Aerobic Exercise Training in Acute Ischaemic Stroke: A Single-centre, Single-blinded, Randomised, Controlled Feasibility Study of an Aerobic Exercise Training Intervention Versus Standard Care Conducted in the Acute Phase of Stroke.
Phase: NA
Conditions: Ischemic Stroke, Acute Stroke, Cerebrovascular Accident
Sponsor: Sheffield Hallam University

 
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The ATAS Trial 
Title page 
 
 
 
Full trial title:  
 
Aerobic exercise training in acute ischaemic stroke: A single-centre, single-blinded, 
randomised, controlled feasibility study of an aerobic exercise training intervention 
versus standard care conducted in the acute phase of stroke. 
 
 
 
Short trial title and acronym:  
 
Aerobic Exercise Training in Acute Ischaemic Stroke (ATAS) 
 
 
 
Research reference numbers 
 
Sheffield Teaching Hospitals (STH) project reference: 
STH21298 
Sheffield Hallam University Research Ethics 
Committee reference:  
ER25055563 
NHS Research Ethics Committee reference: 
20/YH/0285 
IRAS project ID: 
280320 
Clinical trials registration number:  
NCT04742686 
Protocol version and date: 
3 – 14.12.2020 

 
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Protocol amendment history 
 
 
Protocol 
 
Amendments 
 
Version 
no. 
 
Date 
(dd/mm/yy) 
 
Amendment 
no. 
 
Protocol 
section/page 
number(s) 
 
Summary of key changes from previous 
version 
 
2 
18/11/20 
1 
7.2 
23 
Added: 
• 
Patients will be provided with a 
participant information sheet and will 
be politely asked to contemplate the 
information and make a decision 
within 48 hours of the initial 
discussion. This is due to the time-
sensitive nature of the research. 
Deleted: 
• 
Patients will be given at least 24 
hours to consider the information. 
 
2 
18/11/20 
2 
7.5 
24 
Added following items to exclusion criteria:  
• 
Pain during mobilisation of lower-
limbs. 
• 
Lower-limb spasticity or contracture 
which impairs ability to cycle. 
. 
2 
18/11/20 
3 
9 
33-35 
 
Within ‘Table 3 -  Schedule of 
investigations and outcome measures’,  
the tick colour representing SOC activities 
has been changed from black to orange. The 
remaining black ticks represent research 
activities that are additional to SOC.   
2 
18/11/20 
4 
10 
46 
Added ‘Section 10 – COVID-19 
contingency plan’. 

 
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2 
18/11/20 
5 
10 
46-48 
Added ‘Table 5 – COVID-19 contingency 
plan’. 
 
Declaration  
 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Principal Investigator agrees to conduct the trial in compliance with the approved 
protocol and will adhere to the principles outlined in the UK Policy Framework for Health and 
Social Care Research, Good Clinical Practice (GCP) guidelines, the Sponsor’s and Site’s 
standard operating procedures, and other regulatory requirements as amended. 
 
I agree to ensure that the confidential information contained in this document will not be 
used for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
 
I also confirm that I will make the findings of the trial publicly available through publication or 
other dissemination tools without any unnecessary delay, an honest accurate and 
transparent account of the trial will be given, and any discrepancies and serious breaches of 
GCP from the trial as planned in this protocol will be explained. 
 
Trial Sponsor: 
 
Signature:  
 
...................................................................................................... 
 
Date:  
 
....../....../...... 
 
Name (please print): 
 
...................................................................................................... 
 
 
 
Position:  
 
...................................................................................................... 
 
 
 
 
 
Principal Investigator: 
 
Signature:  
 
...................................................................................................... 
 
Date:  
 
....../....../...... 
 
Name (please print): 
 
......................................................................................................  
 
 

 
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Position:  
 
...................................................................................................... 
 
