Digital Interventions in Neuro-Rehabilitation (DINR): A Digital Neuro Intervention (DNI) for Word Retrieval (Anomia)
Phase: NA
Conditions: Stroke, Aphasia, Anomia
Sponsor: University College, London

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Clinical Investigational Plan 
 
DINR 
 
 
Full title of Investigation: 
Digital Interventions in Neuro-Rehabilitation: Digital 
Interventions in Neuro-Rehabilitation (DINR): A digital neuro 
intervention (DNI) for word retrieval (anomia).  
 
The development and testing of a web-based therapy 
application for people with naming difficulties who have had 
a Stroke (iTALKbetter). 
Short title: 
 
Digital Interventions in Neuro-Rehabilitation (DINR): 
iTALKbetter 
Version and date of Clinical Investigation 
Plan (CIP): 
Version 4.0, 25.02.2019 
 
Sponsor: 
 
University College London (UCL) 
 
Sponsor CIP number: 
18/0071 
 
Funder (s): 
NIHR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Revision History: 
 
Version 
numbers 
Date 
Summary of revisions in the 
case of amendments 
 
Protocol Updated by [insert 
name & Signature] 
1 
18.03.2018  
 
2 
31.07.2018  
Henry Coley-Fisher 
Dr. Catherine Doogan 
3 
07.02.2019 Separated each app 
Dr Catherine Doogan 
Emily Upton 
4 
25.02.2019 
Statistical recommendations from 
MHRA added. 
Henry Coley-Fisher  
Prof Alex Leff 
 

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Signatures 
 
The Chief Investigator (CI) and the JRO have discussed this Clinical Investigation Plan (CIP). The investigator 
agrees to perform the investigations and to abide by this CIP. 
 
The investigator agrees to conduct the Investigation in compliance with the approved CIP, EU Good Clinical 
Practice (GCP) and UK Regulations for Devices (SI 2002/618; as amended) for regulated studies, the UK Data 
Protection Act (1998), the Trust Information Governance Policy (or other local equivalent), the Research 
Governance Framework (2005 2nd Edition; as amended), the Sponsor’s SOPs, and other regulatory requirements as 
amended. 
 
Chief investigator 
Prof Alex Leff 
 
 
 
 
 
 
 
 
 
 
 
25.02.19 
 
Signature 
Date 
Sponsor Representative 
 
 
 
UCL 
Signature 
Date 
 
 
 
 
 
 
 
 
 

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Contents 
 
Clinical Investigational Plan ...................................................................................................................................... 1 
Sponsor ....................................................................................................................................................................... 8 
Principal Investigator, Coordinating Investigator and Investigation site(s) ........................................................ 8 
A.1 Overall Synopsis of Clinical Investigation ........................................................................................................ 9 
a) 
Inclusion criteria ........................................................................................................................................... 10 
b) 
Exclusion criteria .......................................................................................................................................... 10 
No diagnosis of developmental language disorders ................................................................................................ 10 
No diagnosis of severe dementia or primary progressive aphasia ........................................................................... 11 
No major co-existing neurological or psychiatric diagnosis ................................................................................... 11 
No contraindications to brain scanner (e.g. the presence of ferromagnetic implants or other metallic or electronic 
objects in the body, weight over 24 stone, claustrophobia or pregnancy). .............................................................. 11 
A.2 Background and Rationale .............................................................................................................................. 11 
A.3 Identification and description of the Investigational Device ........................................................................ 12 
A.4 Justification for the design of the clinical investigation ................................................................................ 13 
What new information will the research provide? ................................................................................................... 14 
A.5 Risks and benefits of the Investigational device and clinical Investigation ................................................. 15 
A.6 Objectives and hypotheses of the clinical investigation ................................................................................. 16 
A6.1 Hypotheses ............................................................................................................................................ 16 
A6.2 Primary Objective ................................................................................................................................. 17 
A6.3 Secondary Objective(s) ......................................................................................................................... 17 
A.7 Design of the clinical investigation .................................................................................................................. 17 
A.7.1 General ................................................................................................................................................ 17 
The on-line language battery (Comprehensive Aphasia Test) will be audio and video recorded to ensure accuracy 
when scoring. Other tests of language will also be recorded. ................................................................................. 18 
A.7.2 Investigational device and comparators .............................................................................................. 18 
A.7.3 Subjects ................................................................................................................................................ 18 
a) Inclusion criteria* ............................................................................................................................................... 18 
c) 
Exclusion criteria* ........................................................................................................................................ 19 
No diagnosis of developmental language disorders ................................................................................................ 19 
c) Criteria and procedures for subject withdrawal or discontinuation ................................................................... 19 
d) Point of enrolment. .............................................................................................................................................. 19 
e) Total expected duration of the clinical investigation .......................................................................................... 19 
f) Expected duration of each subject's participation ............................................................................................... 19 
g) Number of subjects included in the clinical investigation ................................................................................... 19 
h) Estimated time needed to select this number (i.e. enrolment period) ................................................................. 20 
Subject Eligibility .................................................................................................................................................. 20 
A7.4 Recruitment ........................................................................................................................................... 20 
A7.5 Randomisation Procedures ................................................................................................................... 21 
A.7.6 Procedures ........................................................................................................................................... 21 
A.8 Informed Consent Process ............................................................................................................................... 22 
Informed consent and aphasia ................................................................................................................................. 22 
Procedure of gaining consent .................................................................................................................................. 23 
A.9 Schedule of assessments and interventions by visit ....................................................................................... 23 
A.10 Device accountability ...................................................................................................................................... 24 
A.11 Monitoring Plan .............................................................................................................................................. 24 
a. 
Confidentiality ............................................................................................................................................... 25 

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b. 
Record keeping and archiving ....................................................................................................................... 25 
A.12 Statistical Considerations ............................................................................................................................... 25 
Design ..................................................................................................................................................................... 25 
A small, well-defined sample of patients with the potential to benefit from the DNI will be recruited. In both cases, 
the main outcome measure is whether the DNI is effective at improving naming impairments. This comparison is 
within-subject and is achieved by comparing post-therapy measures to multiple baseline measures. We also 
compare two different versions of the therapy in order to answer our secondary question of whether the therapy can 
be optimised (a between-groups comparison). ........................................................................................................ 25 
A.13 Data Management ........................................................................................................................................... 28 
A13.1 Procedures for data review, database cleaning, and issuing and resolving data queries. ................. 28 
A13.2 Procedures for verification, validation and securing of electronic clinical data systems .................. 28 
A13.3 Data retention ..................................................................................................................................... 29 
A13.4 Clinical quality assurance .................................................................................................................. 29 
A13.5 Completion of Case Report Forms ..................................................................................................... 29 
A13.6 Review and Return of Completed Documentation .............................................................................. 30 
A13.7 Retention of Documentation ............................................................................................................... 30 
A13.8  
Training ......................................................................................................................................... 30 
A.14 Amendments to the CIP ................................................................................................................................. 31 
A.15 Deviations from clinical investigation plan .................................................................................................. 31 
A.15.1 Procedures for recording, reporting and analysing CIP deviations ................................................. 31 
A.15.2 Procedure for reporting any protocol deviations .............................................................................. 32 
The clinical investigation shall not commence recruitment until all REC, regulatory (if applicable) and local (NHS 
permission) is received. All additional requirements imposed by the REC or regulatory authority will be followed.
 ................................................................................................................................................................................. 32 
A.17 Insurance ......................................................................................................................................................... 32 
A.18 Adverse events, adverse device effects and device deficiencies ................................................................... 33 
a-c) Definitions ......................................................................................................................................................... 33 
An adverse event does not include: ........................................................................................................................ 34 
d) Reporting requirements and timelines ...................................................................................................... 34 
e) Assessments of adverse events................................................................................................................... 36 
Seriousness .............................................................................................................................................................. 36 
Expectedness ........................................................................................................................................................... 36 
f) Procedures for recording and reporting Adverse Events and Device Deficiencies .................................. 37 
Investigator responsibilities: .................................................................................................................................... 37 
Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor responsibilities ........ 38 
Progress reports ....................................................................................................................................................... 38 
a) 
Anticipated adverse events and adverse device effects (ADEs), together with their likely incidence, 
mitigation or treatment. ........................................................................................................................................... 38 
A.19 Oversight Committees .................................................................................................................................... 41 
A.20 Vulnerable population .................................................................................................................................... 41 
A.21 Suspension or premature termination of the clinical investigation ............................................................ 42 
A21.1 Subject Withdrawals and Discontinuation .......................................................................................... 42 
A.22 Definition of End of Trial ............................................................................................................................... 43 
A.23 Publication policy ........................................................................................................................................... 43 
A.24 Bibliography .................................................................................................................................................... 45 
 
 
 

