The Effects of Brain Training on Brain Blood Flow: The Cognition and Flow Study
Phase: NA
Conditions: Dementia, Alzheimer Disease, Mild Cognitive Impairment, Aging, Cognitive Impairment
Sponsor: University of Leicester

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 1 of 57 
The Cognition and Flow Study 
Full Study Title:  The Cognition and Flow Study: The Effects of Brain Training on Brain Blood Flow 
Sponsor Reference No: 0677 
Ethics Ref: YH/18/0396  
Date and Version No: 7 19/12/19 
              
Chief Investigator: 
Professor Thompson G Robinson 
Department of Cardiovascular Sciences 
University of Leicester 
Room 228, Clinical Sciences Building, Leicester 
Royal Infirmary 
Leicester 
LE1 5WW 
Email: tgr2@le.ac.uk 
Tel: 01162523183 
 
Investigators:  
 
 
 
Victoria J Haunton 
Department of Cardiovascular Sciences 
University of Leicester 
Room 225, Clinical Sciences Building, Leicester 
Royal Infirmary 
Leicester 
LE1 5WW 
Email: vjh12@le.ac.uk 
Tel: 01162523183 
 
Ronney B Panerai 
Department of Cardiovascular Sciences 
University of Leicester 
Room 225, Clinical Sciences Building, Leicester 
Royal Infirmary 
Leicester 
LE1 5WW 
Email: rp9@le.ac.uk 
Tel: 01162523130 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 2 of 57 
The Cognition and Flow Study 
 
 
Hari Subramnaiam 
Old Age Psychiatry 
Leicestershire Partnership Trust 
Evington Centre 
Leicester General Hospital 
Gwendolen Road 
LE5 4PW 
Email: hs338@le.ac.uk 
Tel: 01162251452 
 
Professor Elizabeta Mukaetova-Ladinska 
Old Age Psychiatry 
Leicestershire Partnership Trust 
Evington Centre 
Leicester General Hospital 
Gwendolen Road 
LE5 4PW 
Email: eml12@le.ac.uk 
Tel: 01163736405 
 
Dr Rachel Evley 
Department of Clinical Neurosciences  
University of Nottingham 
Queens Medical Centre 
Room E/C1718 QMC 
Nottingham 
NG7 2UH 
Email: rachel.evley@nottingham.ac.uk 
Tel: 0115 8231004 
 
 
Sponsor:  
University of Leicester  
Funder: 
Dunhill Medical Trust 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 3 of 57 
The Cognition and Flow Study 
Signatures:  
The approved protocol should be signed by 
author(s) and/or person(s) authorised to sign the 
protocol 
 
 
 
  
Confidentiality Statement 
All information contained within this protocol is regarded as, and must be kept 
confidential.  No part of it may be disclosed by any Receiving Party to any Third 
Party, at any time, or in any form without the express written permission from the 
Chief Author/Investigator and / or Sponsor. 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 4 of 57 
The Cognition and Flow Study 
Authors 
 
Professor Thompson G Robinson 
Dr Victoria J Haunton 
Professor Ronney B Panerai 
Dr Lucy Beishon 
Dr Hari Subramaniam 
Prof Elizabeta Mukaetova-Ladinska 
Dr Rachel Evley 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 5 of 57 
The Cognition and Flow Study 
Signature Page 
 
Chief Investigator Name: 
___________________________________ 
Chief Investigator signature: 
_________________________________ 
Date: _________________________________________________ 
  
 
Sponsor Representative Name: 
________________________________ 
Sponsor Representative signature: _____________________________ 
Date: 
________________________________________________ 
  
 
Principal Investigator Name: __________________________________ 
Principal Investigator signature: ________________________________ 
Date: 
________________________________________________ 
  
(In cases of Multi-centre studies, this must be replicated for each site)

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 6 of 57 
The Cognition and Flow Study 
TABLE OF CONTENTS 
1. 
AMENDMENT HISTORY ......................................................................................................... 9 
2. 
SYNOPSIS ............................................................................................................................ 11 
3. 
ABBREVIATIONS .................................................................................................................. 13 
4. 
BACKGROUND AND RATIONALE ........................................................................................ 15 
5. 
OBJECTIVES ......................................................................................................................... 18 
5.1 
Primary Objectives .......................................................................................................... 19 
5.2 
Secondary Objectives ..................................................................................................... 19 
5.3 
Qualitative Study Objectives ........................................................................................... 19 
6. 
STUDY DESIGN .................................................................................................................... 20 
6.1 
Summary of Trial Design ................................................................................................ 20 
6.2 
Primary and Secondary Endpoints/Outcome Measures .................................................. 21 
7. 
TRIAL PARTICIPANTS .......................................................................................................... 22 
7.1 
Overall Description of Trial Participants .......................................................................... 22 
7.2 
Inclusion Criteria ............................................................................................................. 22 
7.3 
Exclusion Criteria ............................................................................................................ 22 
8. 
STUDY PROCEDURES ......................................................................................................... 24 
8.1 
 Participant identification ................................................................................................. 24 
8.2 
Eligibility visit (cognitive assessment) ............................................................................. 26 
8.3  
Informed Consent ........................................................................................................... 27 
8.4 
Baseline Assessments .................................................................................................... 29 
8.5 
Randomisation and Codebreaking (if applicable) ............................................................ 30 
8.6 
Subsequent Assessments .............................................................................................. 30 
8.8  
Definition of End of Trial .................................................................................................. 32 
8.9 
Discontinuation/Withdrawal of Participants from Study Treatment .................................. 32 
8.10 Source Data .................................................................................................................... 33 
9. 
TREATMENT OF TRIAL PARTICIPANTS ............................................................................. 34 
9.1 
Description of Study Treatment ....................................................................................... 34 
9.2 
Storage of Study Equipment or Related apparatus ......................................................... 34 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 7 of 57 
The Cognition and Flow Study 
9.3 
Compliance with Study Treatment .................................................................................. 34 
10. SAFETY REPORTING ........................................................................................................... 35 
10.1 Definitions ....................................................................................................................... 35 
10.2 Reporting Procedures for All Adverse Events ................................................................. 36 
10.3 Reporting Procedures for Serious Adverse Events ......................................................... 37 
11. STATISTICS .......................................................................................................................... 38 
11.1 Description of Statistical Methods ................................................................................... 38 
11.2 The Number of Participants ............................................................................................ 39 
11.3 The Level of Statistical Significance ................................................................................ 39 
11.4 Criteria for the Termination of the Trial. ........................................................................... 39 
11.5 Procedure for Accounting for Missing, Unused, and Spurious Data. ............................... 39 
11.6 Procedures for Reporting any Deviation(s) from the Original Statistical Plan .................. 39 
11.7 Inclusion in Analysis........................................................................................................ 40 
12. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................................... 41 
13. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES .................................... 42 
14. CODES OF PRACTICE AND REGULATIONS ....................................................................... 43 
14.1 Ethics .............................................................................................................................. 43 
14.2 Sponsor Standard Operating Procedures ....................................................................... 44 
14.3 Declaration of Helsinki .................................................................................................... 44 
14.4 ICH Guidelines for Good Clinical Practice ....................................................................... 44 
14.5 Approvals ........................................................................................................................ 45 
14.6 Participant Confidentiality ............................................................................................... 45 
14.7  Other Ethical Considerations .......................................................................................... 45 
15. DATA HANDLING AND RECORD KEEPING ......................................................................... 46 
15.1 Data Extraction ................................................................................................................. 46 
15.2 Data Analysis ................................................................................................................... 46 
16. STUDY GOVERNANCE......................................................................................................... 47 
16.1 Trial Steering Committee (TSC) ...................................................................................... 47 
16.2 Data Safety Monitoring Committee (DSMC) .................................................................... 47 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 8 of 57 
The Cognition and Flow Study 
17. FINANCING AND INSURANCE ............................................................................................. 48 
18. PUBLICATION POLICY ......................................................................................................... 49 
19. REFERENCES ...................................................................................................................... 50 
APPENDIX A: Patient recruitment flow chart ................................................................................. 53 
20. Appendix B: STUDY FLOWCHART ....................................................................................... 54 
21. APPENDIX C: SCHEDULE OF PROCEDURES .................................................................... 55 
22. APPENDIX D: EXPECTED EVENTS NOT SUBJECT TO EXPEDITED REPORTING ........... 57 
 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 9 of 57 
The Cognition and Flow Study 
1. 
AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) of changes 
Details of Changes 
made 
 
0.1 
29/6/18 
 
V.J Haunton 
R.B Panerai 
T.G Robinson 
R. Evley 
L. Beishon 
Revision of the protocol 
pre-sponsor 
submission.  
 