Contact information 
 
Contact 
Name and title 
Position 
Organisation 
Address 
Email / 
Telephone 
Sponsor 
Representative 
Dr Keith Fildes 
 
Research 
Development 
Manager (Policy 
and Performance) 
Sheffield  
Hallam 
University 
Sheffield Hallam 
University, Science 
Park, City Campus, 
Howard Street, 
Sheffield, S1 1WB. 
 
ethicssupport@ 
shu.ac.uk 
 
0114 2254530 
 
Principal 
Investigator 
 
Dr Tom Maden-
Wilkinson 
Senior Research 
Fellow - Clinical 
Exercise Physiology 
Sheffield  
Hallam 
University 
Sheffield Hallam 
University,  
Collegiate Hall, 
Collegiate Campus, 
Sheffield,  
S10 2BP. 
t.maden-
wilkinson@shu.ac.uk 
 
 
Local Principal 
Investigator 
(Study Doctor)  
Dr Ali Ali 
Consultant Stroke 
Physician 
 
Sheffield 
Teaching 
Hospitals NHS 
Foundation 
Trust 
Royal Hallamshire 
Hospital, Glossop 
Road, Sheffield, S10 
2JF. 
ali.ali9@nhs.net 
0114 271 1768     
Co-Investigator 
#1 
Mr Nik 
Kudiersky 
PhD Student - 
Clinical Exercise 
Physiology 
Sheffield  
Hallam 
University 
Sheffield Hallam 
University,  
Chestnut Court, 
Collegiate Campus, 
Sheffield,  
S10 2BP. 
 
n.kudiersky@shu.ac.
uk 
07983354006 
 
Co-Investigator 
#2 
Dr Simon 
Nichols 
Senior Research 
Fellow - Clinical 
Exercise Physiology 
Sheffield 
Hallam 
University 
Sheffield Hallam 
University,  
Collegiate Hall, 
Collegiate Campus, 
Sheffield,  
S10 2BP. 
s.j.nichols@shu.ac.uk  
Co-Investigator 
#3 
Dr Helen 
Humphreys 
Senior Research 
Fellow – Exercise 
Psychology 
Sheffield  
Hallam 
University 
Sheffield Hallam 
University,  
Collegiate Hall, 
Collegiate Campus, 
Sheffield,  
S10 2BP. 
h.humphreys@shu.ac
.uk 

 
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Table of Contents 
 
Title page ...................................................................................................................... 1 
Research reference numbers .................................................................................... 1 
Protocol amendment history ..................................................................................... 2 
Declaration ................................................................................................................... 3 
Contact information .................................................................................................... 4 
i. 
Abbreviations ............................................................................................................... 8 
ii. 
Trial summary .............................................................................................................. 9 
iii. Funding ....................................................................................................................... 10 
iv. Role of Sponsor and Funder .................................................................................... 11 
v. 
Trial Management Group .......................................................................................... 11 
vi. Expertise and protocol contributions ..................................................................... 11 
vii. 
Patient and public contributions.......................................................................... 12 
viii. 
Keywords ................................................................................................................ 13 
1. 
Main research question ..................................................................................... 13 
2. 
Abstract ............................................................................................................... 13 
3. 
Background ........................................................................................................ 14 
4. 
Rationale ............................................................................................................. 15 
4.1. 
Acute aerobic exercise: proposed mechanisms ............................................... 15 
4.2. 
Aerobic exercise training during acute stroke: pre-clinical evidence overview
 
16 
4.3. 
Aerobic exercise training during acute stroke: clinical evidence overview ... 17 
4.4. 
Aerobic exercise in clinical practice ................................................................... 18 
4.5. 
Accessibility of aerobic exercise ......................................................................... 19 
5. 
Aims and objectives .......................................................................................... 20 
6. 
Study overview ........................................................................................................... 21 
6.1. 
Study design........................................................................................................... 21 
6.2. 
Study setting .......................................................................................................... 21 
6.3. 
Success criteria ..................................................................................................... 21 
6.4. 
Study flow chart ..................................................................................................... 22 
7. 
Recruitment ........................................................................................................ 22 
7.1. 
Patient throughput and planned recruitment ..................................................... 23 
7.2. 
Recruitment strategy ............................................................................................. 23 
7.3. 
Sample size............................................................................................................. 23 
7.4. 
Inclusion criteria .................................................................................................... 24 
7.5. 
Exclusion criteria ................................................................................................... 24 
7.6. 
Patient screening ................................................................................................... 24 