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LIST OF ABBREVIATIONS 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
CA 
Competent Authority 
CI 
Chief Investigator 
CIA 
Clinical Investigation Agreement 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
DINR 
Digital interventions in Neuro-rehabilitation 
DNI 
Digital Neuro-intervention 
DCF 
Data Clarification Form 
DD 
Device Deficiency 
EC 
European Commission 
EU 
European Union 
EUDAMED 
European Medical Devices Regulatory Database 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HRA 
Health Research Authority 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IMD 
Investigational Medical Device 
ISF 
Investigator Site File 
JRO 
Joint Research Office 
MA 
Marketing Authorisation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NCA 
National Competent Authority 
NHS 
National Health Service 
NHS R&D 
National Health Service Research & Development 
NICE 
National Institute of Clinical Excellence 
NIHR 
National Institute of Health Research 
NIST 
National Institute of Standards and Technology 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SALT 
Speech and Language Therapy 
SOP 
Standard Operating Procedure 
TMG 
Trial Management Group 
UADE 
Unanticipated Adverse Device Effect 
UK 
United Kingdom 
USADE 
Unanticipated Serious Adverse Device Effect 

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WTCN 
Wellcome Trust Centre for Neuroimaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Sponsor 
 
Sponsor’s representative 
Keith Boland 
Joint Research Office, UCL, 1st Floor 
Maple House, 
149 Tottenham Court Road, 
London W1T 7NF 
Postal address: 
Joint Research Office, UCL 
Gower Street, 
London WC1E 6BT 
 
Principal Investigator, Coordinating Investigator and Investigation site(s) 
 
Chief Investigator (CI) 
Professor of Neurology 
Prof Alex Leff,17-19 Alexandra House, Queen Square, WC1N 3AZ 
a.leff@ucl.ac.uk 
0207 279 1129 
 
Principal Investigator (PI) 
Professor of Cognitive Neurology 
& Honorary Consultant Neurologist 
Prof Alex Leff,17-19 Alexandra House, Queen Square, WC1N 3AZ 
a.leff@ucl.ac.uk 
0207 279 1129 
 
Co-Investigator 
 
Dr. Catherine Doogan, UCL, c.doogan@ucl.ac.uk, (Clinical 
Psychologist) 
Dr. Jennifer Crinion, UCL, j.crinion@ucl.ac.uk (Speech and Language 
therapist) 
Henry Coley-Fisher, henry.coley-fisher.15@ucl.ac.uk, Research 
Assistant, 
NeurotherapeuticsLab 
ICN 17-19 Queen 
Square, London, 
WC1N 3AZ 
0207 279 1134 
 
Add in other involved investigators 
as required 
Wellcome Centre for Human Neuroimaging (WCHN), Institute of 
Neurology, UCL 
Head of Center Prof Cathy Price. 
Statistician 
Dr Tom Hope, 
Senior Research Associate 
Wellcome Centre for Human Neuroimaging 
University College London 
London WC1N 3AR 
 
 

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A.1 Overall Synopsis of Clinical Investigation 
 
Title: 
Digital Interventions in Neuro-Rehabilitation (DINR): A digital neuro intervention 
(DNI) for word retrieval (anomia). The development and testing of a web-based therapy 
application for people with naming difficulties who have had a Stroke (iTALKbetter). 
 
Short title: 
 
Digital Interventions in Neuro-Rehabilitation (DINR): iTALKbetter 
 
Device: 
A digital intervention in Neuro-rehab (DNI). A word-retrieval app for people who have 
had a Stroke. 
 
Objectives: 
Digital Interventions in Neuro-Rehabilitation (DINR): A digital neuro intervention 
(DNI) for word retrieval. The testing of a web-based therapy application for people 
with naming difficulties through a small scale randomized controlled trial. 
iTALKBetter will provide an app-based therapy for people with word retrieval 
difficulties who have had a stroke (naming app for a wide variety of common words 
and phrases). 
 
The primary objective is to ascertain if iTALKbetter does improve performance on 
the trained items (compared to untrained). 
 
Secondary outcomes will include improvements in social activity and participation 
and participant and/or carer reported outcome measures (PROMS). 
 
We also plan to capture brain-based data (structural MRI) in order to test a series of 
secondary hypotheses relating to both how and why the therapy may work in some 
participants but not in others. 
 
Type of Investigation: 
A single site, randomised, control trial. 
 
Investigation design 
and methods: 
This is a summary of the protocol for the study funded by the National Institute of 
Health Research (NIHR). The main aim of this Phase 2 study is to test the clinical 
efficacy of the DNI through a randomised small-scale clinical trial. The participants 
will take the app home on a mobile device and ‘play’ the therapy. After the trial the 
participant will return the device and we will delete any content on the device and 
reload the DNI.  

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iTALKbetter is a small-scale, randomised, clinical trial for people with word retrieval 
difficulties who have had a stroke. Participants will be randomised (using 
minimisation) to one of two versions of the therapy: 1) deterministic iTALKbetter, 2) 
reactive iTALKbetter. 
Participants will complete 5 assessment sessions (T1-T5) at UCL – they will complete 
neuropsychological assessments, receive brain imaging scans, and complete a program 
of therapy using the DNI. 
 
Investigation 
duration per 
participant: 
30 weeks 
 
Estimated total 
Investigation 
duration: 
3 years 
 
Planned Investigation 
sites: 
Single-site is UCL. 
 
Total number of 
participants planned: 
 
30 
 
Main 
inclusion/exclusion 
criteria: 
a) Inclusion criteria 
 
Any type of stroke but at least 6 months after onset. 
 
Evidence of aphasia on the Comprehensive Aphasia Test (Swinburn, 
2004). 
English as their dominant language 
 
Able to tolerate MRI brain scan 
 
Able to give informed consent 
 
Able to use the DNI (app) 
 
b) Exclusion criteria 
 
No diagnosis of developmental language disorders 

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No diagnosis of severe dementia or primary progressive aphasia 
No major co-existing neurological or psychiatric diagnosis 
 
No contraindications to brain scanner (e.g. the presence of ferromagnetic 
implants or other metallic or electronic objects in the body, weight over 
24 stone, claustrophobia or pregnancy). 
 
Statistical 
methodology and 
analysis: 
Behavioural data: 
 
Behavioural baseline data will be analysed using minimisation (Altman, BMJ 2005) to 
ensure that the two groups are not unbalanced on key demographic variables, including 
baseline performance during the randomisation procedure. 
 
Data from all timepoints will be analysed using a repeated-measures ANOVA to 
determine whether there is an interaction between time (therapy block vs baseline) and 
item (trained vs untrained). The effect of the between-group factor (therapy type) is a 
secondary outcome measure which will also be analysed using a repeated measure 
ANOVA but with this extra factor added in: more formally, a three-way interaction 
between time (therapy block vs baseline), item (trained vs untrained) and therapy type 
(iTB: deterministic vs reactive). 
 
Neuroimaging data: 
 
Collected at three of the time points. Structural magnetic resonance imaging (MRI) data 
will be used to identify the lesion location. Brain structure at three time points (T2, T3 
and T4) will be analysed using Voxel-Based Morphometry (Ashburner and Friston, 
2000) within the Statistical Parametric Mapping software (SPM12) to identify whether 
the therapy induces any structural brain changes over time. We will employ multi- 
parameter mapping MRI methodology for the structural brain scans (Callaghan et al, 
2014). 
 
A.2 Background and Rationale 
 
Background 

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Mortality from stroke in the UK has reduced from 21% in 1999 to 12% in 2008. However, stroke prevalence has 
been increasing, the consequence of socioeconomic and scientific advances that have improved survival; which 
means that more people are surviving with long-standing disability. Language impairment (aphasia) is the 
second most common major impairment after stroke, with a prevalence of 250,000 in the UK. Aphasia may 
respond to therapy many months and years after the stroke occurs, but provision of specialist therapy (speech 
and language therapy - SALT) is far below that needed to provide optimal rehabilitation (Code and Heron, 
2003). 
We will address this by targeting a common symptom of post-stroke aphasia: impaired word retrieval problems. 
This is particularly important in patients receiving rehabilitation for associated disabilities as poor speech 
production can impair participation/compliance with treatment programmes. Our study is designed to improve 
word retrieval in patients with post-stroke aphasia, who are in the chronic phase (>6 months post-stroke). 
The main aim is to test the clinical efficacy of a novel, web-based, DNI. iTALKbetter will provide an effective 
training tool that patients can use to practice independently. This will free-up SALT time to provide additional 
assessment, supervision and functional intervention in a highly cost effective manner. 
 
iTALKbetter will provide an app-based therapy for people with word retrieval difficulties who have had a stroke 
(naming app for a wide variety of common words and phrases). 
 
This Digital Neuro Intervention (DNI) will provide the opportunity for the necessary increased rehabilitation to 
help people recover lost naming function. This will alleviate NHS Speech and Language Therapist (SALT) time 
and put users in control of when and where they carry out practice-based language therapy. 
A.3 Identification and description of the Investigational Device 
 
Purpose 
iTALKbetter will provide an app-based therapy for people with word retrieval difficulties who have had a stroke 
(naming app for a wide variety of common words and phrases). 
 