0.2 
8/8/18 
L. Beishon 
Pre-sponsor 
submission 
 
0.3 
22/8/18 
L. Beishon 
Post-sponsor 
review 
revisions 
 
1 
30/8/18 
L. Beishon 
Post-sponsor review 
 
2 
30/10/18 
L. Beishon 
Post-Rec review 
 
3 
14/11/2018 
L.Beishon 
Substantial 
amendment: 
1. Change to 
order of study 
assessments 
2. Participants will 
be asked to 
take dietary and 
lifestyle 
measures prior 
to assessment 
3. Participants will 
not be 
withdrawn for 
low compliance 
4. Participants 
cannot use 
tablet devices 
 
5 
21/2/19 
L. Beishon 
Substantial 
amendment: 
1. Addition of a 
post-stroke 
sub-group 
2. Provision of 
laptops to 
participants 
where 
necessary 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 10 of 57 
The Cognition and Flow Study 
3. To interview the 
healthy 
participant sub-
group 
4. To remove the 
upper limit on 
the MoCA cut-
off 
 
6 
5/9/19 
L.Beishon 
Substantial 
amendment: 
To increase the number 
of cognitive tasks for 
the post-stroke sub-
group 
To collect data on the 
type, location, and size 
of the infarct 
 
7 
19/12/19 
L.Beishon 
Removal of age limit on 
stroke sub-group (50 
years) 
List details of all protocol amendments here whenever a new version of the protocol is produced. 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 11 of 57 
The Cognition and Flow Study 
2. 
SYNOPSIS 
 
Study Title 
The Cognition and Flow Study: The Effects of Brain Training on Brain 
Blood Flow 
 
Internal ref. no. 
0677 
 
 
Trial Design 
Feasibility Randomised Controlled Trial 
Trial Participants 
Healthy older adults, adults with mild cognitive impairment 
(undifferentiated), adults with mild to moderate Alzheimer’s disease, 
adults 12 months post-ischaemic stroke.  
Planned Sample Size 
80 participants in total, 20 participants in each of the four sub-groups.  
Follow-up duration 
Three to six months 
Planned Trial Period 
12 -18 months 
Primary Objective 
The primary objective of this study is to determine the ability to carry out 
(feasibility) of a large scale randomised controlled trial (RCT) of cognitive 
training (CT) in healthy older adults (HC), and people with Alzheimer’s 
disease (AzD), mild cognitive impairment (MCI), and people post-
ischaemic stroke.  
 
Secondary 
Objectives 
Are there any clinical benefits of a CT program in patients with dementia 
and any difference between groups (MCI/AzD/healthy older adults/post-
ischaemic stroke) in ability to carry out everyday activities, memory, 
mood, and quality of life outcomes? 
 
Primary Endpoints 
1) Percentage of participants successfully recruited  
2) Percentage of participants able to successfully complete CT program 
and complete all assessments 
3) Percentage of participants with full bilateral data for CBFv 
4) Feasibility of randomisation to waiting list control 
 
Secondary 
Endpoints 
1) Change in cognition score as detected by the Addenbrooke’s cognitive 
examination (ACE-III) 
2) Change in functional status - Lawton Instrumental Activities of Daily 
Living (IADL)  

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 12 of 57 
The Cognition and Flow Study 
3) Change in mood – Geriatric Depression Scale (GDS-15)  
4) Change in quality of life measure – Dementia Quality of Life Measure 
(DEMQOL) 
5) Change in task activation increase in CBFv from baseline 
 
Qualitative 
objectives 
The third element to this study is a qualitative component which will seek 
to explore any patient or carer benefits or harms not identified by the 
traditional measures listed above, specifically: 
 
• What are the barriers to CT in patients with dementia? 
• What are the facilitators (benefits) to brain training in patients with 
dementia? 
• Could CT programs be adapted further to support the participation of 
patients with dementia? 
• Are there any additional benefits to CT programs not measured by 
traditional methods as perceived by the patients and their carers? 
• To explore the lived experience of the patient and their carer and the 
impact CT has on them and their life 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 13 of 57 
The Cognition and Flow Study 
3. 
ABBREVIATIONS 
AE 
Adverse event 
ACE-III 
Addenbrooke’s Cognitive Examination III 
ADL 
Activities of Daily Living 
ANOVA 
Analysis of Variance 
AR  
Adverse reaction 
AzD 
Alzheimer’s disease 
CBFv 
Cerebral blood flow velocity 
CHIASM 
Cerebral Haemodynamics in Ageing and Stroke Medicine 
CI 
Chief Investigator 
CRA 
Clinical Research Associate (Monitor) 
CRF 
 
Case Report Form 
CRN 
 
Clinical Research Network 
CRO  
Contract Research Organisation 
CT 
Cognitive Training 
DEMQOL  
Dementia Quality of Life Measure 
EC 
 
Ethics Committee (see REC) 
ETCO2 
 
End-tidal CO2 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GP 
General Practitioner 
GTAC 
Gene Therapy Advisory Committee 
HC 
Healthy control 
HR 
Heart Rate 
IADL 
Instrumental Activity of Daily Living 
ICF 
Informed Consent Form 
MAP 
Mean Arterial Pressure 
MCA 
Middle Cerebral Artery 
MCI 
Mild cognitive impairment 
NHS 
National Health Service 
NRES 
National Research Ethics Service  
PI 
Principal Investigator 
PIL/S 
Participant/ Patient Information Leaflet/Sheet 
QoL 
Quality of Life 
RCT 
Randomised controlled trial 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TCD 
Transcranial Doppler ultrasonography 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 14 of 57 
The Cognition and Flow Study 
TMF 
Trial Master File 
TSC 
Trial Steering Committee 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 15 of 57 
The Cognition and Flow Study 
4. 
BACKGROUND AND RATIONALE 
 
 
Disease Characteristics and Population Studied 
 
The incidence of dementia is rising as the population ages, with 850,000 patients currently 
living in the UK alone (1).  By 2026, this is projected to have risen by a further 40% (1).  
However, there are currently few diagnostic or therapeutic strategies available to offer 
patients. Dementia is a progressive condition characterised by gradual loss of cognitive or 
non-cognitive higher functions (i.e. language, visuospatial, attention) (2). Dementia is an 
umbrella term that encompasses a number of cognitive disorders including; Alzheimer’s 
disease (AzD), vascular dementia, Lewy body dementia, fronto-temporal dementia and 
Parkinson’s dementia (2). Mild cognitive impairment (MCI) is characterised by subjective and 
objective decline in cognitive function, but with preserved functional independence in daily 
living (3). It has become increasingly recognised that deranged vascular function is an early 
contributor to the deposition of amyloid plaques and tau tangles in AzD, and that these 
pathologies exacerbate one another (two-hit hypothesis) (4). In a recent systematic review 
and meta-analysis undertaken by this group, we demonstrated clear abnormalities in 
vascular function across a number of imaging modalities at the MCI stage (5). Thus, 
treatments that can improve cerebral perfusion or vascular function could represent an early 
treatment option for dementia (5). In this study, the target populations are; healthy older 
adults (as controls), adults with AzD, and MCI, to capture the effects of brain training (BT) on 
vascular physiology at an early stage in the dementia process.  
 
Summary of the Project and Evidence Base 
This project is a feasibility randomised controlled trial (RCT) as part of a PhD qualification to 
examine the use of a brain training (BT) program in adults with MCI, early AzD and healthy 
older adults (HC). In addition to measuring cognitive and functional outcomes, this study will 
also use transcranial Doppler ultrasonography (TCD) to measure changes in cerebral blood 
flow before and after an 8-12-week CT program. A recent systematic review found that 
longer, more intensive programs appeared to have no benefit over shorter programs, which 
are more likely to encourage adherence for patients with cognitive impairment (6, 7). 
The evidence for CT in MCI, AzD, and vascular dementia (VaD) is heterogeneous, and 
frequently of low quality (8, 9). Few studies have included neuroimaging outcomes to explore 
brain plasticity or neural mechanisms underlying changes in cognition after CT (10). 
Therefore, this study not only addresses the development of a future high quality RCT of CT 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 16 of 57 
The Cognition and Flow Study 
in dementia, but also aims to fill the evidence gap on the use of TCD to assess neurovascular 
plasticity.  
The use of TCD is a novel method to investigate for neurovascular training effects and for 
markers predictive of which patients may benefit from particular CT programs. This would 
allow the development of a personalised approach to developing CT programs for people 
with dementia. Given its low cost, portability and acceptability (11, 12), further studies are 
required to investigate the utility of TCD in older people and those living with dementia.  
CT provides an attractive treatment target in dementia given there are few side effects and it 
is relatively cheap (7). However the evidence base at present is unclear, largely due to the 
poor quality studies that have been carried out to date (8, 9). Therefore, this study provides 
the basis for designing a high quality RCT of CT in dementia that can help address this issue.  
Furthermore, this study will include a qualitative component to explore any benefits, problems 
or barriers to engaging with the training program that could be improved upon in future 
studies, and identify any benefits not measured by traditional outcomes.  
 
TCD 
TCD is a non-invasive, ultrasound based imaging modality that allows measurements of 
cerebral blood flow velocity (CBFv) at rest (13) and following activation by cognitive tasks 
(14). TCD has a number of advantages over other functional imaging techniques (magnetic 
resonance imaging (MRI) and positron emission tomography (PET)), including lower cost, 
portability, relative ease of operator training, and higher acceptability to patients (12, 15). 
TCD is particularly suited to older people, and those with dementia, as it can be used in 
patients with pacemakers, metal implants and claustrophobia (12).  
 