 
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7.9. 
Blinding ................................................................................................................... 26 
7.11. Physical accessibility ............................................................................................ 26 
8. 
Safety ................................................................................................................... 26 
8.1. 
Contraindications to aerobic exercise ................................................................ 26 
8.2. 
Aerobic exercise termination criteria .................................................................. 28 
8.3. 
Safety of aerobic exercise .................................................................................... 28 
8.4. 
Risk management .................................................................................................. 30 
8.4.1. 
Risk categorisation ............................................................................................ 31 
8.5. 
Risks and benefits to be communicated to patients (lay summary): .............. 31 
8.5.1. Potential benefits of aerobic exercise training ...........................................................31 
8.5.2. Risks of aerobic exercise training................................................................................31 
9. 
Investigations ..................................................................................................... 33 
9.1. 
Qualitative data ...................................................................................................... 36 
9.1.1. Participant interviews ....................................................................................................36 
9.1.2. Healthcare professional interviews..............................................................................37 
9.1.3. Minimising bias ..............................................................................................................37 
9.2. 
Justification of investigations and outcome measures .................................... 38 
9.3. 
Scheduling research activity ................................................................................ 45 
9.4. 
Participant food and drink consumption ............................................................ 45 
9.5. 
Preparation, storage and analysis of blood samples ........................................ 45 
10. 
COVID-19 contingency plan .......................................................................... 46 
11. 
Feasibility outcome measures...................................................................... 48 
12. 
Intervention ..................................................................................................... 49 
12.1. Usual care ............................................................................................................... 49 
12.2. Usual care therapy dose ....................................................................................... 49 
12.3. Aerobic exercise training protocol ...................................................................... 50 
12.3.1. 
Exercise equipment ...................................................................................................50 
12.3.2. 
Exercise supervision .................................................................................................50 
12.3.3. 
Aerobic exercise ........................................................................................................51 
12.4. Operational definitions for (S)AEs ....................................................................... 53 
12.5. Recording and reporting of serious adverse events ......................................... 53 
12.6. Responsibilities ..................................................................................................... 54 
13. 
Data management........................................................................................... 55 
14. 
Ethical and regulatory considerations ........................................................ 56 
14.1. Research Ethics Committee review and reports ............................................... 56 
14.2. Patient and public involvement............................................................................ 56 
14.2.1. 
Protocol amendments based on patient and public involvement ........................57 
14.3. Financial and other competing interests ............................................................ 57 
14.4. Notification of serious breaches to GCP and/or the protocol .......................... 57 
14.5. Data protection and patient confidentiality ........................................................ 58 
14.6. Access to the final dataset ................................................................................... 58 

 
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15. 
Dissemination ................................................................................................. 58 
15.1. Lay summaries ....................................................................................................... 59 
16. 
References ...................................................................................................... 60 
17. 
Appendix ......................................................................................................... 70 
 
 
List of tables 
 
Table 1. Contraindications to aerobic exercise. ......................................................... 27 
Table 2. Aerobic exercise termination criteria. ........................................................... 28 
Table 3. Schedule of investigations and outcome measures. Note: orange ticks 
indicate standard care. ................................................................................................ 33 
Table 4. Justification of investigations and outcome measures ................................ 38 
Table 5. COVID-19 contingency plan ......................................................................... 46 
Table 6. Feasibility outcome measures ...................................................................... 48 
Table 7. Standardised verbal communication during aerobic exercise ..................... 70 
 