What does it do? 
The DNI works via mass practice and feedback to the users on a trial-by-trial basis. The DNI is very simple in a 
way; it just presents a long series of pictures for users to name. The DNI will use speech recognition (SR) software 
in order to make a binary decision as to whether the user said the correct word or not. This affects what the next 
trial (object to name) is and what auditory cue (if any) is provided the next time the user has to name the same item 
(see below): 

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*The speech will be recorded on the device but no other identifiable information will be stored on it. When the 
participant finishes the trial, we will delete all information on the device. 
What is the clinical trial design?  
A small, well-defined sample of patients with the potential to benefit from the DNI will be recruited. The main 
outcome measure is whether the DNI is effective at improving naming impairments. This comparison is within-
subject and is achieved by comparing post-therapy measures to multiple baseline measures. We are also comparing 
two different versions of the therapy (a between group comparison) to answer our secondary question of whether 
the therapy can be optimised. Outcome measures will be collected by the research team using a variety of 
standardized and non-standardized tests of language and cognition. These outcome measures are not built into the 
DNI at this point. 
The DNI will be introduced to the participant when attending a testing session. One of the research team will 
explain how to use the DNI, provide instructions for the user, and give some time for practice items. When 
confident that the participant can use the DNI independently, the participant will take the device home and 
continue their therapy (suggested therapy time is 5-10 hours per week) which will be simultaneously monitored 
by the research team. The research team will also check in on the participant weekly to trouble shoot any 
difficulties they may have (whether motivational or technical). When the participant has completed the therapy 
block, we will invite them in again for testing and they will return the mobile device with the DNI on it. The 
participants who continue to receive standard care during the therapy block will be asked to record and submit 
details to the research team.  
 
A.4 Justification for the design of the clinical investigation 
 
Why is the research considered worth doing? 
Standard (face to face) Speech and Language Therapy (SALT) has a huge evidence-base but patients in the 
NHS have unmet therapy needs due to a lack of resources. The evidence from speech-therapy highlights the 

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amount of time-on-task required to improve patients' ability to communicate. Naming problems are common 
and impact on the patients’ wellbeing and social inclusion. There is also good evidence that current existing 
therapeutic approaches work. 
A Cochrane review of 39 RCT's involving 2518 participants concluded that speech-therapy results in significant 
benefits to patients' functional communication (Brady, 2012). Many of these studies involve high doses of 
therapy. A meta-analysis examining dose found that positive therapy studies averaged 98 hours of speech 
therapy in total, while negative studies averaged 43 (Bhogal, 2003). In the NHS a patient with aphasia can 
expect a total average of 6-10 hours of SALT (Code, 2003). When the intervention takes place or how intensely 
seems less relevant to recovery (Moss, 2006). Our solution to the lack of available SALT therapy is to produce 
digital neuro-interventions that give patients the opportunity to practice scientifically validated, impairment 
based therapy when and where it suits them which gives them access to optimum therapy dose. 
Recent improvements in acute stroke care means that demand for already limited NHS resources will increase. 
Commissioners will need to address this growing unmet need and innovative relatively cheap interventions like 
this one will provide necessary rehabilitation. 
 
We know that therapy is effortful for patients who can sometimes be too fatigued when the therapist comes to 
do their session. This digital neuro-intervention will provide optimum availability of therapy and therefore place 
the patient in control of how much they do. However, as we recognise it is still effortful we hope to make the 
therapy engaging through adaptive and exciting software. The adaptiveness will serve to reward the patients for 
their efforts without ever making them feel like they are failing. This will hopefully boost how long they spend 
in therapy and therefore make greater gains. 
There are therapy 'apps" available for patients with aphasia but the scientific basis for them is lacking and none 
are targeted for speech production. By using voice recognition software our intervention will be uniquely 
designed to be used by patients with word retrieval impairments. 
 
What new information will the research provide? 
The concept of the therapy component is based on standard SALT practice and thus has a strong proof of 
concept basis, as do our proposed outcome measures. The novel component is packaging it in a user- friendly 
web-app that is designed for and by people with word-retrieval problems. This is ambitious and yet we believe a 
realistic goal to provide a world-wide evidence-based therapy that can benefit many. This digital neuro-
intervention will be in contrast to the plethora of apps available online claiming cognitive training without 
having scientific proof. 
The iTALKbetter research study is a small-scale, randomised, clinical trial for participants with word retrieval 
impairments post-stroke. The main research question is whether iTALKbetter improves patients’ naming ability 

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for trained items. We test this hypothesis by assessing participants naming abilities on two matched lists of 
items, half are trained items and half are untrained. A secondary question is whether it matters how the software 
progresses patients through the therapy. We will test this hypothesis by creating two different versions of 
iTALKbetter: ‘deterministic’ and ‘reactive’. Participants will be randomised (using minimisastion) to one of 
two of these versions of the therapy. Participants practice with the therapy for set periods of time (therapy 
block) following a series of (three) baseline measures split over a single, pre-therapy block (see Trial design 
section 5). The main outcome measure will be a clinically relevant improvement on the naming ability of the 
trained items (compared to untrained control items). Secondary outcomes include investigating which therapy 
version optimises recovery on naming accuracy and also improvements in social activity and participation and 
participant and/or carer reported outcome measures (PROMS). 
 
We also plan to capture brain-based data (structural MRI) in order to test a series of secondary hypotheses relating 
to both how and why the therapy may work in some participants but not others. All brain imaging will be outside 
of standard care for the participants and take place at UCL by trained staff. 
A.5 Risks and benefits of the Investigational device and clinical Investigation 
 
The potential clinical benefit to the participants is that they will be receiving more therapy through the DNI that 
they could ever receive from the NHS. This in turn will provide opportunity for them to improve their word 
retrieval which can be a distressing impairment. 
 
A full risk assessment and mitigation plan for each risk relating to the investigational device and the clinical 
investigation is detailed in a separate document entitled: Risk Assessment CTIMP iTALKbetter. 
 
 
The table below summaries the risks and mitigations of all tests above standard care that are being performed: 
 
Table 1 
 
Intervention 
 
 
Potential risk 
 
Risk Management 
MRI 
Only if any contraindications are 
missed or not reported. 
These contraindications may include 
the presence of any metal in the body. 
 
 
Performed by trained member of 
staff. 
Follow trust standard operational 
procedures by obtaining surgical 
history of exposure to metal, 
metallic dental work and other 

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Discomfort or anxiety in the MRI 
scanner may occur due to the noise and 
enclosed space. 
potential MRI contraindications. 
 
These potential risks will be 
reduced by providing an alarm bulb 
in the case of any uncertainty 
discomfort, or distress. Noise from 
the scanner will be attenuated by 
the use of earplugs and noise- 
shielding headphones. 
X-Ray 
Exposure to ionising radiation 
Performed by trained member of 
staff. 
 
Following trust protocols. 
 
The standard dose is equivalent to 
~0.005% of average annual 
radiation dose in the UK 
 
The classification of medical devices in the European Union is outlined in Annex IX of the Council Directive 
93/42/EEC (as amended). There are four classes, ranging from low risk to high risk. 
Class I 
Class IIa 
Class IIb 
Class III 
The Medical Device used in this investigation is classified as Class IIa 
A.6 Objectives and hypotheses of the clinical investigation 
A6.1 Hypotheses 
 
H1-Primary: Does iTB improve naming performance on trained items? 
 
This is a within-subject comparison. The criteria for success is a 10% (raw, or unstandardized) relative 
improvement in performance. This effect size was used in the recent Big Cactus study. 
 
H2-Secondary: Does reactive iTB significantly improve performance compared with deterministic iTB?  
 
This is two factor analysis with both a within-subject factor (trained vs. untrained items) and a between-group 
factor (reactive iTB vs. deterministic iTB). The criteria for success is a 5% (raw, or unstandardized) relative 
difference in performance. This is half the effect size used in the recent Big Cactus study, but that was to compare 
therapy with no therapy, here expected gains may be more marginal as both groups are receiving the therapy items, 
just in different orders. 
 

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A6.2 Primary Objective 
 
 Does iTB improve naming performance on trained items? 
 
A6.3 Secondary Objective(s) 
 
We believe that using this DNI will improve word retrieval on trained items by providing a known therapy used by 
SLT’s through a digital app and by enabling an increased dose of therapy. However, we also believe that by using 
this DNI and practicing every day, there will be changes in participants’ brain structure and in the health of the 
participants and their carers. 
 
• Does reactive iTB significantly improve performance compared with deterministic iTB? 
• Are the therapy effects item-specific or do we see generalization to untrained items? 
• Are the effects of the DNI therapy limited to the language domain alone or do they improve in 
other cognitive domains (e.g. sustained attention)? 
• Does the DNI improve participant’s social activity and participation? 
• Is the DNI acceptable to participants (can they use it easily)? 
• Is the DNI acceptable to participants’ carers? 
• Does the DNI improve carer health/well-being? 
• Does the DNI have any economic benefits? 
• Can baseline structural brain imaging explain participants’ responses to the DNI? 
• Can baseline structural brain imaging be used to predict incoming participants’ response to the 
DNI? 
• Can repeated-measures structural brain imaging identify participants’ brain areas that change in 
response to the DNI? 
A.7 Design of the clinical investigation 
A.7.1 General 
 
iTALKbetter is a small-scale, randomised, clinical trial for participants with word retrieval difficulties who 

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have had a stroke. Participants will be randomised (using minimisation) to one of two versions of the therapy: 
1) deterministic iTALKbetter, 2) reactive iTALKbetter. 
Participants will complete 5 assessment sessions (T1-T5) at UCL – they will complete neuropsychological 
assessments, receive brain imaging scans, and complete a program of therapy using the DNI. 
 