Cognitive Training 
Cognitive interventions can be considered as three broad categories; CT, cognitive 
rehabilitation and cognitive stimulation (9, 16). CT describes a structured, guided program of 
standardised tasks designed to provide practice or training with a specified cognitive 
domain(s), to translate into functional benefits (9, 16). This is distinguished from cognitive 
rehabilitation, where patient centered approaches and goals are used to improve everyday 
function, rather than improve cognition function (8, 9, 16), and cognitive stimulation which 
aims to generally improve cognition, social function and quality of life (17). CT is attractive in 
that it offers a cost effective, non-invasive and acceptable intervention to patients, with no 
reported adverse effects (18). A recent systematic review of 51 RCTs demonstrated 
improvements with CT in overall cognition, non-verbal memory, working memory, processing 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 17 of 57 
The Cognition and Flow Study 
speed, and visuospatial skills in healthy older adults (6). High quality RCT evidence is 
however lacking in studies of CT in dementia (7-9, 19). Two previous Cochrane reviews (8, 
9), demonstrated the evidence was sparse, with many of the studies under-powered, of low-
to-moderate quality, and with relatively few for MCI (8, 9). Recent systematic reviews of CT 
in MCI have demonstrated moderate benefits in verbal learning and memory, global 
cognition, non-verbal learning, working memory, attention and psychosocial functioning (19, 
20). Thus far, studies of CT in dementia have been heterogeneous in study design, 
participants included, type and definition of training, outcome measures, and duration and 
intensity of intervention (7-9, 21, 22). This hampers the adequate meta-analysis of data and 
of conclusions that can be drawn from pooled analyses (7, 10).  
 
Neuroimaging and CT 
The use of neuroimaging outcomes has also been limited in CT studies (10, 23), but 
understanding the training effects occurring at the physiological level would provide important 
mechanistic information to any potential benefits conferred by CT (24-26). Belleville et al 
demonstrate increased parietal activation in patients with MCI, following a multi-modal CT 
program designed to improve episodic memory (24). In a near-infrared spectroscopy study 
by Vermeij et al, patients with MCI had greater training benefits at high load working memory 
where participants had greater pre-frontal activation (27), and baseline global and 
hippocampal atrophy were predictive of poorer training gains in healthy older adults and 
those with MCI (25). Therefore, imaging biomarkers can potentially be used to predict and 
tailor interventions to individual patient’s needs (25, 26). Whilst a number of studies have 
demonstrated positive structural and functional effects of CT (26, 28, 29), they have largely 
focused on healthy older adults (28), the use of structural (28) or functional MRI (24, 25), and 
PET (30, 31), but there have been no TCD studies examining changes in neurovascular 
response to CT in patients with cognitive impairment.  
 
 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 18 of 57 
The Cognition and Flow Study 
5. 
OBJECTIVES 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 19 of 57 
The Cognition and Flow Study 
 
5.1 
Primary Objectives 
 
 
The primary objective of this study is to determine the ability to carry out (feasibility) a large 
scale RCT of CT in healthy older adults, and people with AzD and MCI.  
 
 
5.2 
Secondary Objectives 
 
1) Are there any clinical benefits of a brain training program in patients with dementia and 
any difference between groups (MCI/AzD/healthy older adults/post-ischaemic stroke) in 
ability to carry out everyday activities, memory, mood, and quality of life outcomes? 
2) Are there any changes in blood flow responses to cognitive tasks using TCD before and 
after brain training?  
3) Are there any brain blood flow markers that can be used to predict who will benefit from 
brain training, and in which memory areas to generate a personalised training plan for 
individual patients? 
 
 
5.3 
Qualitative Study Objectives 
 
1) What are the barriers to brain training in patients with dementia? 
2) What are the facilitators (benefits) to brain training in patients with dementia? 
3) Could brain training programs be adapted further to support the participation of patients 
with dementia? 
4) Are there any additional benefits to brain training programs not measured by traditional 
methods as perceived by the patients and their carers? 
5) To explore the lived experience of the patient and their carer and the impact brain training 
has on them and their life. 
 
 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 20 of 57 
The Cognition and Flow Study 
6. 
STUDY DESIGN 
6.1 
Summary of Trial Design 
 
 
This is a prospective, feasibility, RCT of CT in healthy older adults, and adults with 
AzD, MCI, or post-ischaemic stroke. This trial is un-blinded, due to the nature of the 
intervention. The expected duration of participation per individual is three to six 
months. Initially, participants will be approached by a member of the clinical care team 
or research support staff, who will screen and identify eligible participants. Study 
specific information will then be provided by the researcher. Following this, 
participants will undergo informed consent. Each participant will have two visits (initial 
and follow-up assessment). After the first visit, participants will be randomised to 
control or intervention (CT), and will complete an 8-12 week CT program, if selected 
for the intervention group. Participants will be randomised using Sealed Envelope ©, 
an online, commercially available randomisation tool. At the end of the trial, 
participants will be given the option to participate in a qualitative study by semi-
structured interviews or focus group. A flow chart for this process can be seen in 
Appendix A.  
 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 21 of 57 
The Cognition and Flow Study 
 
6.2 
Primary and Secondary Endpoints/Outcome Measures 
 
Primary end point measures: 
 
1) Number of participants successfully recruited  
2) Percentage of participants able to successfully complete the CT program and all 
assessments 
3) Percentage of participants with full bilateral data for CBFv 
4) Feasibility of randomisation to waiting list control 
 
Secondary end points: 
 
1) Change in cognition score as detected by the Addenbrooke’s cognitive examination 
(ACE-III) 
2) Change in functional status - Lawton IADL  
3) Change in mood – GDS-15  
4) Change in quality of life measure – DEMQOL  
5) Change in task activation increase in CBFv from baseline 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 22 of 57 
The Cognition and Flow Study 
7. 
TRIAL PARTICIPANTS 
7.1 
Overall Description of Trial Participants 
 
1) Participants with mild-moderate AzD 
2) Participants with MCI 
3) Healthy older adults 
4) Post-ischaemic stroke  
 
 
7.2 Inclusion Criteria 
 
 
 
 
Study specific inclusion criteria will be as follows: 
 
 
One of: 
1) Healthy controls will be free of any medical co-morbidity or medication that could 
adversely affect cognition. Volunteers with well-controlled co-morbidities (i.e. 
hypertension, diabetes, will be considered for inclusion) 
2) MCI as defined by NIA/AA 2011 and Petersen criteria 
3) AzD as defined by the NIA/AA 2011 criteria 
4) Ischaemic stroke within the last 12 months 
And: 
5) Deficits will be mild to moderate as defined by Montreal Cognitive Assessment 
(MoCA) score of >/=9 for all participants with MCI or Alzheimer’s disease (32-34).  
6) Willing to participate 
7) Capacity to consent to the study/personal consultee 
8) Patients 
on 
and 
off 
anti-dementia 
medications 
will 
be 
included 
(acetylcholinesterase inhibitors, glutamate receptor antagonists) 
9) Good understanding of written and spoken English 
10) Age >50 years (MCI, AzD, and healthy controls only) 
11) Access to the internet and a computer or laptop.  
 
7.3 
Exclusion Criteria 
 
Study specific exclusion criteria as follows: 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 23 of 57 
The Cognition and Flow Study 
1) Healthy controls with any medical co-morbidity or medication that could adversely 
affect cognition, or poorly controlled medical co-morbidities (i.e. hypertension, 
diabetes) 
2) Unwilling to take part 
3) Unable to consent/no personal consultee 
4) Major medical co-morbidity; severe heart failure (ejection fraction <20%), 
significant carotid artery stenosis >50%), severe respiratory disease, major stroke 
(MCI and AzD groups only) 
5) Pregnancy, planning pregnancy, or lactating 
6) Inadequate bilateral TCD windows 
7) Participants already enrolled into other interventional studies 
8) Insufficient understanding of written and spoken English 
9) Age <50 years (MCI, AzD, and healthy controls only) 
10) No access to the internet and a computer or laptop. 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 24 of 57 
The Cognition and Flow Study 
8. 
STUDY PROCEDURES 
 
8.1 
 Participant identification 
This study has broad recruitment strategy to ensure that recruitment targets are met. 
Our previous pilot study, and other dementia studies have demonstrated that this is 
the most appropriate recruitment strategy. Appendix A outlines the participant 
recruitment pathway for this study. Appendix B outlines the overall study flow process, 
and Appendix C outlines the schedule of procedures for each participant.  
 
Healthy volunteer identification 
Healthy volunteers will be recruited through poster advertisement at the University of 
Leicester, University Hospitals of Leicester (UHL), LPT, and GP surgeries, and 
pharmacies in the East Midlands. In addition, healthy volunteers will be recruited from 
friends, family, and carers of enrolled patient participants, and through the healthy 
volunteer section of Join Dementia Research (see below). In addition, the University 
of Leicester holds a research interested list of healthy volunteers who will be 
contacted by the researcher to provide study specific information if they are interested 
in participating. Interested participants will self-refer directly to the researcher who will 
provide study specific information. Participants will be allowed a minimum of 24 hours 
to decide if they would like to enrol in the study, and to contact the researcher who 
will arrange for them to undergo an eligibility assessment (see Section 8.2) and the 
formal consent (Section 8.3) and study enrolment.  
 
Patient identification 
Secondary care services - geriatric and memory service recruitment 
Eligible participants will be identified by Consultants and specialist registrars in 
Geriatric Medicine, or Old Age Psychiatry, or specialist nurses from the memory 
service, by screening their medical records for the inclusion and exclusion criteria. 
Eligible participants will be approached by the above members of the direct care team 
and referred to the researcher or research delivery team for further information. In 
addition, screening of eligible participants under the geriatric and memory service will 
be undertaken by research delivery officers from the NIHR CRN, UHL, and LPT, and 
eligible participants that are interested will be approached by a member of their direct 
care team, and if interested referred to the researcher or research delivery team and 
provided with study specific information.  

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 25 of 57 
The Cognition and Flow Study 
 
Research interested list 
The LPT hold a research interested list of patients whom they may approach if they 
are eligible for the study. Research delivery staff at the LPT will eligibility screen the 
list and contact participants who meet the inclusion and exclusion criteria. Interested 
participants will then be provided with study specific information by the LPT research 
delivery team.  
 