List of figures 
 
Figure 1. Framework depicting key post-stroke phases and temporally related 
biological processes. ................................................................................................... 17 
Figure 2. A bed-side power-assisted cycle ergometer (Medimotion, Letto 2). ......... 19 
Figure 3. Study flow chart ........................................................................................... 22 
Figure 4. Pie charts displaying the risk of adverse events related to aerobic exercise.
 ..................................................................................................................................... 32 
Figure 5. Schematic diagram of 5-day exercise protocol. ......................................... 52 
 
 
 
 
 
 
 
 
 
 

 
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i. 
Abbreviations 
 
Abbreviation 
 
Meaning 
AE 
Adverse event 
ASU 
Acute stroke unit 
ATAS 
Aerobic exercise training in acute ischaemic stroke 
AWRC 
Advanced Wellbeing Research Centre 
BDNF 
Brain-derived neurotrophic factor 
BHRU 
Beech Hill Rehabilitation Unit 
CBF 
Cerebral blood flow 
CO2 
Carbon dioxide 
CPET 
Cardiopulmonary exercise test 
EQ-5D 
EuroQol Quality of Life Index 
FSS 
Fatigue Severity Scale 
GAD-7 
Generalised Anxiety Disorder 
GCP 
Good Clinical Practice 
GPAQ 
Global Physical Activity Questionnaire 
HASU 
Hyper acute stroke unit 
HR 
Heart rate 
HRmax 
Maximum heart rate 
HRR 
Heart rate reserve 
mBDNF 
Mature brain-derived neurotrophic factor 
MoCA 
Montreal Cognitive Assessment 
mRS 
Modified Rankin Scale 
NHS 
National Health Service 
NIHSS 
National Institutes of Health Stroke Scale 
PHQ-9 
Patient Health Questionnaire 
PI 
Principal Investigator 
PPI 
Patient and public involvement 
RCT 
Randomised controlled trial 
REC 
Research Ethics Committee 
RHH 
Royal Hallamshire Hospital 
rLOT 
Revised Life Orientation Test 
RoFS 
Rating of Fatigue Scale 
RPE 
Rating of perceived exertion 
SAE 
Serious adverse event 
SHU 
Sheffield Hallam University 
SPPB 
Short physical performance battery 
STH 
Sheffield Teaching Hospitals 
TMG 
Trial Management Group 
V̇ O2 
Oxygen consumption 
 
 
 
 
 
 
 
 
 

 
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ii. 
Trial summary 
 
 
Trial title 
Aerobic exercise training in acute ischaemic stroke: A single-
centre, single-blinded, randomised, controlled feasibility study of 
an aerobic exercise training intervention versus standard care in 
the acute phase of stroke 
Internal ref. no. (or short title) 
Aerobic Exercise Training in Acute Ischaemic Stroke (ATAS). 
Clinical phase  
II 
Trial design 
A single-centre, single-blinded, two-arm parallel group, 
randomised, controlled feasibility trial 
Trial participants 
Acute ischaemic stroke patients (1-7 days post stroke) 
Planned sample size 
30  
Intervention duration 
5 working days 
Trial duration per participant 
3 months 
Estimated total trial duration 
21 months 
 
 
 
Objectives 
Outcome Measures 
Primary 
 
To determine the feasibility 
of conducting a randomised 
controlled trial (RCT) to 
assess the effects of an 
aerobic exercise intervention 
on stroke outcomes. 
 
• 
safety 
• 
recruitment rate 
• 
exclusion rate 
• 
consent rate 
• 
dropout rate 
• 
participant fidelity to 
intervention 
• 
acceptability 
• 
completeness of data 
 
 
Secondary 
 
 
 
To identify potential primary 
outcomes for a subsequent 
definitive RCT. 
 