 
The on-line language battery (Comprehensive Aphasia Test) will be audio and video recorded to ensure 
accuracy when scoring. Other tests of language will also be recorded. 
 
A.7.2 Investigational device and comparators 
 
The tablets which the DNI will be uploaded onto will be stored in a secure cabinet in the ICN building. After the 
trial ends, the DNI will be deleted from the app and the devices will be stored or used by Prof Leff as he sees fit. 
No data will remain on the individual devices. 
A.7.3 Subjects 
a) Inclusion criteria* 
 
Any type of stroke but at least 6 months after onset. 
 
Evidence of aphasia on the Comprehensive Aphasia Test (Swinburn, 2004). 
 
English as their dominant language 
 
Able to tolerate MRI brain scan 

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Able to give informed consent 
 
c) Exclusion criteria* 
 
No diagnosis of developmental language disorders 
 
No diagnosis of dementia or primary progressive aphasia 
 
No major co-existing neurological or psychiatric diagnosis 
 
No contraindications to brain scanner (e.g. the presence of ferromagnetic implants or other metallic or 
electronic objects in the body, weight over 24 stone, claustrophobia or pregnancy). 
 
 
c) Criteria and procedures for subject withdrawal or discontinuation 
A participant may be withdrawn from the trial whenever continued participation is no longer in the 
participant’s best interests, but the reasons for doing so must be recorded. Reasons for discontinuing the 
trial may include: 
• 
Disease progression whilst in the study 
• 
Intercurrent illness 
• 
Patients withdrawing consent 
• 
Persistent non-compliance to protocol requirements. 
 
d) Point of enrolment. 
Participants are enrolled at T1 (first time point) as this is where consent is obtained. They are randomised 
at T3 (after all three baseline measurements have been collected). 
 
e) Total expected duration of the clinical investigation 
3 years 
 
f) Expected duration of each subject's participation 
30 weeks 
 
g) Number of subjects included in the clinical investigation 
30 

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h) Estimated time needed to select this number (i.e. enrolment period) 
2.5 years 
Subject Eligibility 
 
Once written informed consent has been obtained, the Case Report Form will be completed to document adherence 
to the inclusion and exclusion criteria. 
 
Where a subject fails to fulfil any element of the inclusion and exclusion criteria, this will be documented and the 
signed consent form and completed inclusion/exclusion criteria will be retained by the Principal Investigator. The 
subject will not advance any further into this clinical investigation. 
 
Subject Identification 
 
When a subject is identified and considered eligible for entry into this clinical investigation, the subject will be 
allocated the next available investigation number (subject ID number). 
 
For subjects enrolled, this number will consist of 01 for the first subject, 02 for the second subject and so on.  This 
number will be the unique identifier of the subject and written on each page of the paper/electronic Case Report 
Form booklet and all other documentation relating to that subject. 
 
Each subject that is enrolled into the study will have their study participation recorded and details of the device 
recorded in their hospital notes. A copy of their signed consent form and patient information sheet should also be 
placed on his/her hospitals notes to identify the subject as participating in a Clinical Investigation. 
 
A7.4 Recruitment 
 
Participant recruitment at a site will only commence when the trial has been initiated by the Sponsor (or it’s 
delegated representative), and issued with the ‘Open to Recruitment’ letter. 
 
Suitable participants will be identified by the clinical care team (Prof Leff, Dr. Crinion) and the study will be 
advertised in their clinics. If the participant has already consented to be contacted about the research, they will 
be contacted by telephone by a member of the research team (usually Dr Doogan or a research assistant but may 
include other members of the team). Participants will be initially identified from UCL and UCLH clinics run by 
the clinicians on the clinical care team and existing databases that we have permission to use (e.g. the PLORAS 

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stroke database in London CI: Professor Cathy Price, REC reference number 13/LO/1515). We may also 
advertise in local community rehab services and support groups. Participants who consent to be contacted by the 
research team will be consented to take part in the study at time-point 1. 
 
The basic details of our studies will be publicised on other appropriate websites and social media. 
 
A7.5 Randomisation Procedures 
 
Following participant consent, and confirmation of eligibility, the randomisation procedure described below will 
be carried out. 
 
After consent has been gained and the participants have completed 3 sessions of baseline testing, the CI will 
randomise the participants using minimisation. This will determine which version of the therapy the participant 
will use: deterministic or reactive. After time point 2, the participant will also be randomised to which list of words 
they will be trained on. This will be computer generated. 
 
Participants are considered to be enrolled into the trial following: consent, pre-treatment assessments, confirmation 
of eligibility, completion of the randomisation process, allocation of the participant trial number and treatment by 
the central coordinating team/remote system. 
 
A.7.6 Procedures 
 
The intervention which will be an application (DNI) on a tablet will be introduced to the participant when 
attending a testing session. One of the research team will explain how to use the DNI, provide instructions for 
the user, and give some time for practice items. When confident that the participant can use it independently 
then the participant will take the device home and continue their therapy (suggested therapy time is 5-10 hours 
per week) which will be simultaneously monitored by the research team. However, the research team will also 
check in on them weekly to trouble shoot any difficulties they may have (whether motivational or technical). 
When the participant has completed the therapy block, we will invite them in again for testing. The participants 
who continue to receive standard care during the therapy block will be asked to record and submit details to the 
research team. 
Brain Imaging will also take place. This will happen 3 times, at time-points 2, 3 and 4. The scans will take 
place in UCL, carried out by trained staff, on the same day as the participants are coming in for behavioural 
testing and will last approximately 30 minutes. 

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A.8 Informed Consent Process 
 
We understand it is the responsibility of the Investigator, or a person delegated by the Investigator, to obtain 
written informed consent from each subject prior to participation in the Investigation, following adequate 
explanation of the aims, methods, anticipated benefits and potential hazards of the study. 
 
The person taking consent will be GCP trained, suitably qualified and experienced, and have been delegated this 
duty by the CI/PI on the delegation log. 
 
A week will be given for consideration by the patient before taking part. The PI must record when the patient 
information sheet (PIS) has been given to the patient. [If the amount of time between the PIS being given and the 
date of consent are less than 24 hours, the PI will explain the rationale for this]. It must be recorded in the medical 
notes when the participant information sheet (PIS) has been given to the participant. 
 
The Investigator or designee will explain the patients are under no obligation to enter the Investigation and that 
they can withdraw at any time during the Investigation, without having to give a reason. 
 
No clinical Investigation procedures will be conducted prior to taking consent from the participant. Consent will 
not denote enrolment into Investigation. A copy of the signed Informed Consent Document will be given to the 
participant.  The original signed form will be retained at the study site and a copy placed in the medical notes. 
 
If new safety information results in significant changes in the risk/benefit assessment, the consent form will be 
reviewed and updated if necessary and subjects will be re-consented as appropriate 
 
Informed consent and aphasia 
 
Aphasic patients do require extra care when informed consent is being sought. All information materials will be 
offered in written and aural forms, and supplemented by pictorial information to ensure that they are 
comprehensible to all participants. Participants (and, where appropriate, their carers) will be given a minimum 
of one week to carefully consider the information materials before deciding about participation. 
Patients who are incapable of providing informed consent (patients without capacity) will not be recruited. 
The vast majority of patients with post-stroke aphasia are able to consistently communicate their wishes and 
desires, including consent to a treatment trial, see: 
Stroke and Aphasia Handbook, Parr, S., Pound, C., Byng, S. and Long, B. 2003. Connect Press, UK. 
 

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The procedures for consent outlined in the Standard Operating Procedure for informed consent form (UCL) 
will be adhered to. A written record of the checks made for competence to consent will be kept along with 
other information in each patient’s Case Report Form. The CI will also ensure that written consent is 
witnessed, preferably by a relation or carer of the patient, or if not, by an independent witness present at the 
Welcome Trust Centre for Neuroimaging, UCL (WTCN). 
Written, informed consent will be obtained for all participants. We plan to follow published guidelines for 
addressing consent issues in aphasic patients (Penn, Frankel et al. 2009). 
Only members of the clinical care team will be identifying and approaching patients. 
The research team has considerable experience of working with patients with impaired speech and language 
abilities (there are four speech and language therapists on the team), and will take the required time and 
attention to ensure that the requirements and risks of the study are thoroughly understood (by both the 
participant and, where appropriate, a family member or carer) before consent is obtained. 
 
Procedure of gaining consent 
 
Two of the research team hold weekly clinics for stroke survivors in UCLH/NHHN. They will identify 
potential participants for iTALKbetter and gain verbal consent to be contacted to discuss the study in more 
detail. 
Potential participants will be telephoned again at least 1 week after initial contact, by Dr Doogan or the 
research assistant to answer any further questions and, if appropriate, to arrange the first testing appointment at 
the participating site. When participants come into their first testing appointment, written consent will be 
obtained. 
At the first and subsequent appointments, potential participants will have a further opportunity to ask 
questions about the study. 
 