Primary care recruitment 
A database search will be conducted with the support of the NHR CRN for GP 
surgeries in Leicester and Leicestershire. Eligible participants will be screened from 
the database by a member of the direct care team at that practice. Participants that 
meet the inclusion and exclusion criteria will be invited to join the study through letter 
invitation from their GP surgery. Participants who contact the researcher or research 
delivery officer after letter invitation will then be provided with study specific 
information by the research team.   
 
Community group recruitment 
Study specific information will be provided to attendees at local community groups 
(i.e. Alzheimer’s society memory café) by volunteers and the members of the 
research team. In order to eligibility screen the interested participants, a referral will 
be made to their GP practice or LPT research delivery team (depending on participant 
location) to check eligibility prior to study recruitment. This will be prior to consent and 
will be limited to the GP practice or LPT research delivery team confirming to the 
researcher that the participant meets the inclusion and exclusion criteria to enrol in 
the study.  
 
Join Dementia Research recruitment 
Join Dementia Research is an online platform that patients with dementia can access 
to register their interest in dementia research studies. Participants upload information 
to allow researchers to screen their medical history to check for study eligibility prior 
to contacting them. JDR provides formal training to researchers using JDR to recruit 
eligible patients. For this study, the researcher or research delivery officers will screen 
potential participants utilising the information provided on JDR and contact eligible 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 26 of 57 
The Cognition and Flow Study 
participants by their preferred contact method or chosen representative to provide 
study specific information. 
 
Self-referral 
Posters advertising the study will be displayed in the GP practices and pharmacies in 
the East midlands. In addition, posters will be displayed on the University of Leicester 
campus, and in the University of Leicester newsletter, outpatient clinics in the 
Geriatric and memory services at University Hospitals of Leicester and LPT. The 
researcher’s contact details will be displayed on the poster’s and leaflets. Participants 
can contact the researcher for further information, and if interested, a referral will be 
made to their GP practice or LPT research delivery team (depending on participant 
location) to check eligibility prior to study recruitment. This will be prior to consent and 
will be limited to the GP practice or LPT research delivery team confirming to the 
researcher that the participant meets the inclusion and exclusion criteria to enrol in 
the study.  
Participants must be enrolled into the study and randomised to control or intervention 
within four to six weeks of initial screening.  
 
Post stroke sub-group 
Participants in the stroke sub-group will be recruited from ongoing observational 
studies in the department, stroke and rehabilitation wards, and stroke and TIA clinics 
at UHL, and stroke community groups and organisations. Potential participants will 
be screened and approached by a member of the direct care team, or research 
nurses from the NIHR CRN, in the first instance, and referred to the research team to 
provide study specific information. Stroke specific posters will be displayed in the 
stroke and rehabilitation wards, and stroke and TIA clinics at UHL. In the same 
manner as the main study, any participant who self refers or is identified through a 
community group, will be screened either by their direct clinical care team, or NIHR 
CRN research nurse to ensure they meet the study inclusion and exclusion criteria. 
Participants in the post-stroke sub-group will then undergo identical study procedures 
as outlined below.   
 
8.2 
Eligibility visit (cognitive assessment) 
 
 
 
Healthy volunteer eligibility assessment 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 27 of 57 
The Cognition and Flow Study 
Eligibility assessment will take place by discussion with the volunteer and researcher 
to confirm the inclusion and exclusion criteria, prior to provision of study specific 
information. Medical records will not be screened to eligibility assess healthy 
volunteers. Volunteers who meet the inclusion and exclusion criteria will be invited to 
the cerebral haemodynamics in ageing and stroke medicine (CHiASM) research 
space for formal consent.  
 
 
 
 
Patient eligibility assessment 
Medical records will be reviewed by the direct care team referring the participant for 
study inclusion, or by LPT/UHL research delivery officers to ensure they meet the 
inclusion and exclusion criteria prior to referral to the researcher or research delivery 
team and provision of study specific information. Eligibility screening will only be 
undertaken by the direct clinical care team for potential participants, or by research 
delivery officers that are authorised to do so. Members of the research team will only 
screen medical records to confirm medical and medication history after formal 
consent to the study has taken place. 
In all cases, a permission to screen consent form will be undertaken to allow a 
Montreal Cognitive Assessment (MoCA) to take place, to ensure deficits are classified 
as mild to moderate to be eligible for study inclusion. Participants will be counselled 
that this may preclude them from enrolling in the study, and will be detailed on the 
permission to screen consent form.  
8.3  Informed Consent 
 
Healthy volunteer consent procedure 
 
Participants who meet the inclusion and exclusion criteria will then be invited by the 
researcher to attend the CHiASM research space at UHL to undergo formal consent 
and the baseline assessments outlined in Section 8.3. All informed consent procedures 
and healthy volunteer assessments will be undertaken by the researcher. 
 
Patient consent procedure 
 
Informed consent will be undertaken by either Dr Lucy Beishon (researcher) or an 
appropriately qualified research delivery officer at the LPT research delivery team. This 
will take place in the most convenient location for the participant including; their home, 
memory service, dedicated research space at the LPT, or invited to the Cerebral 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 28 of 57 
The Cognition and Flow Study 
Haemodynamics in Ageing and Stroke Medicine (CHiASM) research space.  
 
Both participants who have capacity, and those that lack capacity will be suitable for 
inclusion in this study. In cases where the participant lacks capacity, a friend, relative 
or carer will act as a personal consultee to consent on behalf of the participant.  Please 
see section 14.1 for more information on the ethical code of practice for the inclusion 
of adults lacking capacity in this study.  
 
The participant or personal consultee must personally sign and date the latest 
approved version of the informed consent form before any study specific procedures 
are performed. 
 
The qualitative arm of the study will be consented alongside the feasibility RCT. All 
participants will be offered to take part in the qualitative arm of the study. Participants 
will be consented at enrolment into the RCT to be contacted at later date to discuss 
the option of the qualitative study. Participants that completed the RCT and all 
assessments will be suitable for inclusion in the qualitative study, and their carers will 
also be invited to participate. Qualitative study specific information will be provided by 
the researcher alongside information for the feasibility RCT at study enrolment.  
 
Written and verbal versions of the participant information and Informed consent will be 
presented to the participants/personal consultee detailing no less than: the exact 
nature of the study; the implications and constraints of the protocol; the known side 
effects and any risks involved in taking part.  It will be clearly stated that the participant 
is free to withdraw from the study at any time for any reason without prejudice to future 
care, and with no obligation to give the reason for withdrawal. 
 
The participant will be allowed a minimum of 24 hours to consider the information, and 
the opportunity to question the Investigator, their GP or other independent parties to 
decide whether they will participate in the study.  Written Informed Consent will then 
be obtained by means of participant or personal consultee dated signature and dated 
signature of the person who presented and obtained the informed consent. The person 
who obtained the consent will be suitably qualified and experienced, and have been 
authorised to do so by the Chief/Principal Investigator as detailed on the Delegation of 
Authority and Signature log for the study. The original signed form will be retained at 
the study site within the Trial Master File (TMF) or Investigator Site File (ISF). A copy 
of the signed Informed Consent will be given to participants and a copy retained in the 
participant medical notes.   

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 29 of 57 
The Cognition and Flow Study 
 
8.4 
Baseline Assessments 
 
Participants who meet the inclusion criteria, will undergo baseline assessments with a 
member of the research team, or research delivery officer, either at home, designated 
LPT research space, or invited to attend the CHiASM research space. The first visit 
will take place at the CHiASM research space, based at the Leicester Royal Infirmary, 
for an assessment of cognition (ACE-III) and neurovascular function (outline below). 
Approximately 20-25% of potential participants will have insufficient bilateral temporal 
windows for assessment, and this would preclude their study entry. Following 
successful window insonation, and completion of the neurovascular assessment, the 
following baseline assessments will be undertaken at the same visit or within two 
weeks at the participant’s home: mood (GDS-15), function/ADLs (Lawton-IADL), 
quality of life (DEMQOL), handedness (Edinburgh handedness inventory).  
 
An assessment of neurovascular function will take place using a protocol validated by 
this group previously (35). Participants will be asked to refrain from caffeine, nicotine, 
alcohol, heavy meals, or strenuous exercise for at least four hours prior to the 
neurovascular assessment. In summary, participants will under-go continuous beat-to-
beat monitoring of cerebral blood flow velocity (CBFv) using transcranial Doppler 
ultrasound (TCD, DWL Doppler box), blood pressure (Finometer), heart rate (3-lead 
ECG), and end-tidal CO2 (ETCO2, capnography, nasal speculum). Participants will 
undergo a five-minute baseline recording. Participants will be asked five selected tasks 
from the ACE-III (attention, memory, language, fluency and visuospatial domains) to 
stimulate changes in CBFv, which can be measured by the above methods.  
 
For the post-stroke sub-group, a further four tasks will be undertaken. The serial 
sevens will be completed in addition to serial 2s and 17s, and the naming words with 
“p” will be completed in addition to words beginning with “r” and “v”. This is to identify 
subtler deficits that may be present in the stroke sub-group.  
 
Data collected on baseline demographic information will include the following: 
 
Demographics 
The age, sex, ethnicity, smoking status, alcohol intake, height, weight, BMI, years of 
education, and socioeconomic status (postcode) will be recorded.  
 