 
 
 
 
 
 
 
 
For example: 
• 
physical 
function/disability 
• 
health-related quality 
of life 
• 
cognitive function 
• 
mood 
• 
fatigue 

 
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To develop mechanistic 
knowledge of the 
intervention. 
• 
physical activity levels 
 
 
• 
Cerebral blood flow 
velocity  
• 
Mature brain-derived 
neurotrophic factor 
Type of intervention 
Power-assisted aerobic exercise training. 
Intervention components 
A 10-30 minute session of low-moderate aerobic interval exercise 
conducted once per day for 5 working days. Exercise type: semi-
recumbent power-assisted in-bed cycling. 
 
 
iii. 
Funding and support in kind 
 
 
Funder(s) 
Financial and non-financial support given 
 
Sheffield Hallam University 
 
 
Tel: 0114 225 5044 
Email: HWB-DoctoralAdmin@shu.ac.uk 
 
 
Vice Chancellor’s PhD Scholarship: 
 
£15,009 per annum salary for PhD student for 3 years 
(£45,027) 
 
£1,500 per academic year for research-related costs 
including consumables, patient transport and research 
dissemination (£4,500) 
 
Total = £49527 
 
Sheffield Teaching Hospitals NHS Foundation Trust, 
Department of Neurosciences. 
 
Tel: 0114  2711768 
Email: ali.ali9@nhs.net 
 
Transcranial Doppler ultrasound device provided in 
kind. 
 
Cycle ergometer provided in kind. 
 
 
 
 
 

 
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iv. 
Role of Sponsor and Funder 
 
Sheffield Hallam University (SHU) is both the Sponsor and Funder of the ATAS trial. Some 
SHU equipment has been funded by the European Regional Development Fund. SHU holds 
professional indemnity insurance (Royal & Sun Alliance; policy no. RKK856067) to meet the 
potential legal liability of the Sponsor and employees for harm to participants arising from the 
design and management of the research. The professional indemnity insurance policy is due 
for renewal in July 2021; policy details will be updated accordingly. Indemnity to meet the 
potential legal liability of Investigators for harm to participants arising from the conduct of the 
research is provided by the NHS indemnity scheme or through professional indemnity.  
 
Both the research team and the Sponsor are responsible for: 
• 
The trial design 
• 
The trial conduct 
• 
Data analysis and interpretation 
• 
Manuscript writing 
• 
Dissemination of results 
 
v. 
Trial Management Group 
 
This is a small-scale study which will only include a Trial Management Group (TMG). The 
TMG will comprise of the PI, the Study Doctor and all Co-Investigators. The Sponsor will 
have no representation on the TMG but will be kept updated of progress. 
 
vi. 
Expertise and protocol contributions 
 
Dr Simon Nichols is a senior research fellow in clinical exercise physiology with expertise in 
conducting exercise-based cardiovascular rehabilitation trials in clinical populations. Dr 
Nichols is also the scientific chair for the British Association for Cardiovascular Prevention 
and Rehabilitation and the academic lead for physiology at the Advanced Wellbeing 
Research Centre at SHU. In addition, Dr Nichols is the co-principal investigator for the 
ongoing ESCAPE trial (STH20750) which is a proof of concept study investigating the safety 
and feasibility of a single bout of aerobic exercise during the acute phase of stroke. Dr 
Nichols has provided strategic guidance on the design and conduct of this research and will 
be the Principal Investigator for this trial. 
 

 
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Dr Ali Ali is a consultant physician specialising in stroke and geriatrics with extensive 
experience in recruiting patients to clinical trials. Dr Ali is also a senior honorary lecturer at 
the University of Sheffield and the research lead for the Integrated Geriatric and Stroke 
Medicine Directorate at STH NHS Foundation Trust. In addition, Dr Ali is the co-principal 
investigator and study doctor for the ESCAPE trial (STH20750). Dr Ali has provided clinical 
expertise and guidance on logistical and practical aspects of conducting the research at The 
Royal Hallamshire Hospital. Dr Ali will oversee the medical safety aspects of this trial.  
 