If there is any change in capacity as indicated by a carer, the participant or a member of the research team, Dr 
Doogan, a Clinical Psychologist, will assess this and discontinue if found to be changed. 
A.9 Schedule of assessments and interventions by visit 
 
Time- 
point 
iTALKbetter 

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T1 
• 
Baseline neuropsychological testing 
• 
Baseline language and cognitive assessment (including Electronic 
Comprehensive Aphasia Test (eCAT)) 
• 
Self-report and carer-report outcome measures 
 
T2 
• 
Language and cognitive assessment (including eCAT) 
• 
Self-report and carer-report outcome measures 
• 
Brain imaging 
T3 
• 
Language and cognitive assessment (including eCAT) 
• 
Self-report and carer-report outcome measures 
• 
Brain imaging 
Participants are randomised at this point to one of the two versions of iTALKbetter. 
Participants receive a mobile device with the DNI on it. 
T4 
• 
Language and cognitive assessment (including eCAT) 
• 
Self-report and carer-report outcome measures 
• 
Brain imaging 
 
The mobile device with the DNI is taken away. 
T5 
• 
Language and cognitive assessment (including eCAT) 
• 
Self-report and carer-report outcome measures. 
 
Some assessments may be audio and video recorded to ensure accuracy when scoring. 
 
We will inform participants’ GPs and therapists (if they have one) of their involvement in the study. 
A.10 Device accountability 
 
The DNI (software) will be given to each participant to use on hardware (a tablet computer) purchased from the 
grant and thus belonging to UCL. Because the software uploads data periodically to the database (on the UCL 
secure virtual server) we are able to tell when participants are using it. At the end of the trial block, the DNI (and 
tablet computer) are passed back to the research team and will be recycled for a future participant to use. 
A.11 Monitoring Plan 
 
Case Report Forms (CRFs) will be completed by the investigator and/or his/her delegates at each timepoint. These 
will record any potential AEs or ADEs. These data will be collated and passed onto the IDMC for their view on 

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safety. As each participant has several timepoints when they are not using the DNI, we will be able to perform 
within-subject analyses for the IDMC to see if rates of AEs or ADEs are higher in the DNI therapy blocks. 
a. Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998. The CRFs will not bear the subject’s 
name or other personal identifiable data. The subject’s Investigation identification number, will be used for 
identification. Subjects will be assigned an Investigation identification number by the study site sequentially 
starting with 001 upon enrolment into the study. The study site will maintain a master Subject Identification Log. 
b. Record keeping and archiving 
Archiving will be authorised by the Sponsor following submission of the end of study report. Chief Investigators 
are responsible for the secure archiving of essential Investigation documents as per their Trust policy. All essential 
documents will be archived for at least 5 years after completion of Investigation. Destruction of essential 
documents will require authorisation from the Sponsor. 
 
The Chief Investigator will ensure there are adequate quality and number of monitoring activities conducted 
by the study team. This will include adherence to the protocol, procedures for consenting and ensuring 
adequate data quality. 
The Chief Investigator will inform the sponsor should he/she have concerns which have arisen from 
monitoring activities, and/or if there are problems with oversight/monitoring procedures. 
An independent data monitoring committee (IDMC) will be set up to deal with patient safety issues related 
to this project. The IDMC will comprise of three independent researchers at the Institute of Neurology not 
linked to this project. 
The data to be monitored by the IDMC will be taken from the CRFs (which will include all AEs and ADEs), 
as indicated above. 
A.12 Statistical Considerations 
 
Design 
 
A small, well-defined sample of patients with the potential to benefit from the DNI will be recruited. In both cases, 
the main outcome measure is whether the DNI is effective at improving naming impairments. This comparison is 
within-subject and is achieved by comparing post-therapy measures to multiple baseline measures. We also 
compare two different versions of the therapy in order to answer our secondary question of whether the therapy can 

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be optimised (a between-groups comparison). 
 
Sample size calculation 
 
Sample-size calculation based on data from a more recent trial: The Big Cactus trial using step-by-step software:  
https://www.sheffield.ac.uk/scharr/sections/dts/ctru/bigcactus.  
 
Therapy group improved by 14.4% compared with a control group (no therapy) on word finding ability (95% CI = 
10.8-18.1%). There was no use of control items, but using this data to model the trained items (14% improvement) 
and the untrained items (0% improvement) we entered the data into a sample size calculator as before (DSS one on 
percentages) we find the calculation to be in each iTB group (see screenshot) to be 13. In total this means 26 total 
but with an expected 15% drop out this means we recruit 30. 
 
 
Planned recruitment rate 
 
We will begin recruitment prior to the start of the trial and hope to have 50% of patients enrolled by the 
time the first patient enters the trial. 
 
Randomisation methods 
 
After iTALKbetter participants complete baseline testing (time-point 3) they will be randomised using 
minimisation to make sure the groups do not become unbalanced on key baseline variables. This will determine 
which version of the therapies participants will use and which of the word lists they are allocated (computer 
generated). 
Participants will be randomised on the following variables: aphasia severity and time since stroke. 
Multivariate analyses that adjust for all factors used in the minimisation algorithm will be performed as will the 
appropriate sensitivity analyses. 
 
 
Statistical analysis 
Behavioural baseline data will be used to ensure that the two therapy groups are not unbalanced on key 
demographic variables, including baseline performance during the randomisation procedure. This process of 
randomisation is called minimisation (Altman, BMJ 2005). 
 
Data from all timepoints will be analysed using a repeated-measures ANOVA to determine whether there is an 

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interaction between time (therapy block vs baseline) and item (trained vs untrained). The effect of the between-
group factor (therapy type) is a secondary outcome measure which will also be analysed using a repeated measure 
ANOVA but with this extra factor added in: more formally, a three-way interaction between time (therapy block vs 
baseline), item (trained vs untrained) and therapy type (iTB: deterministic vs reactive). 
 
Neuroimaging data, collected at three of the time points: Structural magnetic resonance imaging (MRI) data will be 
used to identify the lesion location. Brain structure at the three time points will be analysed using Voxel-Based 
Morphometry (Ashburner and Friston 2000) within the Statistical Parametric Mapping software (SPM12) to 
identify whether these therapies induce any structural brain changes over time. We will employ multi- parameter 
mapping MRI methodology for the structural brain scans (Callaghan et al, 2014). Structural MRI scans will be 
analysed using Voxel Based Morphometry (VBM, Ashburner & Friston, 2000) to test for therapy-induced changes 
in brain structure. 
 
Missing Data 
 
We expect a 15% drop out rate (see sample size correlation above). If the drop out rate is less than 5% then we will 
remove these cases and proceed with a per-protocol analysis. For drop out rates over 5% we will assess the impact 
of any potential missing data on our study by conducting the following sensitivity analyses: 
 
1) Categorise the missing data – Missing completely at random (MCAR), Missing at random (MAR) or 
Missing not at random (MNAR). 
 
If any patients drop out of this study details as to why will be collected from the patient at the time of dropout. The 
reasons given will be used to categorise the missing data and justify subsequent handling of the missing data. 
 
2) Handling missing data –  
a) MCAR: 
 
In this case the relevant cases will be deleted using listwise or pairwise deletion as appropriate using SPSS. 
 
b) MAR and MNAR: 
 
We will use multiple imputation methods to generate multiple copies of the original dataset by replacing missing 
values using an appropriate model. Analyse as complete data sets and combine the different parameter estimates 
across the data sets to produce a unique point estimate and standard error taking into account the uncertainty of the 
imputation process. 

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3) Sensitivity Analyses 
 
We will compare the results of the full dataset analysis (dataset with imputed values) to those of the complete case 
analysis (dataset with observed data only) on a case-by-case basis. To assess the impact of any missing data on the 
conclusions of the study. 
  
A.13 Data Management 
 
The handling of all data on the CRFs will be the responsibility of UCL. 
It will be the responsibility of the investigator to ensure the accuracy of all data entered in the CRFs. The 
delegation log will identify all those personnel with responsibilities for data collection and handling, including 
those who have access to the trial database. 
 
 
We believe that the DNI will be easy to use and that participants will want to do their therapy as the 
experience of it being a digital game will be pleasurable. However, therapy is difficult and tiring so in order 
to minimise possible distress or frustration, the research team will systematically call the participants if they 
are struggling to meet their targets of therapy week by week. This will enable the participant to discuss any 
barriers to doing the therapy and researchers can check in with participants to solve any possible, but 
unlikely, technical issues. 
 
A13.1 Procedures for data review, database cleaning, and issuing and resolving data queries. 
 
Data entered on the CRFs will be source verified by a sponsor representative trained on the CIP and who has 
current GCP training. Data Clarification Forms (DCF) will be issued to the Investigator should a discrepancy be 
found between the source and CRF. The Investigator will be required to verify and correct all errors or provide an 
explanation for the discrepant data. Sponsor representatives will re-verify the corrected data and mark the 
clarification as resolved at the next monitoring visit. 
 
A13.2 Procedures for verification, validation and securing of electronic clinical data systems 
 
All data from the examinations and investigations listed in Appendix A will be transferred to media 
provided by the sponsor and collected at the time of CRF collection. 

