsor irrespective of how long after the reaction has 
occurred until resolved. 
8.10 
Development safety update reports 
The Chief Investigator will provide Development Safety Update Reports (DSURs) once a year 
throughout the clinical trial, or as necessary, where relevant to the REC and the Sponsor.   
The report will be submitted within 60 days of the Developmental International Birth Date (DIBD) of the 
trial each year until the trial is declared ended. 
9 
STATISTICAL ANALYSIS PLAN 
9.1 
Sample size calculation 
Based on an effect size of d = 0.70 (Meron et al., 2015; Mutz et al., 2018) following a 6-week course of 
tDCS treatment (consisting of 15-21 sessions) with 90% power, we will enrol 50 participants to 
achieve a sample size of 45 participants with bipolar depression who will complete the course of 
treatment, based on a 10% attrition rate.  
9.2 
Planned recruitment rate 
The planned recruitment rate is 4-6 participant/s per month. 
 
 

 
 
15 
 
9.3 
Statistical analysis plan 
 
9.3.1 Summary of baseline data and flow of patients 
 
Consort Flow Diagram: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.2 Primary outcome analysis  
The primary outcome analysis clinical response which will be measured by the number of enrolled 
participants who show a clinical response at the end of treatment (MADRS score improvement of >= 
50% following the course of tDCS treatment), divided by the total number of enrolled participants, 
expressed as a percentage. 
9.3.3 Secondary outcome analysis  
The secondary outcome analyses are; participant retention, which will be measured by the number of 
enrolled participants who do not drop out before the 6 week course of tDCS, divided by the total 
number of enrolled participants, expressed as a percentage; Acceptability, which will be measured by 
the percentage of participants rating the intervention as acceptable at the end of the 6 week course of 
tDCS. The acceptability scale consists of the question ‘How acceptable did you find the tDCS 
Assessed for eligibility (n=  ) 
Excluded  (n=   ) 
• 
Not meeting inclusion criteria (n=  ) 
• 
Declined to participate (n=  ) 
• 
Other reasons (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
• 
Received allocated intervention (n=  ) 
• 
Did not receive allocated intervention (give reasons) (n=  ) 
Analysed  (n=  ) 
• 
Excluded from analysis (give reasons) (n=  ) 
Allocation 
Analysis 
Follow-Up 
Enrolment 

 
 
16 
 
sessions?’ with responses ranging from ‘Very unacceptable’ to ‘Very acceptable’ on a 7-point 
anchored Likert scale with the acceptable ratings being from rating 5-7, and safety outcomes, which 
will be measured by calculating the number of severe, moderate and mild adverse events and their 
relation to the intervention. 
9.4 
Subgroup analyses: N/A 
9.5 
Adjusted analysis: N/A 
9.6 
Interim analysis and criteria for the premature termination of the trial: N/A 
9.7 
Participant population 
All participants will be included in the analysis in an intention to treat analysis and participants who 
have completed the study will be included in a completer analysis. 
9.8 
Procedure(s) to account for missing or spurious data  
Any missing data will be imputed in a last observation carried forward model. 
9.9 
Other statistical considerations: N/A 
9.10 
Economic evaluation: N/A 
 
 

 
 