Dr Tom Maden-Wilkinson is a senior research fellow in clinical exercise physiology 
specialising in neuromuscular physiology and resistance training interventions to promote 
healthy ageing. Dr Maden-Wilkinson is the academic lead for imaging at the Advanced 
Wellbeing Research Centre at SHU. In addition, Dr Maden-Wilkinson is a co-investigator for 
the ESCAPE trial (STH20750). Dr Maden-Wilkinson has provided strategic guidance on the 
design and conduct of this research. 
 
Dr Helen Speake is a research fellow in exercise psychology specialising in user-centred 
design and participatory approaches to physical activity interventions. In addition, Dr Speake 
is a co-investigator for the ESCAPE trial (STH20750). Dr Speake has provided expertise on 
the design and conduct of this research, particularly patient and public involvement (PPI) 
events and qualitative evaluation of the exercise intervention. 
 
Mr Nikolaus Kudiersky is undertaking a PhD in clinical exercise physiology. Mr Kudiersky is 
a recipient of the SHU Vice Chancellor’s PhD Scholarship and has a research focus on 
exercise-based rehabilitation for clinical populations. Mr Kudiersky is a co-investigator for the 
ESCAPE trial (STH20750) and provides technical support to the RICFAST trial (STH19508)   
where his role is to conduct cardiopulmonary exercise tests for people affected by stroke (>6 
weeks post-stroke). 
 
vii. 
Patient and public contributions 
 
We have facilitated three PPI events which were used to gather feedback from people 
affected by stroke, and healthcare practitioners. For the first two PPI events, the topic of 
interest was the acceptability of our proposed exercise protocol and overall research design. 
Adjustments to the research protocol have been made based on feedback from the events 
(see ATAS - Patient and Public Involvement. January 2020). In response to a suggestion at 
this PPI event, we created an aphasia-friendly participant information sheet (ATAS - 
Aphasia-Friendly Participant Information Sheet. Version 2. 25.08.2020) using the Stroke 

 
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Association guidelines for accessible information. This document has been reviewed by Ms 
Jenni Crisp (Speech and Language Therapist, and Patient and Public Involvement Research 
Coordinator for Integrated Stroke and Geriatric Medicine, Sheffield) who has stated that the 
document is well-designed and provides sufficient information for individuals with aphasia to 
make an informed decision. 
 
In October 2020, we hosted an online PPI event which was attended people affected by 
stroke and aphasia, and Ms Jenni Crisp. The purpose of this event was to review the style 
and content of visual aids that we intend to use to facilitate participant engagement in the 
research. These visual aids have been designed using the Stroke Association guidelines for 
accessible information. The PPI feedback was generally positive, and some minor 
amendments were made based on the PPI panel’s suggestions (Aphasia-Friendly Visual 
Aids. V1 – 23.10.2020). 
 
We will deliver a final PPI event after the data collection period. The purpose of this event is 
to seek the support of study participants and the wider stroke population to determine the 
most appropriate ways to translate and disseminate our findings to people affected by 
stroke. This will be held at a community venue with accessible parking and facilities for 
people with disabilities. Travel expenses will be paid to PPI participants for this event. 
 
 
viii. 
Keywords 
 
ATAS, acute ischaemic stroke, aerobic exercise, feasibility, stroke rehabilitation. 
 
1.  Main research question 
 
Is a full-scale randomised controlled trial (RCT) (to test the hypothesis that aerobic exercise 
training initiated in the acute phase of stroke leads to better clinical outcomes compared to 
standard care) feasible? 
 
2. Abstract 
 
Ischaemic stroke is a leading cause of death and long-term disability which affects over 
100,000 people per year in the UK. The condition involves the blockage of a cerebral blood 
vessel which restricts blood supply to part of the brain and results in brain tissue death. 

 
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Despite major advances in stroke care in recent decades, over half of stroke survivors suffer 
with a long-term disability and have a reduced quality of life. This poses a major burden on 
stroke survivors and their support network, as well as health and social care services. Early-
initiated aerobic exercise training is a promising, novel intervention which may enhance 
recovery from stroke and thereby improve stroke survivors’ level of independence and 
quality of life. 
 