Medical History 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 30 of 57 
The Cognition and Flow Study 
Details of any history of disease or surgical interventions in the following systems will 
be recorded; cardiovascular, abdominal, respiratory, neurological, and hearing and 
visual impairment. Data will be collected on the type, size, and location of the infarct in 
the post-stroke sub-group, and any complications of the infarct.  
 
Concomitant Medication  
All over-the-counter or prescription medication, vitamins, and/or herbal supplements 
will be recorded on CRFs. Medication, dose, duration, strength and frequency will be 
recorded.  
 
 
8.5 
Randomisation and Codebreaking (if applicable) 
 
Randomisation will be performed using Sealed Envelope©, by the researcher. This is 
an online-based randomisation tool which uses random permuted blocks to allocate 
participants to waiting list control or intervention. Participants will be enrolled and 
assigned a PIN consecutively, and randomised to a treatment arm corresponding to 
the PIN. Given the nature of the trial, it is not possible to blind participants to the 
intervention. The Investigator will be providing weekly telephone support with the 
intervention, in addition to undertaking baseline and follow-up measurements, and 
therefore blinding of the investigator is also not possible. However, data analysis will 
be blinded by generating a batch-anonymised data set. Randomisation will be 
undertaken at the initial visit. As this is an un-blinded trial, code breaking will not be 
required.  
 
Once participants have been randomised to the intervention arm, they will be provided 
with information on how to access and use the CT program.  
 
8.6 
Subsequent Assessments 
 
Participants randomised to the intervention will be followed-up on a weekly basis by 
the investigator with a telephone call to troubleshoot any problems arising with 
software/cognitive training program, or any changes in circumstance that would 
preclude ongoing study involvement. Participants will be followed up after 8-12 weeks 
of cognitive training, and will return to the CHIASM laboratory to repeat the baseline 
assessments (cognition (ACE-III), mood (GDS-15), function/ADLs (Lawton-IADL), 
quality of life (DEMQOL), neurovascular function (TCD), blood pressure (Finometer),  
heart rate (3 lead ECG) and end-tidal CO2 (ETCO2, capnography, nasal speculum). 
Adverse events will also be assessed at this time point. 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 31 of 57 
The Cognition and Flow Study 
 
8.7 Qualitative Data Collection 
 
Patient participants will be offered to participate in a qualitative study at the end of the 
cognitive training RCT. Participants will be invited to take part in either an interview or 
a focus group. Not all participants will be required to participate in the qualitative arm 
of the study. 
 
Semi-structured Interviews 
At least 1 week after the completion of the CT program, participants will be invited to 
participate in semi-structured interviews to be held in the CHiASM research space, or 
the participant’s home.  All travel expenses will be paid to allow participants to attend 
the interviews. Participants will need to produce a receipt to claim expenses, and this 
will be outlined in the PIS.  
A digital audio recorder will be used to record all the discussions continuously, and 
notes of non-verbal and paralinguistic clues will be made.  
All digital recordings will be transcribed within 5-7 days of the interviews.  
Semi-structured interviews are an iterative process, following the first couple of 
interviews the transcripts will be analysed and the themes and concepts emerging 
from this initial data will be further explored at the following interviews. 
Focus Group 
At the end of the study period participants will be offered the option to take part in a 
focus group instead of participating in a semi-structured interview; the focus group will 
be held at the University of Leicester. All travel expenses will be paid to allow 
participants to attend the focus group. Participants will need to produce a receipt to 
claim expenses, and this will be outlined in the PIS.  
The focus Group will be run by two named investigators, one of them will act as the 
moderator and the other will take written notes. A digital audio recorder will be used 
to record all the discussions. The interview schedule will be used to start the focus 
group discussions. The questions within the schedule will be the same as for the semi-
structured interviews. The focus group will be taped continuously. 
The digital recordings will be transcribed within 5-7 days of holding the focus group.  
The typed transcript will be read, and checked against the tape recordings for the 
completeness and accuracy, and any further comments will be added. 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 32 of 57 
The Cognition and Flow Study 
Interview & Focus Group Schedule 
An interview guide will be used in the semi-structured interviews and the focus group 
to provide a prompt for the topics that need to be discussed; these will be changed or 
modified as appropriate to the context of the conversation. The interview guide is a 
dynamic tool; it is not there to be prescriptive or ask closed response questions (36). 
The interview guide will consist of questions on the following themes, specifically 
designed to explore the six predictors of health behaviours of the health belief model 
(risk susceptibility, risk severity, benefits to action, barriers to action, self-efficacy, and 
cues to action) (37) and to evaluate the cognitive training program and the experience 
of the participant and their carer: 
 
1. What are the barriers to brain training in patients with dementia? 
2. What are the facilitators (benefits) to brain training in patients with dementia? 
3. Could brain training programs be adapted further to support the participation 
of patients with dementia? 
4. Are there any additional benefits to brain training programs not measured by 
traditional methods as perceived by the patients and their carers? 
5. To explore the lived experience of the patient and their carer and the impact 
brain training has on them and their life 
 
 
8.8  Definition of End of Trial 
 
The end of trial is the date of the last visit of the final participant. The end of the 
qualitative study will be at the date of the last interview or focus group.   
 
8.9 
Discontinuation/Withdrawal of Participants from Study Treatment 
 
 
Each participant has the right to withdraw from the study at any time. In addition, the 
investigator may discontinue a participant from the study at any time if the investigator 
considers it necessary for any reason including: 
 
Ineligibility (either arising during the study or retrospective having been overlooked at 
screening) 
Significant protocol deviation 
An adverse event which requires discontinuation of the study or results in inability to 
continue to comply with study procedures 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 33 of 57 
The Cognition and Flow Study 
Disease progression which requires discontinuation of the study or results in inability 
to continue to comply with study procedures 
Consent withdrawn 
Lost to follow up 
 
  
If the participant is withdrawn due to an adverse event, the investigator will arrange for 
follow-up visits or telephone calls until the adverse event has resolved or stabilised. If 
a participant has been withdrawn from the study, they will not be required to attend any 
further assessments or follow-up. Participants who have withdrawn from the study will 
be included in the data analysis (intention to treat analysis) and will be consented to 
do so. In the healthy volunteer arm, as this is a feasibility study, withdrawn participants 
will not be replaced. The reason for withdrawal will be recorded in the CRF.   
 
 
 
8.10 Source Data 
 
Source documents are original documents, data, and records from which participants’ 
CRF data are obtained.  These include, but are not limited to, hospital records (from 
which medical history and previous and concurrent medication may be summarised 
into the CRF), clinical and office charts, laboratory and pharmacy records, 
radiographs/scan reports, and correspondence, interview and focus group recordings 
and transcripts.  
 
CRF entries will be considered source data if the CRF is the site of the original 
recording (e.g., there is no other written or electronic record of data). In this study the 
CRF will be used as the source document for; cognition (ACE-III), mood (GDS-15), 
function/ADLs (Lawton-IADL), quality of life (DEMQOL), handedness (Edinburgh 
Handedness Inventory), and assessments of neurovascular function (TCD), blood 
pressure, heart rate and ETCO2.   
 
 All documents will be stored safely in confidential conditions.  On all study-specific 
documents, other than the signed consent, the participant will be referred to by the 
study participant number/code, not by name. 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 34 of 57 
The Cognition and Flow Study 
9. 
TREATMENT OF TRIAL PARTICIPANTS 
9.1 
Description of Study Treatment  
 
Participants randomised to the intervention will complete an 8-12 week CT program. 
Participants will be required to complete five, 30 minute sessions per week for eight 
to twelve weeks. The CT program will be provided by Lumosity© as part of a 
collaboration through the Human Cognition Project. Lumosity© is a commercially 
available software, developed by a group of neuropsychologists, which has been used 
across several studies of brain training and disciplines (38-40). These studies have 
also been included in a number of systematic reviews and meta-analysis (6, 19). It is 
a multi-domain, online based cognitive training tool, which is relatively easy to use 
and administer. It has been designed to adapt to the individual’s cognitive function in 
order to personalise the training program to their needs. Exercises will be selected 
with the support of Lumosity© to target the following cognitive domains; attention, 
memory, visuospatial, verbal fluency, and language. 
 
9.2 
Storage of Study Equipment or Related apparatus 
 
Study equipment is stored securely in the CHIASM laboratory and maintained 
annually by the medical physics department at the University Hospitals of Leicester 
NHS Trust.  
 
9.3 
Compliance with Study Treatment 
 
Compliance will be monitored through Lumosity© online software which will log and 
track the number of minutes and times per week a participant has spent training, to 
determine the training dose received by each participant. Participants will not be 
excluded based on non-adherence, as this is considered an integral component to 
the feasibility assessment. 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 35 of 57 
The Cognition and Flow Study 
10. 
SAFETY REPORTING 
10.1 Definitions 
10.1.1 Adverse Event (AE) 
 
An AE or adverse experience is: 
 
Any untoward medical occurrence in a patient or clinical investigation participants, 
which does not necessarily have to have a causal relationship with this treatment. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the study, 
whether or not considered related to the study. 
10.1.2 Adverse Reaction (AR) 
 
All untoward and unintended responses related to the study. 
All cases judged by either the reporting medically qualified professional or the sponsor 
as having a reasonable suspected causal relationship to the study qualify as adverse 
reactions.   
 