17 
 
10 
REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. 
American Psychiatric Association; 2013.  
Al-Kaysi AM, et al. Predicting brain stimulation treatment outcomes of depressed patients through the 
classification of EEG oscillations. Annu Int Conf IEEE Eng Med Biol Soc. 2016:5266-5269.  
Brunoni AR, et al. A systematic review on reporting and assessment of adverse effects associated 
with transcranial direct current stimulation. Int J Neuropsychopharmacol. 2011; 14:1133-45.  
Brunoni AR, et al. Brain Stimul. 2017; 10:260-262.  
Hamilton, M. The assessment of anxiety states by rating. 1959. Br. J. Med. Psychol; 32: 50-55.  
Hamilton, M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry. 1960; 23:56-62.  
Hashemi A, et al. eNeuro. 2016; 3:ENEURO.0275-16.2016.  
Meron D, et al. Transcranial direct current stimulation (tDCS) in the treatment of depression: 
Systematic review and meta-analysis of efficacy and tolerability. Neurosci Biobehav Rev. 2015; 57:46-
62.  
Miniussi C, et al. Clin EEG Neurosci. 2012; 43:184-91.  
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br. J. 
Psychiatry J. Ment. Sci. 1979;134:382–9 
Mutz J, Edgcumbe DR, Brunoni AR, Fu CHY. Efficacy and acceptability of non-invasive brain 
stimulation for the treatment of adult unipolar and bipolar depression: a systematic review and meta-
analysis of randomised sham-controlled trials. Neurosci Biobehav Rev. 2018; 92:291-303.  
Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and 
acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in 
adults: systematic review and network meta-analysis. BMJ. 2019; 364:l1079.  
Sheehan DV. The Sheehan Disability Scales. Anxiety Dis. Overcome It. New York: Charles Scribner 
and Sons; 1893. p. 151.  
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International 
Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic 
psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry. 1998;59. 
Woodham R, Rimmer RM, Mutz J, Fu CHY. Is tDCS a potential first line treatment for major 
depression? Int Rev Psychiatry. 2021; 33:250-265.  
Woodham et al. Adjunctive home-based transcranial direct current stimulation treatment for major 
depression with real-time remote supervision: An open-label, single-arm feasibility study with long 
term outcomes.  Journal of Psychiatric Research. 2022; 153:197-205. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. 
Br. J. Psychiatry. 1978;133(5):429–35. 
 

 
 
18 
 
11 
SCHEDULE OF EVENTS 
Study Procedure 
Screening 
Treatment Period 
Follow up 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
Location 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H 
C/H/T 
Week of Treatment 
Wk -4 to 0 
Wk1 
Wk1 
Wk1 
Wk1 
Wk1 
Wk2 
Wk2 
Wk2 
Wk2 
Wk2 
Wk3 
Wk3 
Wk3 
Wk3 
Wk3 
Wk4 
Wk4 
Wk5 
Wk5 
Wk6 
Wk6 
Wk18 
Day of Visit 
-20 
1 
2 
3 
4 
5 
8 
9 
10 
11 
12 
15 
16 
17 
18 
19 
22 
25 
29 
32 
36 
39 
126 
Visit Window (days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 14 
Screen Information & 
Consent 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Study Information Sheet 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
x 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      Demographics 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      Height 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      Weight 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      Clinical Interview 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      Pre-existing conditions 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      History or treatments 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      Concomitant treatments 
x 
x 
 x 
x  
 x 
x 
 x 
 x 
x  
 x 
x 
 x 
 x 
 x 
x  
x 
 x 
x 
 x 
x 
 x 
x 
x 
tDCS training session 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tDCS intervention 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
Rating Scales 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
     MINI 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
     IQ assessment 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
     MADRS 
x 
x 
  
  
  
 
  
  
  
  
x 
  
  
  
  
 
  
 
  
 
  
x 
x 
     PHQ-9 
  
x 
  
  
  
 
  
  
  
  
x 
  
  
  
  
 
  
 
  
 
  
x 
x 
     HAMA 
  
x 
  
  
  
 
  
  
  
  
x 
  
  
  
  
 
  
 
  
 
  
x 
x 
     YMRS 
  
x 
  
  
  
 
  
  
  
  
x 
  
  
  
  
 
  
 
  
 
  
x 
x 
     SDS 
  
x 
  
  
  
 
  
  
  
  
x 
  
  
  
  
 
  
 
  
 
  
x 
x 
     Q-LES-Q 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
     tDCS Adverse Events Scale 
  
x 
 x 
 x 
x  
x 
 x 
 x 
x  
 x 
x 
 x 
 x 
x  
 x 
x 
 x 
x 
 x 
x 
x  
x 
x 
Acceptability questionnaire 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
 x 
EEG 
  
x 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
x 
  
Neuropsychological tasks 
(eg.  SDMT, RAVLT,) 
  
x 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
x 
  
Location: Clinic (C), Home (H), Telephone (T)