The purpose of this study is to determine whether it is feasible to conduct a RCT to test the 
hypothesis that aerobic exercise training initiated in the acute phase of ischaemic stroke (1-7 
days post-stroke) results in better clinical outcomes than standard care alone. The proposed 
mode of aerobic exercise is power-assisted cycling which enables people with hemiplegia or 
hemiparesis to exercise whilst remaining in their hospital bed. The study will focus on 
feasibility outcomes including recruitment, safety and acceptability. Exploratory outcomes 
will also be measured to advance mechanistic knowledge of the intervention and to identify 
suitable outcome measures for a full-scale clinical trial.  
 
3. Background  
 
Stroke is the primary cause of long-term disability worldwide (1). It is estimated that 50-65% 
of stroke survivors live with a long-term disability or depend on a caregiver (2,3). The 
emotional impact of stroke is also profound, with approximately 30% of stroke survivors 
living with depression (4). The total economic burden of stroke in the UK is £26 billion per 
year, and this figure is estimated to rise to £75 billion over the next 20 years due to 
improvements in stroke survival rates and an ageing population (5). 85% of stroke events 
are diagnosed as ischaemic stroke (6) which is defined as an episode of neurological 
dysfunction lasting longer than 24 hours, attributed to vascular occlusion (7). Following 
ischaemic stroke, a complex cascade of pathological events occurs. Briefly, depleted energy 
stores lead to ionic imbalance, excitotoxicity, oxidative stress, inflammation, blood brain 
barrier dysfunction, oedema and ultimately, infarction of the cerebral parenchyma (8). The 
extent of cell death and stroke-induced disability is dependent on the volume, location and 
duration of cerebral ischaemia (9). Surrounding the infarct core is a region of hypoperfused 
but potentially salvageable tissue called the ischaemic penumbra which is estimated to be 
viable for 24-48 hours post-stroke (10). The fate of the ischaemic penumbra is dependent on 
the speed of reperfusion relative to stroke onset, and the residual blood flow supplied by 
collateral blood vessels (11–13). In addition, after the initial ischaemic insult, a delayed 
cascade of pathological events occurs including vasogenic oedema, inflammation and 
programmed cell death. These events may lead to secondary infarct expansion up until ~4 

 
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days post-stroke (14,15). Currently, there are no medical treatments that mitigate delayed 
lesion expansion (9,16–18). Available treatment options are limited to reperfusion therapy 
(intravenous thrombolysis or mechanical thrombectomy) which can only be administered 
during a short time window after stroke (19). Further, 90% of stroke patients do not receive 
reperfusion therapy due to arriving at hospital after the licensed treatment timeframe, 
contraindications (e.g. high risk of bleeding), or lack of service provision (re: thrombectomy) 
(20,21). In addition, reperfusion therapy is not always successful and can exacerbate 
inflammation and oedema, inducing secondary cell death and possibly haemorrhagic 
transformation (22,23). As the incidence of stroke continues to rise, there is an urgent need 
to develop innovative treatments that enhance brain repair processes post-stroke and 
thereby reduce stroke-induced disability. Emerging evidence suggests that aerobic exercise 
training initiated in the acute phase of stroke (1-7 days post-stroke) may enhance brain 
repair, mitigate neurological deficit and augment neuroplasticity. However, this line of 
evidence is limited to rodent models of stroke. Research is required to attempt to translate 
these promising findings to the clinical setting (24–27).  
 