10.1.3 Severe Adverse Events 
 
To ensure no confusion or misunderstanding of the difference between the terms 
"serious" and "severe", which are not synonymous, the following note of clarification 
is provided: 
 
The term "severe" is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  This is not 
the same as "serious," which is based on patient/event outcome or action criteria 
usually associated with events that pose a threat to a participant's life or functioning.  
Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
 
10.1.4 Serious Adverse Event or Serious Adverse Reaction 
 
A serious adverse event or reaction is any untoward medical occurrence that at any 
dose: 
 
Results in death, 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 36 of 57 
The Cognition and Flow Study 
 
Is life-threatening, 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the participant was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe. 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect. 
 
Other important medical events* 
*Other events that may not result in death, are not life threatening, or do not require 
hospitalisation, may be considered a serious adverse event when, based upon 
appropriate medical judgement, the event may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
10.1.5 Expected Serious Adverse Events/Reactions 
 
See Appendix D for a complete list of expected adverse events not subject to 
immediate reporting.  
 
 
 
10.1.6 Suspected Unexpected Serious Adverse Reactions 
 
Not applicable for this type of study.  
 
10.2 Reporting Procedures for All Adverse Events 
 
All AEs occurring during the study observed by the investigator or reported by the 
participant, whether or not attributed to study, will be recorded on the CRF.   
The following information will be recorded: description, date of onset and end date, 
severity, assessment of relatedness to study, other suspect device and action taken.  
Follow-up information should be provided as necessary.  
 
AEs considered related to the study as judged by a medically qualified investigator or 
the sponsor will be followed until resolution or the event is considered stable.  All 
related AEs that result in a participant’s withdrawal from the study or are present at 
the end of the study, should be followed up until a satisfactory resolution occurs. 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the participant’s removal from the study. A participant may also 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 37 of 57 
The Cognition and Flow Study 
voluntarily withdraw from the study due to what he or she perceives as an intolerable 
AE.   
 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 
3 = severe.   
 
The relationship of AEs to the study will be assessed by a medically qualified 
investigator.  
 
10.3 Reporting Procedures for Serious Adverse Events 
 
All SAEs, except those expected ones defined in section 10.1.5 that do not require 
immediate reporting (see 10.1.5), must be reported to the Sponsor within one working 
day of discovery or notification of the event.  The Sponsor will perform an initial check 
of the information and ensure that it is reviewed at the next R&D Management 
meeting.  All SAE information must be recorded on an SAE form and sent to the 
Sponsor using the appropriate reporting form and the contact details on there. 
Additional information received for a case (follow-up or corrections to the original 
case) needs to be detailed on a new SAE form which must be sent to the Sponsor 
using the appropriate reporting form and the contact details on there.  
 
The Sponsor will report all SUSARs to the Research Ethics Committee concerned. 
Fatal or life-threatening SUSARs must be reported within 7 days and all other 
SUSARs within 15 days. The CI will inform all investigators concerned of relevant 
information about SUSARs that could adversely affect the safety of participants. 
 
In addition to the expedited reporting above, the CI shall submit once a year 
throughout the study or on request an Annual Report to the Ethics Committee which 
lists all SAEs / SUSARs that have occurred during the preceding 12 months. 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 38 of 57 
The Cognition and Flow Study 
11. 
STATISTICS 
 
11.1 Description of Statistical Methods 
 
All data will be tested for normality prior to statistical testing using Shapiro-Wilks or 
visual inspection of histograms. Where data are found to be non-parametric, data will 
be appropriately transformed prior to statistical testing, and parametric tests then 
applied. Data will be recorded in Microsoft Excel. Statistical analyses will be performed 
using the latest version of SPSS for Windows, and graphs will be produced using the 
latest version of GraphPad Prism for Windows.  
 
Feasibility and Baseline Demographics 
 
Data will be reported as mean (standard deviation) for continuous variables, and 
number (percentage) for nominal data. Differences between the intervention and 
control groups will be analysed within population group (HC/AzD/MCI)   using Chi-
Square for nominal data, and independent t-testing for continuous data. Any 
differences between population groups will also be reported. 
 
Outcome Data 
 
The difference for each participant between baseline and follow-up assessment for 
each of the continuous outcome measures described in Section 6.2 (secondary 
outcome measures) will be reported along with the overall mean difference. To assess 
the impact of the intervention and population group on each of these differences, a 
two-way ANOVA will be carried out. The interaction between population group and 
treatment group will also be included to assess if the difference between the treatment 
groups is different between the population groups. 
 
Power calculation 
 
The results from this study will be used to inform a power calculation to determine the 
sample size for a larger trial investigating the outcome measures described in Section 
6.2. Specific statistical support will be sought within the Department of Cardiovascular 
Sciences to carry out this power calculation using the outcome data from this study.  
 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 39 of 57 
The Cognition and Flow Study 
 
11.2 The Number of Participants 
 
60 participants will be required to complete the programme, in three sub-groups of 
twenty (healthy older adults, AzD and MCI). This does not include participants who 
did not have adequate bilateral TCD windows, which has been listed in section 7.3 as 
an exclusion criterion. Authors generally agree that recruiting between 24 and 50 
participants for a feasibility study is adequate and therefore the planned target of 60 
participants is sufficiently large enough whilst giving a margin for drop-outs and loss 
to follow-up (41, 42). Given the primary aim of this study is feasibility, a formal power 
calculation has not been performed.  
 
For the qualitative arm, participants will be recruited as a sub-set of those who were 
enrolled into the training arm of the trial. Both participants who did and did not 
complete the training programme will be invited for interview or focus group to better 
understand any issues that arose during the programme, reasons for non-adherence, 
or premature withdrawal. The sample size will therefore be determined by the number 
who were randomised to the treatment arm and are willing to return for interview or 
focus group. At the point at which responses to interview questions become saturated, 
no further participants will be recruited to the qualitative arm.  
 
11.3 The Level of Statistical Significance 
 
Statistical significance will be set at p<0.05.  
 
11.4 Criteria for the Termination of the Trial. 
 
This is a feasibility trial, therefore trial termination will be after the final participant has 
completed all assessments or interview.  
 
11.5 Procedure for Accounting for Missing, Unused, and Spurious Data. 
 
Unused data will be reported, with reasons in the final report after study completion, 
and in any publication. Spurious and missing data will be reported, but not included in 
final analyses. 
 
11.6 Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 40 of 57 
The Cognition and Flow Study 
Statistical support, including any deviations will be supported by the departmental 
statistician, Dr Chris Nelson. Any deviations will be reported to the Trial Steering 
Committee (TSC), and included in any reports to Sponsor or REC.  
 
11.7 Inclusion in Analysis 
 
All randomised participants will be included in the analysis.  
 
11.8 Qualitative data analysis 
 
The findings from the semi-structured interviews and focus groups will be evaluated 
using framework analysis (41). The digital recordings of the interviews and focus 
groups will be transcribed verbatim, the transcripts will be read in detail, i.e. line-by-
line, and open codes will be formed categorising and conceptualising the responses 
and identifying the major themes. Two researchers LB & RE will independently code 
the first few transcripts to ensure consistency in coding.  
Following this initial coding the analytical framework will be developed, this is an 
iterative process and will develop through coding of additional transcripts. Once the 
final transcript has been coded the analytic framework will be used to generate the 
framework matrix. The framework matrix will be developed in NVivo 11 (QSR 
International), and allow for the recognition of patterns and outliers within the data.  
 
Respondent Validation 
The technique of showing the transcripts to the research participants and ascertaining 
their opinions on the accuracy of the transcripts will be used, to establish the degree 
of correspondence between the researcher’s views and those of the research 
participants (36). Once completed the transcripts of the semi-structured interviews will 
be sent to the participants for their approval. Any comments by the participant will be 
added prior to analysis. This technique ensures the researchers accurately portray 
the experiences and viewpoints of the research participants. It is also hoped that by 
involving research participants in analysis and interpretation it will increase their 
engagement with the research.  
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 41 of 57 
The Cognition and Flow Study 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Direct access will be granted to authorised representatives from the sponsor, host 
institution, and the regulatory authorities to permit trial-related monitoring, audits and 
inspections. 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 42 of 57 
The Cognition and Flow Study 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
 
The study will be conducted in accordance with the current approved protocol, ICH 
GCP, relevant regulations and standard operating procedures.  
 
The University of Leicester operate a risk based audit programme to which this study 
will be subject.  
 
 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 43 of 57 
The Cognition and Flow Study 
14. 
CODES OF PRACTICE AND REGULATIONS 
14.1 Ethics 
 
Consent and Capacity 
 
This study plans to recruit participants with dementia or cognitive impairment. We 
anticipate that a number of participants will not have sufficient capacity to consent to 
the study. Given the nature of dementia, we feel it would be unethical to exclude 
participants who are unable to consent to the study, particularly where they have 
expressed prior willingness to be involved in research should they lose capacity. 
Therefore, for those individuals who do not have capacity, we plan to consent a close 
relative, friend or carer (personal consultee) who is able to express the views of the 
participant and consent on their behalf to the study. Any volunteer who has been 
recruited through this process who appears distressed or unwilling to participate in 
the study at any point will be withdrawn accordingly. Participants who have capacity 
will be asked at the point of consent what they would like to happen should they lose 
capacity, i.e. be withdrawn from the study, or continue in the study. Any participant 
who then loses capacity, an assessment of this pre-disclosed opinion, any available 
personal consultee opinion and their ongoing engagement/willingness or lack of 
distress will be used to decide whether study participation should continue. If there is 
any doubt about ongoing participation, this can be referred to the trial steering 
committee and/or research supervisors. Participants who lack capacity at study 
inclusion who later regain capacity will be re-consented before ongoing study 
participation.  
 