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The CI will manage and maintain the study database throughout the Investigation. At the conclusion of the 
Investigation, the database will then be locked and data transferred for analysis. A final copy of the database will 
be provided to the study site. Where data is transferred electronically, this will be in accordance with the UK Data 
Protection Act 1998 as well as Trust Information Governance Policy. There will be a documented record of data 
transfer and measures in place for the recovery of original information after transfer. 
 
The database maintained by the CI shall be validated and secured according to the UCL standard operating 
procedures. Access to the data shall be limited to sponsor representatives directly involved in the collection, 
analysis, maintenance or safety monitoring of the data. Any study data released shall be done according to 
the publication policy and in accordance with the UK Data Protection Act 1998. 
 
A13.3 Data retention 
 
Archiving will be authorised by the Sponsor following submission of the end of study report. Chief Investigators 
are responsible for the secure archiving of essential Investigation documents and the Investigation database as per 
their trust policy. All essential documents will be archived for at least 20 years after completion of Investigation. 
Destruction of essential documents will require authorisation from the Sponsor. 
 
A13.4 Clinical quality assurance 
 
The Clinical Investigators will meet monthly, to discuss any issues with data quality and any concerns will be 
discussed with the Sponsor. 
 
A13.5 Completion of Case Report Forms 
 
The Principal investigator will be responsible for the timing, accuracy and completeness of a CRF for each 
individual subject.  All entries are to be made in black ink and are to be legible.  All corrections made are to be 
completed by placing a single line through the incorrect data and the individual making the correction must initial 
and date the correction. Typing correction fluid must not be used. The personal data recorded on all documents will 
be regarded as confidential. 
 
The Principal investigator must record the subject’s participation in this clinical investigation in the subject’s 
hospital notes.  In addition, the Principal investigator must keep a separate list of all subjects entered into the 
clinical investigation showing each subject’s name, date of birth and assigned subject number (for identification 

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purposes). A Subject Identification Log will also be provided in the Investigation Site File to record the subject’s 
initials and assigned subject number. 
 
All data will be handled in accordance with the UK Data Protection Act 1998. 
The CRFs will not bear the subject’s name or other personal identifiable data.  The subject’s initials, date of birth 
and trial identification number, will be used for identification. 
 
A13.6 Review and Return of Completed Documentation 
 
The Principal investigator will make the original Case Report Forms available to the Sponsor’s designated monitor 
at each visit.  At the conclusion of the clinical investigation, completed Case Report Forms will be signed by the 
Principal investigator, collected (the original left with the Principal investigator) and a copy returned to the 
Sponsor. 
 
A13.7 Retention of Documentation 
 
The Principal investigator will retain all copies of the records for a period of 20 years from the discontinuation of 
the clinical investigation.  In all cases, the Principal investigator must contact the Sponsor prior to disposing of 
any records related to the clinical investigation.  Included in records to be maintained are signed Clinical 
Investigation Plan, copies of the CRFs, signed consent forms, ethics committee approval letters, product 
accountability records, correspondence concerning the clinical and any other documents to identify the subjects. 
 
In addition, if the Principal investigator moves/retires, etc., he should provide University College London with 
the name and address of the person who will look after and be responsible for the clinical investigation related 
records. 
 
A13.8  Training 
During the initiation of the investigation site, the sponsor will ensure the investigators and the site study staff are 
trained on the device. The investigator is then responsible for ensuring that the investigation staff uses the device 
in the same way. All training will be documented in a Site Training Log. 
The monitor will also ensure that the investigator and investigation site team have received and understood the 
requirements and content of: 
* CIP (Clinical Investigation Plan) 

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* IB (Investigators Brochure) 
* The informed consent forms 
* CRFs (Case Report Forms) 
* IFUs (Instructions For Use) 
* All written clinical investigation agreements as appropriate 
A.14 Amendments to the CIP 
 
Amendments to this CIP may be necessary to protect the safety of the patients and integrity of the data. In 
collaboration with the Investigator(s), the CIP amendments will be documented and submitted for ethical and 
regulatory approval (as required) prior to implementation. All changes will be evaluated for impact per sponsor 
SOPs. Amendments will be considered implemented after all ethical and regulatory approvals (as required) are 
received and all key sponsor and site staff have been trained. This process does not affect the individual clinician’s 
responsibility to take immediate action if thought necessary to protect the health and interest of individual patients. 
A.15 Deviations from clinical investigation plan 
 
A deviation is considered a departure from the conditions and principles of GCP in connection with that 
Investigation; or the CIP relating to that Investigation, as amended from time to time. 
 
The Investigator shall not deviate from this CIP except in situations that affect the subject’s rights, safety and well-
being, or the scientific integrity of the clinical investigation. 
 
A.15.1 Procedures for recording, reporting and analysing CIP deviations 
 
If possible, prior approval from the sponsor and REC, if appropriate, shall be obtained by the investigator. All 
spontaneous CIP deviations shall be recorded and reported to the sponsor as agreed. A deviation log shall be 
maintained by the study site. Deviations shall be reported to the REC and the regulatory authorities if required by 
national regulations. All deviations will be included, as required in the final study report. 
 
Notification requirements and time frames. 
 
Requests for deviations by the investigator will be responded to within 48 hours of receipt. 
 
Corrective and preventive actions and principal investigator disqualification criteria. 

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Refer to the Monitoring Plan (as applicable) for corrective and preventative actions and principal investigator 
disqualification criteria. 
 
A.15.2 Procedure for reporting any protocol deviations 
 
Any deviation from the protocol that has not been previously approved by the sponsor (JRO at University College 
London), must be reported to the sponsor within 2 working days of the deviation occurrence.  Any deviations from 
the clinical investigation plan that are identified during routine monitoring visits will be reported to the sponsor 
(JRO, University College London) within 24 hours of being identified. 
 
A.16 Statements of compliance 
 
The clinical investigation shall be conducted in accordance with the ethical principles of the Declaration of 
Helsinki, ISO standard 14155 and all other applicable device and UK regulations. 
The clinical investigation shall not commence recruitment until all REC, regulatory (if applicable) and local (NHS 
permission) is received. All additional requirements imposed by the REC or regulatory authority will be followed. 
A.17 Insurance 
 
University College London holds insurance against claims from participants for injury caused by their participation 
in the clinical trial. Participants may be able to claim compensation if they can prove that UCL has been negligent. 
However, as this clinical trial is being carried out in a hospital, the hospital continues to have a duty of care to the 
participant of the clinical trial.  University College London does not accept liability for any breach in the hospital’s 
duty of care, or any negligence on the part of hospital employees. This applies whether the hospital is an NHS 
Trust or otherwise. 
 
Participants may also be able to claim compensation for injury caused by participation in this clinical trial without 
the need to prove negligence on the part of University College London or another party.  Participants who sustain 
injury and wish to make a claim for compensation should do so in writing in the first instance to the Chief 
Investigator, who will pass the claim to the Sponsor’s Insurers, via the Sponsor’s office. 
 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance cover for harm 
caused by their employees and a copy of the relevant insurance policy or summary shall be provided to University 
College London, upon request. 

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There must also be indemnity arrangements in place, with the manufacturer, to cover the malfunction and 
breakdown of the device. N/A 
A.18 Adverse events, adverse device effects and device deficiencies 
a-c) Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory findings) in subjects, users or other persons, 
whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical device 
or the comparator 
Note 2: This definition includes events related to the procedures involved 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices 
Adverse Device Effect 
(ADE) 
Adverse Event related to the use of an investigational device. 
Note 1: This definition includes AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational device 
Note 2: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device 
Serious Adverse Event 
(SAE) 
Any adverse event that: 
• 
Led to death, 
• 
Led to serious deterioration in the health of the subject, that either resulted in 
• a life-threatening illness or injury, or 
• a permanent impairment of a body structure or a body function, or 
• in-patient or prolonged hospitialisation, or 
• medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function, 
• 
Led to foetal distress, foetal death or a congenital anomaly or birth defect 
 
 
Serious Adverse Device Effect 
(SADE) 
An ADE that has resulted in any of the consequences characteristic of an SAE 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
An SADE, which by its nature, incidence, severity or outcome, has not been 
identified in the current version of the risk analysis report. 
Device Deficiency (DD) 
Inadequately of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. 
Note 1: this includes malfunctions, use errors, and inadequate labeling 
 

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An adverse event does not include: 
• 
Medical or surgical procedures; the condition that leads to the procedure is an adverse event. 
• 
Pre-existing disease, conditions, or laboratory abnormalities present at the start of the study that do not 
worsen in frequency or intensity. 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalizations for cosmetic or 
elective surgery or social/convenience admissions); 
• 
The disease being studied or signs/symptoms associated with the disease unless more severe than expected 
for the subject’s condition. 
d) Reporting requirements and timelines 
 
AEs and ADEs are not considered reportable. 
 
Term 
Reporter 
Reported to 
Reporting Timeline from awareness 
of the event 
Adverse Event (AE) 
Investigator 
Sponsor 
As agreed with sponsor. CI to record 
fully all AEs. 
Adverse Device Effect 
(ADE) 
Investigator 
Sponsor/Manufacturer 
As agreed with sponsor. CI to record 
fully all ADEs. 
 