Waiting list control for intervention 
 
All study participants who are randomised to the control arm will be offered the 
intervention at the end of the study (waiting list control). This is not a cross over trial, 
and therefore these participants will not have any further assessments after provision 
of the CT program. This is to remove any ethical concerns about participants not 
being able to undertake the CT program through study participation. Some 
participants may deteriorate over the course of the study and may be unable to utilise 
the intervention effectively as waiting list control.  
 
Recruitment 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 44 of 57 
The Cognition and Flow Study 
A broad recruitment strategy has been developed to ensure this project can recruit to 
target (total 60 participants, 20 healthy older adults, 20 MCI and 20 AzD). This will 
encompass memory and geriatric clinics, GP surgeries, and community groups. This 
recruitment strategy and rate has been based on a recent pilot study undertaken in 
the department where 55 participants were recruited over a period of 6 months. 
 
  
Study procedures 
 
All methods in this study have been tested in a recent pilot observational study. The 
TCD device utilises a head-frame which exerts a slight pressure; but has been used 
previously in several studies in the department and is well tolerated in patients with 
stroke and dementia. Participants will wear a finger blood pressure monitor, which 
exerts intermittent pressure.  Again, this has been well tolerated in previous studies 
of patients with stroke and dementia.  
 
Industry collaboration 
 
This study is being undertaken as a collaboration between Lumosity and University 
of Leicester. Lumosity are providing the CT program free of charge but have not 
funded this study, and therefore the study is financially independent of Lumosity. A 
contract has been checked by the University of Leicester who will retain the rights to 
publication. 
 
14.2 Sponsor Standard Operating Procedures 
 
All relevant Sponsor SOPs will be followed to ensure that this study complies with all 
relevant legislation and guidelines  
 
14.3 Declaration of Helsinki 
 
The Investigator will ensure that this study is conducted in full conformity with the 
current revision of the Declaration of Helsinki (last amended October 2000, with 
additional footnotes added 2002 and 2004). 
 
14.4 ICH Guidelines for Good Clinical Practice 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 45 of 57 
The Cognition and Flow Study 
The Investigator will ensure that this study is conducted in full conformity with relevant 
regulations and with the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) 
July 1996. 
 
14.5 Approvals  
 
Once Sponsor authorisation has been confirmed, the protocol, informed consent form, 
participant information sheet and any proposed advertising material will be submitted 
to an appropriate Research Ethics Committee (REC), Health Research Authority 
(HRA),   and host institution(s) for written approval.   
 
Once Sponsor authorisation has been confirmed, the Investigator will submit and, 
where necessary, obtain approval from the above parties for all substantial 
amendments to the original approved documents.    
 
14.6 Participant Confidentiality 
 
The trial staff will ensure that the participants’ anonymity is maintained.  The 
participants will be identified only by initials and a participants ID number on the CRF 
and any electronic database.  All documents will be stored securely and only accessible 
by trial staff and authorised personnel. The study will comply with the Data Protection 
Act which requires data to be anonymised as soon as it is practical to do so.   
 
14.7  Other Ethical Considerations 
 
As outlined above.  
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 46 of 57 
The Cognition and Flow Study 
15. 
DATA HANDLING AND RECORD KEEPING 
 
15.1 Data Extraction 
 
As supportive evidence of the diagnosis of MCI or AzD, results and significant findings 
from Computerised Tomography (CTo) head/Brain Magnetic Resonance Imaging 
(MRI), if undertaken, will be recorded on the CRF. 
Other information which will be extracted from the medical notes and recorded on the 
CRF include results and details of any previous cognitive testing, and the date of 
diagnosis of MCI or AzD. 
 
 15.2 Data Analysis 
 
All other parameters recorded, including CBFv, heart rate, blood pressure, and 
ETCO2 will be simultaneously recorded onto a computer system (PHYSIDAS), 
providing data for subsequent analyses. Off-line analyses will be undertaken using 
software designed by the University of Leicester’s Department of Cardiovascular 
Sciences.  
 
 
15.3 Data Management 
 
All parameters (signals) that are collected during the measurement will be saved using 
a coded filename. The name and other identifying detail will NOT be included in any 
study data electronic file. All study data will be entered into Microsoft Excel for 
Windows. 
All files will be encrypted and stored on a password secured computer/laptop, which 
will have restricted access to members who are authorised on the authorisation log.  
The participants will be identified by a study specific participant number and/or code 
in any database.  The name and any other identifying detail will NOT be included in 
any study data electronic file.  
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 47 of 57 
The Cognition and Flow Study 
16. 
STUDY GOVERNANCE 
16.1 Trial Steering Committee (TSC) 
 
A TSC consisting of lay members, and independent academics from the host 
institution, will be convened. The TSC will meet at six monthly intervals, and will 
assess the progress of the trial, recruitment, compliance with study protocol, ethical 
and regulatory standards, and safety or adverse outcomes.  
 
16.2 Data Safety Monitoring Committee (DSMC) 
 
As this is a non-pharmacological feasibility RCT, a DSMC is not required, but adverse 
events will be reviewed at TSC meetings.  
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 48 of 57 
The Cognition and Flow Study 
17. 
FINANCING AND INSURANCE 
 
This study is funded as part of Research Training Fellowship by the Dunhill Medical 
Trust. A full breakdown of the study costs are included in the approved grant 
application which has been submitted in PDF format with this protocol.  
 
17.1 Research Costs  
 
The research costs have been calculated by the NIHR CRN East Midlands to include 
time for research support staff, or clinical staff to screen eligible participants for the 
study in the memory and geriatric services as £3250.80 
 
The NIHR CRN have also calculated the relevant costs for screening General Practice 
databases and mailing out invitation letters to potential, eligible participants at 
£328.60. 
 
NHS Treatment Costs 
None. 
 
NHS Support Costs 
None. 
 
 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 49 of 57 
The Cognition and Flow Study 
18. 
PUBLICATION POLICY 
 
On all publications, the funding body and Lumosity© will be acknowledged, and each 
author will be required to disclose details of their own involvement/contribution in the 
study (specific publication).  
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 50 of 57 
The Cognition and Flow Study 
19. 
REFERENCES 
1. 
Alzheimer's-society. Demography: Alzheimer's Society; 2016 [updated 2016-11-28. 
Available from: https://www.alzheimers.org.uk/info/20091/position_statements/93/demography. 
2. 
Robinson L, Tang E, Taylor JP. Dementia: timely diagnosis and early intervention. Bmj. 
2015;350:h3029. 
3. 
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 
2004;256(3):183-94. 
4. 
Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and 
other disorders. Nat Rev Neurosci. 2011;12(12):723-38. 
5. 
Beishon L, Haunton VJ, Panerai RB, Robinson TG. Cerebral Hemodynamics in Mild 
Cognitive Impairment: A Systematic Review. J Alzheimers Dis. 2017;59(1):369-85. 
6. 
Lampit A, Hallock H, Valenzuela M. Computerized cognitive training in cognitively healthy 
older adults: a systematic review and meta-analysis of effect modifiers. PLoS Med. 
2014;11(11):e1001756. 
7. 
Gates NJ, Sachdev PS, Fiatarone Singh MA, Valenzuela M. Cognitive and memory training 
in adults at risk of dementia: a systematic review. BMC Geriatr. 2011;11:55. 
8. 
Bahar-Fuchs A, Clare L, Woods B. Cognitive training and cognitive rehabilitation for persons 
with mild to moderate dementia of the Alzheimer's or vascular type: a review. Alzheimers Res Ther. 
2013;5(4):35. 
9. 
Martin M, Clare L, Altgassen AM, Cameron MH, Zehnder F. Cognition-based interventions 
for healthy older people and people with mild cognitive impairment. Cochrane Database Syst Rev. 
2011(1):Cd006220. 
10. 
Coyle H, Traynor V, Solowij N. Computerized and virtual reality cognitive training for 
individuals at high risk of cognitive decline: systematic review of the literature. Am J Geriatr 
Psychiatry. 2015;23(4):335-59. 
11. 
Tomek A, Urbanova B, Hort J. Utility of transcranial ultrasound in predicting Alzheimer's 
disease risk. J Alzheimers Dis. 2014;42(Suppl 4):S365-74. 
12. 
van Beek AH, Claassen JA, Rikkert MG, Jansen RW. Cerebral autoregulation: an overview 
of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab. 
2008;28(6):1071-85. 
13. 
Panerai RB. Transcranial Doppler for evaluation of cerebral autoregulation. Clin Auton Res. 
2009;19(4):197-211. 
14. 
Stroobant N, Vingerhoets G. Transcranial Doppler ultrasonography monitoring of cerebral 
hemodynamics during performance of cognitive tasks: a review. Neuropsychol Rev. 2000;10(4):213-
31. 
15. 
Tomek A, Urbanova B, Hort J. Utility of transcranial ultrasound in predicting Alzheimer's 
disease risk. J Alzheimers Dis. 2014;42:S365-S74. 
16. 
Belleville S. Cognitive training for persons with mild cognitive impairment. Int Psychogeriatr. 
2008;20(1):57-66. 
17. 
Woods B, Aguirre E, Spector AE, Orrell M. Cognitive stimulation to improve cognitive 
functioning in people with dementia. Cochrane Database Syst Rev. 2012(2):Cd005562. 
18. 
Gates NJ, Sachdev P. Is cognitive training an effective treatment for preclinical and early 
Alzheimer's disease? J Alzheimers Dis. 2014;42 Suppl 4:S551-9. 
19. 
Hill NT, Mowszowski L, Naismith SL, Chadwick VL, Valenzuela M, Lampit A. Computerized 
Cognitive Training in Older Adults With Mild Cognitive Impairment or Dementia: A Systematic Review 
and Meta-Analysis. Am J Psychiatry. 2017;174(4):329-40. 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 51 of 57 
The Cognition and Flow Study 
20. 
Li H, Li J, Li N, Li B, Wang P, Zhou T. Cognitive intervention for persons with mild cognitive 
impairment: A meta-analysis. Ageing Res Rev. 2011;10(2):285-96. 
21. 
Huntley JD, Gould RL, Liu K, Smith M, Howard RJ. Do cognitive interventions improve 
general cognition in dementia? A meta-analysis and meta-regression. BMJ Open. 2015;5(4). 
22. 
Reijnders J, van Heugten C, van Boxtel M. Cognitive interventions in healthy older adults and 
people with mild cognitive impairment: a systematic review. Ageing Res Rev. 2013;12(1):263-75. 
23. 
Vemuri P, Fields J, Peter J, Klöppel S. Cognitive interventions in Alzheimer's and Parkinson's 
diseases: emerging mechanisms and role of imaging. Curr Opin Neurol. 2016;29(4):405-11. 
24. 
Belleville S, Clement F, Mellah S, Gilbert B, Fontaine F, Gauthier S. Training-related brain 
plasticity in subjects at risk of developing Alzheimer's disease. Brain. 2011;134(Pt 6):1623-34. 
25. 
Vermeij A, Claassen JA, Dautzenberg PL, Kessels RP. Transfer and maintenance effects of 
online working-memory training in normal ageing and mild cognitive impairment. Neuropsychol 
Rehabil. 2016;26(5-6):783-809. 
26. 
Belleville S, Bherer L. Biomarkers of Cognitive Training Effects in Aging. Curr Transl Geriatr 
Exp Gerontol Rep. 2012;1(2):104-10. 
27. 
Vermeij A, Kessels RPC, Heskamp L, Simons EMF, Dautzenberg PLJ, Claassen JAHR. 
Prefrontal activation may predict working-memory training gain in normal aging and mild cognitive 
impairment. Brain Imaging and Behavior. 2016:1-14. 
28. 
Engvig A, Fjell AM, Westlye LT, Moberget T, Sundseth O, Larsen VA, et al. Effects of memory 
training on cortical thickness in the elderly. Neuroimage. 2010;52(4):1667-76. 
29. 
Yang H, Leaver AM, Siddarth P, Paholpak P, Ercoli L, St. Cyr NM, et al. Neurochemical and 
Neuroanatomical Plasticity Following Memory Training and Yoga Interventions in Older Adults with 
Mild Cognitive Impairment. Front Aging Neurosci. 2016;8. 
30. 
Ciarmiello A, Gaeta MC, Benso F, Del Sette M. FDG-PET in the Evaluation of Brain Metabolic 
Changes Induced by Cognitive Stimulation in aMCI Subjects. Curr Radiopharm. 2015;8(1):69-75. 
31. 
Forster S, Buschert VC, Teipel SJ, Friese U, Buchholz HG, Drzezga A, et al. Effects of a 6-
month cognitive intervention on brain metabolism in patients with amnestic MCI and mild Alzheimer's 
disease. J Alzheimers Dis. 2011;26 Suppl 3:337-48. 
32. 
Saczynski JS, Inouye SK, Guess J, Jones RN, Fong TG, Nemeth E, et al. The Montreal 
Cognitive Assessment (MoCA): Creating a Crosswalk with the Mini-Mental State Examination. J Am 
Geriatr Soc. 2015;63(11):2370-4. 
33. 
Borland E, Nagga K, Nilsson PM, Minthon L, Nilsson ED, Palmqvist S. The Montreal 
Cognitive Assessment: Normative Data from a Large Swedish Population-Based Cohort. J 
Alzheimers Dis. 2017;59(3):893-901. 
34. 
Tan JP, Li N, Gao J, Wang LN, Zhao YM, Yu BC, et al. Optimal cutoff scores for dementia 
and mild cognitive impairment of the Montreal Cognitive Assessment among elderly and oldest-old 
Chinese population. J Alzheimers Dis. 2015;43(4):1403-12. 
35. 
Beishon LC, Williams CAL, Panerai RB, Robinson TG, Haunton VJ. The assessment of 
neurovascular coupling with the Addenbrooke's Cognitive Examination: a functional Transcranial 
Doppler Ultrasonographic Study. J Neurophysiol. 2017:jn.00698.2017. 
36. 
Hansen EC. Successful Qualitative Health Research: A Practical Introduction: Maidenhead: 
Open University Press; 2006. 
37. 
Jones CL, Jensen JD, Scherr CL, Brown NR, Christy K, Weaver J. The Health Belief Model 
as an Explanatory Framework in Communication Research: Exploring Parallel, Serial, and 
Moderated Mediation. Health Commun. 2015;30(6):566-76. 
38. 
Kesler S, Hadi Hosseini SM, Heckler C, Janelsins M, Palesh O, Mustian K, et al. Cognitive 
training for improving executive function in chemotherapy-treated breast cancer survivors. Clin 
Breast Cancer. 2013;13(4):299-306. 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 52 of 57 
The Cognition and Flow Study 
39. 
Finn M, McDonald S. A single case study of computerised cognitive training for older persons 
with mild cognitive impairment. NeuroRehabilitation. 2014;35(2):261-70. 
40. 
Ballesteros S, Prieto A, Mayas J, Toril P, Pita C, Ponce de León L, et al. Brain training with 
non-action video games enhances aspects of cognition in older adults: a randomized controlled trial. 
Front Aging Neurosci. 2014;6. 
41. 
Sim J, Lewis M. The size of a pilot study for a clinical trial should be calculated in relation to 
considerations of precision and efficiency. J Clin Epidemiol. 2012;65(3):301-8. 
42. 
Julious SA. Sample sizes for clinical trials with normal data. Stat Med. 2004;23(12):1921-86. 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 53 of 57 
The Cognition and Flow Study 
APPENDIX A: PATIENT RECRUITMENT FLOW CHART

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 54 of 57 
The Cognition and Flow Study 
20. 
APPENDIX B: STUDY FLOWCHART 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 55 of 57 
The Cognition and Flow Study 
21. 
APPENDIX C: SCHEDULE OF PROCEDURES 
 
Procedures 
Visits 
 
Screening 
 
Baseline 
Follow-up 
Qualitative 
arm 
Windows 
Informed consent 
x 
 
 
x 
1 month 
Screening MoCA 
x 
 
 
 
1 month 
Demographics 
x 
x 
 
x (carers) 
1 month 
Medical history 
x 
x 
 
 
1 month 
Concomitant 
medications 
x 
x 
 
 
1 month 
Eligibility assessment 
x 
 
 
 
N/A 
Randomisation 
 
x 
 
 
4-6 weeks 
Compliance  
 
x 
x 
 
N/A 
Cognition (ACE-III) 
 
x 
x 
 
Baseline: 4-6 weeks, 
Follow-up: 8-12 
weeks from 
randomisation 
Mood (GDS) 
 
x 
x 
 
Baseline: 1 month, 
Follow-up: 8-12 
weeks from 
randomisation 
Edinburgh handedness 
Inventory 
 
x 
 
 
Baseline: 1 month, 
Follow-up: 8-12 
weeks from 
randomisation 
Function (Lawton-IADL) 
 
x 
x 
 
Baseline: 1 month, 
Follow-up: 8-12 
weeks from 
randomisation 
Quality 
of 
Life 
(DEMQOL) 
 
x 
x 
 
Baseline: 1 month, 
Follow-up: 8-12 
weeks from 
randomisation 
Neurovascular function 
(TCD, blood pressure, 
ECG, ETCO2) 
 
x 
x 
 
Baseline: 4-6 weeks, 
Follow-up: 8-12 
weeks from 
randomisation 
Adverse event 
assessments 
 
 
x 
 
N/A 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 56 of 57 
The Cognition and Flow Study 
Telephone  Support 
(intervention arm only) 
 
x 
x 
 
Weekly telephone 
support to 
participants in 
intervention arm. 
Qualitative 
interview/focus group 
(optional) 
 
 
 
x 
At least 1 week 
after trial 
completion 
 

Date and Version No: 7 19/12/19 
 
 
 
CONFIDENTIAL 
Page 57 of 57 
The Cognition and Flow Study 
22. 
APPENDIX D: EXPECTED EVENTS NOT SUBJECT TO EXPEDITED REPORTING 
 
Acute Coronary Syndromes 
Malignancy 
Agitation 
Myocardial infarction 
Angina 
Nausea 
Anorexia 
Personality change 
Anxiety 
Peripheral Vascular Disease 
Cognitive decline 
Pressure sores 
Constipation 
Renal impairment 
Delirium 
Sedation 
Depression 
Seizure 
Disease progression 
Sexual dysfunction 
Dysphagia 
Sleep disturbance 
Electrolyte disturbance 
Stroke 
Fall 
Syncope 
Fatigue 
Transient ischemic attack 
Fracture 
Urinary retention/catheterisation 
Gastrointestinal disturbance 
Urinary tract infection 
Hallucinations 
Ulceration 
Heart failure 
Violent behaviour 
Incontinence, faecal 
Visual loss 
Incontinence, urinary 
Vomiting 
Infections 
Wandering 
Institutionalisation / Admission to care home 
Weakness 
Intracerebral Haemorrhage 
Weight loss 
Loss of ability to function or care for self