 
The following events are considered reportable events in accordance with Annex 7, section 2.3.5 and Annex X, 
section 2.3.5 of DIRECTIVES 90/385/EEC AND 93/42/EEC respectively. 
 
Term 
Reporter 
Reported to 
Reporting Timeline from awareness 
of the event 
Serious Adverse Event 
(SAE)**/ Serious 
Adverse Device Effect 
(SADE) 
Investigator 
Sponsor 
Immediately, but no more than 3 
calendar days after becoming aware 
of the event 
CI 
MHRA 
aic@mhra.gsi.gov.uk 
 
Immediately, but not later than 2* 
calendar days after awareness 
*For SAEs which indicate an 
imminent risk of death, serious 
injury, or serious illness and 
that require prompt remedial action 
for other patients/subjects, users or 
other persons 
 
All other events immediately but not 
later than 7 calendar days following 
date of awareness. 
CI 
REC 
N/A 
Unanticipated Serious 
Investigator 
Sponsor 
Immediately, but no more than 3 

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Adverse Device Effect 
(USADE) 
 
 
calendar days after becoming aware 
of the event 
CI 
MHRA 
 
Immediately, but not later than 2* 
calendar days after awareness 
*For SAEs which indicate an 
imminent risk of death, serious 
injury, or serious illness and 
that require prompt remedial action 
for other patients/subjects, users or 
other persons. 
All other events immediately but not 
later than 7 calendar days following 
date of awareness. 
CI 
REC 
Within 15 days of the chief 
investigator becoming aware of the 
event. 
Only reports of related and 
unexpected Serious Adverse Events 
(SAEs) should be submitted to the 
REC. 
 
 
Term 
Reporter 
Reported to 
Reporting Timeline from awareness 
of the event 
Device Deficiency 
(DD) 
Investigator 
Sponsor 
 
Immediately, no more than 24 hours 
of becoming aware of the event 
CI 
 
MHRA 
7 calendar days 
 
Only reportable if the event may 
have led to an SAE if; 
• 
suitable action had not taken 
• 
intervention had not been 
made 
• 
if circumstances had been 
less fortunate 
Urgent Safety 
Measures 
CI 
REC 
(i) 
Immediately-By telephone 
(ii) 
Within 3 days-Notice in 
writing setting out reasons 
for the USM and plan for 
further action 
 
** Note Planned hospitalisation for a pre-existing condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse event 

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e) Assessments of adverse events 
 
Each adverse event will be assessed for the following criteria: 
 
Severity 
 
Category 
Definition 
Mild 
The adverse event does not interfere with the subjects daily routine, and does 
not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the subjects routine, or 
requires intervention, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
Note: A severity rating of severe does not necessarily categorise the event as an 
SAE. 
Seriousness 
Seriousness as defined for an SAE in section a) above. 
 
Causality 
 
The assessment of relationship of adverse events to the study procedure and the investigational device will be a 
clinical decision based on all available information at the time of the completion of the case report form. The 
following categories will be used to define the causality of the adverse event: 
 
Category 
Definition 
Yes 
There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the 
event occurred within a reasonable time after procedure). However, 
the influence of other factors may have contributed to the event (e.g. 
the patient’s clinical condition, other concomitant events). 
No 
There is no evidence of any causal relationship. 
Expectedness 
Category 
Definition 
Expected 
An adverse event that is consistent with the information about the 
device listed in the Investigator Brochure or clearly defined in this 
CIP. 

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Unexpected 
An adverse event that is not consistent with the information about the 
device listed in the Investigator Brochure 
 
The reference document to be used to assess expectedness against the intervention is the IB. The CIP will be used 
as the reference document to assess disease related and/or procedural expected events. 
f) Procedures for recording and reporting Adverse Events and Device Deficiencies 
Investigator responsibilities: 
All adverse events and SAEs will be recorded in the medical records and CRF following consent. 
 
All serious adverse events will need to be reported to the sponsor on a SAE form (using MEDDEV form 2.7/3) 
unless stated in the CIP that some expected SAEs will not be reported to the sponsor, with a justification as to why 
they will not be reported. 
 
The Chief or Principal Investigator will complete the serious adverse event form and the form will be emailed to 
the sponsor UCL, within 3 working day of his/her becoming aware of the event. The Chief or Principal 
Investigator will respond to any SAE queries raised by the sponsor as soon as possible. 
 
The Investigator will report to the MHRA and REC (as applicable) all reportable events within the specified 
timeframes as per section d above. 
 
 
All deaths will be reported to the sponsor irrespective of whether the death is related to disease progression, the 
device, or an unrelated event. 
 
 
All serious adverse events will be recorded in the medical records and the CRF, and the sponsor’s AE log. 
 
All SAEs (except those specified in section d as not requiring reporting to the Sponsor) 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. 
 
All SAEs and UADEs should be reported to the following; [insert REC and MHRA] 

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Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor responsibilities 
 
Investigator responsibilities shall be as per section d).  The sponsor shall keep detailed records of all adverse events 
and device deficiencies relating to the clinical Investigation, which are reported to them by the Investigation 
investigators. The sponsor shall ensure that all relevant information about a reportable event, which occurs during 
the course of this clinical Investigation in the United Kingdom, is reported as soon as possible to the MHRA, and 
the relevant ethics committees per their reporting requirements and according to the timelines in section d.  Any 
additional relevant information should be sent within the same time frame as the initial report. The CI is 
responsible for informing the appropriate regulatory authorities, ethics committees and other investigators of any 
reportable events that have occurred with the study device in any clinical investigation according to the guidelines 
set forth by either the REC of record or regulatory authority in the country where the clinical investigation is taking 
place. 
Progress reports 
Progress reports will be submitted to the REC as per the REC requirements. The chief investigator will prepare the 
annual progress reports. 
 
Foreseeable adverse events and anticipated adverse device effects 
 
a) Anticipated adverse events and adverse device effects (ADEs), together with their likely incidence, 
mitigation or treatment. 
 
Adverse events 
 
Patients with stroke are at risk for both further strokes and morbidity and mortality associated with co-existing 
cardiovascular disease.  
 
1) 
Further strokes. 
 
2) 
Myocardial infarction. 
 
3) 
Angina. 
 
4) 
Peripheral vascular disease. 
 

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If any brain abnormality is found on the MRI scans during the study the following procedure will be adhered to:  
 
All abnormal structural scans will be shown to a Consultant Neuroradiologist from the National Hospital for 
Neurology and Neurosurgery, as soon as possible. 
 
Prof Alex Leff, Consultant Neurologist will have responsibility for reporting the finding to the participant’s GP 
and discussing it with the participant as soon as possible. 
 
A record of events will be kept in the research log, however, they will not be reported to REC and MHRA as they 
are anticipated events that patients are at risk of due to the nature of the underlying condition being studied. The 
records of these events will be discussed by the IDMC. 
 
Adverse device effects and events 
Below is a table summarizing the anticipated adverse device effects and events. 
 
 
 
 
 
 
Adverse event/effect 
Likelihood (low, medium, high) 
Mitigation Strategy 
Despite the user and simulation 
testing carried out on 
development. There is still risk of 
unanticipated bugs in the software 
that may arise due to differences 
in patient usage from the 
recommended usage. 
Medium 
During the clinical trial, all bugs 
will be tracked and logged using 
the Project Locker bug tracking 
tools) and all bugs will be given a 
unique reference code, an 
associated record for that 
reference code is captured, by the 
clinical team, detailing what 
caused the bug to occur, each bug 
is then prioritized and a fix is 
implemented (The clinical team 
will have access to the bug 
tracking code reports). Once a bug 

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is fixed by the engineering team a 
standard formal automated 
verification test (again a test prior 
approved by the clinical team) is 
run on the compiled software to 
verify that the bug has been fixed. 
Speech recogniser gives an 
incorrect binary decision. There is 
a risk that the speech recognition 
system may provide incorrect 
decisions to patient input i.e false 
positive or false negative 
decisions on a patient’s naming 
attempt. 
 
Medium 
During the trial the performance 
of the speech recognizer will be 
monitored by the research team 
via the backend. The speech 
recognizer is expected to work at 
80% accuracy. Thus these types of 
risks are considered an expected 
adverse device event and as such, 
a record of these types of events 
will be kept and reviewed by the 
relevant auditing committee and 
the IDMC for the trial. 
Patient fatigue, headache, 
eyestrain from using the tablet 
device during the therapy and 
from prolonged screen time. 
Low 
The device can be supported by 
the user or can be used with table 
to prevent any patient fatigue if 
holding the tablet.  
Participants will also be 
encouraged to take regular beaks 
and to avoid prolonged screen 
time. 
 
 
 
 
 
 
 

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A.19 Oversight Committees 
 
Trial Management Group (TMG) 
 
The TMG will include the Chief and Principal Investigators and experts from relevant specialties.  The TMG will 
be responsible for overseeing the trial.  The group will meet at least twice per year and all members will sign a 
TMG charter.  The TMG will review substantial amendments to the protocol prior to submission to the REC and 
MHRA. 
 
Trial Steering Committee (TSC ) 
 
As this is not a multicenter trial, the TMG and TSC are one and the same. 
 
Independent Data Monitoring Committee (IDMC) 
 
The role of the IDMC is to provide independent advice on data and safety aspects of the trial.  Meetings of the 
Committee will be held annually to review the safety data generated by the study or as necessary to address any 
issues.  Information about adverse events and device effects will be gathered at each of the clinical trial time-points 
per patient. If the IDMC deems any adverse event or device effect is excessively high (i.e. statistically and 
clinically significant) then they can recommend premature closure of the trial. 
 
The IDMC is advisory to the TSC and can recommend premature closure of the trial to the TSC. All IDMC 
members will sign an IDMC charter. 
A.20 Vulnerable population 
 
a) Description of the vulnerable population. 
 
Stroke 
Some stroke survivors may be considered vulnerable as they may have significant communication and 
cognitive difficulties. However, as part of this clinical trial we will not be recruiting anyone with significant 
cognitive impairment and therefore on an individual basis may not be considered as vulnerable. 
 
There may be some support with travelling to appointments by family members which we will encourage. 
 
b) Description of the specific informed consent process. 

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However, due to the difficulties with communication that aphasic patients do have they require extra care 
when informed consent is being sought. All information materials will be offered in written and aural 
forms, and supplemented by pictorial information to ensure that they are comprehensible to all participants. 
Participants (and, where appropriate, their carers) will be given a minimum of one week to carefully 
consider the information materials before deciding about participation. 
Patients who are incapable of providing informed consent (patients without capacity) will not be 
recruited. The vast majority of patients with post-stroke aphasia are able to consistently communicate 
their wishes and desires, including consent to a treatment trial, see: 
Stroke and Aphasia Handbook, Parr, S., Pound, C., Byng, S. and Long, B. 2003. Connect Press, UK. 
 
c) Description of the EC's specific responsibility.  
 
N/A 
 
d) Description of what medical care, if any, will be provided for subjects after the clinical investigation 
has been completed. 
          N/A 
A.21 Suspension or premature termination of the clinical investigation 
 
Both the Sponsor and the Principal investigator reserve the right to terminate the clinical investigation at any time. 
Should this be necessary, the procedures will be arranged on an individual basis after review and consultation by 
both parties. In terminating the clinical investigation, the JRO at University College London and the Principal 
investigator will assure that adequate consideration is given to the protection of the subject’s interests. 
 
 
A21.1 Subject Withdrawals and Discontinuation 
 
A participant may be withdrawn from the trial whenever continued participation is no longer in the 
participant’s best interests, but the reasons for doing so must be recorded. Reasons for discontinuing the 
trial may include: 
• 
Subject’s rescission of consent. 
• 
Any unexpected adverse device effect which is, in the opinion of the Principal investigator, related to 
the device and will endanger the wellbeing of the subject if the treatment is continued. 

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• 
The development of any undercurrent illness(es), infection or condition(s) that might interfere with the 
Clinical Investigation Plan. 
• 
Any problem deemed by the Principal investigator and/or the JRO at University College London to be 
sufficient to cause discontinuation. 
• 
Disease progression whilst in the study 
• 
Intercurrent illness 
• 
Patients withdrawing consent 
• 
Persistent non-compliance to protocol requirements. 
 
All subjects discontinued from the clinical investigation due to an unexpected adverse device effect, directly 
related to the clinical investigation, will be treated until the effect resolves. The Principal investigator will clearly 
document the date and reason(s) for subject withdrawal in his/her CRF and the monitor must be notified. 
 
Subjects who are withdrawn will not be replaced if they have received the investigational device. If possible, any 
procedures or assessments planned for the subject on withdrawal from the clinical investigation should be 
performed when intention to withdraw the subject is announced. 
 
Subjects who are withdrawn prior to receiving investigational device will be replaced. 
A.22 Definition of End of Trial 
 
The expected duration of the trial is 3 years from recruitment of the first participant. The end of the trial (phase 2) 
is the date of the last visit of the last participant. 
A.23 Publication policy 
 
Yes we plan to publish the findings. 
 
As we are NIHR funded, the NIHR need to be sent a draft at the time of submission. The rules are here: 
“The NIHR actively encourages the dissemination of research. Investigators and their research teams funded under 
an NIHR programme should provide advance notice of research outputs. A copy of the proposed publication 
should be sent to the funding programme at the same time as submission for publication or at least 28 days before 
the date intended for publication whichever is earlier. Please note this also applies to press releases to be issued by 
your host institution, e.g. university, NHS Trust or hospital. (Please see 4.1 on Press Releases)” 
https://www.nihr.ac.uk/funding-and-support/documents/funding-for-research-studies/manage-my-
study/outputs-guidance-notes-2.pdf (page 2). 

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All proposed publications will be discussed with and reviewed by the Sponsor prior to publishing other than those 
presented at scientific forums/meetings. Please refer to UCL publication policy. 
 
The results of the study will be reported in the following ways: peer reviewed scientific journals; internal report; 
conference presentation; written feedback to research participants. 
Please refer to UCL publication policy. 
 
Intellectual Property 
 
All background intellectual property rights (including licences) and know-how used in connection with the 
study shall remain the property of the party introducing the same and the exercise of such rights for 
purposes of the study shall not infringe any third party’s rights. 
All intellectual property rights and know-how in the protocol and in the results arising directly from the 
study, but excluding all improvements thereto or clinical procedures developed or used by each 
participating site, shall belong to UCLH. Each participating site agrees that by giving approval to conduct 
the study at its respective site, it is also agreeing to effectively assign all such intellectual property rights 
(“IPR”) to UCL and to disclose all such know-how to UCL. 
 
Each participating site agrees to, at the request and expense of UCL execute all such documents and do all 
acts necessary to fully vest the IPR in UCL. 
 
Nothing in this section shall be construed so as to prevent or hinder the participating site from using know-
how gained during the performance of the study in the furtherance of its normal activities of providing or 
commissioning clinical services, teaching and research to the extent that such use does not result in the 
disclosure or misuse of confidential information or the infringement of an intellectual property right of 
UCL. This does not permit the disclosure of any of the results of the study, all of which remain 
confidential.

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A.24 Bibliography 
 
List of the literature and data that are relevant to the trial, and that provide background for the trial. Please ensure 
the text contains appropriate cross references to this list 
 
Ashburner, J. and K.J. Friston (2000). “Voxel-based morphometry-the methods”. Neuroimage, 11 
(6 Pt 1): 805-821. 
Bhogal, S.K., R. Teasell, and M. Speechley (2003). “Intensity of aphasia therapy, impact on recovery”. 
Stroke, 34(4): 987-93. 
Brady, M.C., H. Kelly, J. Godwin, and P. Enderby (2013). “Speech and language therapy for 
aphasia following stroke”. Cochrane Database of Systematic Reviews, 12(5). 
Callaghan, J., J. Wells, S. Richardson, H. Holmes, Y. Yichao, S. Walker-Samuel, B. Siow, and 
M.F. Lythgoe (2014). “Is Your System Calibrated? MRI Gradient System Calibration for 
Pre-Clinical, High-Resolution Imaging”. Plos one: 
https://doi.org/10.1371/journal.pone.0096568. 
Code, C. and C. Heron (2003). “Services for aphasia, other acquired adult neurogenic 
communication and swallowing disorders in the United Kingdom, 2000.” Disability 
Rehabilitation 25(21): 1231- 1237. 
Craig P., P. Dieppe, S. Macintyre, S. Michie, I. Nazareth, and M. Petticrew (2008). “Developing 
and evaluating complex interventions: the new Medical Research Council guidance”. 
British Medical Journal, 33(7): a 1655. 
Moss A., and M. Nicholas (2006). “Langauge Rehabilitation in chronic aphasia and time postonset”. 
Stroke, 37(12): 3043-3051. 
Palmer, R., Enderby, P., Cooper, C., Latimer, N., Julious, S., Paterson, G. & Delaney, A. (2012). Computer 
therapy compared with usual care for people with long-standing aphasia poststroke: a pilot randomized 
controlled trial. Stroke, 43(7), 1904-1911. 
Swinburn, K., G. Porter, and D. Howard (2004). “Comprenhensive Aphasia Test”. Psychology Press. 
Werner, P. (2004). “Beliefs about memory problems and help seeking in elderly persons”. 
Clinical Gerontologist, 27(4): 19-30. 

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Appendix A: 
iTALKbetter 
 
 
47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
iTALKbetter 
Baseline 
1 
Baseline    
2 
Baseline 
3 
Treatment 
Time-point 4 
Final Time-point 
Visit # 
1 
2 
3 
 
4 
5 
 
Week 0 
 
Week 6 
 
Week 12 
6 weeks 
duration 
Week 18 
Week 30 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Baseline neuropsych tests 
X 
X 
X 
X 
X 
X 
Language Tests 
X 
X 
X 
X 
X 
X 
Proms 
X 
X 
X 
X 
X 
X 
Randomisation d 
 
 
X 
 
 
 
Brain Scans 
 
X 
X 
 
X 
 
Device/Treatment 
 
 
 
X 
 
 
Adverse Events review 
(CRF) 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
review 
X