4. Rationale 
 
4.1. Acute aerobic exercise: proposed mechanisms  
 
Aerobic exercise induces a variety of neurovascular stimuli which interact with reparative 
processes post-stroke. Two important mediating factors are neurotrophin concentration and 
cerebral blood flow (CBF). Mature brain-derived neurotrophic factor (mBDNF) is a 
neurotrophin which promotes neural cell survival (i.e. neuroprotection), the growth of new 
neurons (i.e. neurogenesis) and structural and functional neural adaptations in response to 
injury and environmental stimuli (i.e. neuroplasticity) (28). mBDNF is produced and stored in 
central and peripheral tissues. Its production is increased in response to neurological injury, 
neuronal activity and aerobic exercise (29). At the onset of aerobic exercise, activated 
cerebral neurons rapidly depolarise and release mBDNF from synaptic terminals. After 
which, mBDNF may exert its positive effects on local neurovascular tissues (29). The 
heightened metabolic rate of active cerebral neurons requires an increased supply of oxygen 
and glucose. Local blood vessels respond to this metabolic perturbation by increasing CBF 
to active regions in a process known as neurovascular coupling (30). In addition, aerobic 
exercise increases the metabolic rate of skeletal muscles which increases carbon dioxide 
(CO2) production, blood pressure and cardiac output. Collectively, these integrated 
mechanisms contribute to a 10-30% increase in CBF during moderate-intensity exercise 
(30). Interestingly, just 20 minutes of moderate-intensity aerobic exercise has been shown to 

 
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increase hippocampal blood flow by 10-12% for at least 65 minutes post-exercise in healthy 
individuals (31). The hippocampus plays a key role in the growth of new neurons, memory 
formation and learning (32). These processes are moderated by the binding of mBDNF to its 
receptor, tropomyosin-related kinase B, which is abundantly expressed in the hippocampus 
(33,34). Increased availability of mBDNF within the hippocampus in response to aerobic 
exercise may therefore promote neurological recovery. In addition, increased blood flow to 
metabolically active tissues exerts shear stress on the vascular endothelium (29). 
Endothelial shear stress stimulates the bidirectional release of mBDNF from endothelial 
cells; mBDNF can be secreted into interstitial fluid via the basal membrane, where it may 
interact with astrocytes and neurons, or can be secreted from the luminal membrane into the 
blood (35). Platelets are the primary storage site of mBDNF in the blood, accounting for 99% 
of the blood-borne mBDNF pool (29,36). During aerobic exercise, sympathetic activation of 
the spleen leads to thrombocytosis which transiently augments the circulating pool of 
mBDNF (29,37).  
 
In summary, during moderate-intensity aerobic exercise, interconnected central and 
peripheral stimuli lead to a heightened production, secretion and transport of mBDNF. 
Increased availability of mBDNF in the brain after stroke may enhance neurological 
recovery, particularly during the acute phase when reparative processes are upregulated.  
 
4.2. Aerobic exercise training during acute stroke: pre-clinical evidence overview 
 
The timing of aerobic exercise training initiation relative to stroke onset is an important 
variable. In the first 24 hours after stroke, most cell death and neurological deficit occurs. 
This critical period is known as the hyperacute phase (38). Pre-clinical evidence suggests 
that undertaking aerobic exercise training in the hyperacute phase of stroke amplifies 
cellular stress which exacerbates cerebral injury and neurological deficit (39–41). During the 
subsequent acute phase (1 to 7 days post-stroke), growth-promoting genes are 
spontaneously upregulated which elicit neurogenesis, axonal growth, dendritic branching 
and synaptogenesis (42,43). During this transient window of heightened neuroplasticity, the 
nervous system is highly amenable to environmental stimuli (e.g. rehabilitation). Delaying 
rehabilitation beyond this sensitive period (e.g. by 14 or 30 days) impairs functional recovery 
and blunts neural reorganisation (43). 
 
 
 
 

 
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Figure 1. Framework depicting key post-stroke phases and temporally related biological 
processes.  
 
Pre-clinical studies demonstrate that aerobic exercise training initiated in the acute phase of 
stroke augments neuroplasticity, evidenced by enhanced structural reorganisation of 
neuronal networks (e.g. dendritic branching and synaptogenesis) and elevations in 
biomarkers of neuroplasticity such as mBDNF (25). In rodent models of ischaemic stroke, 
the optimal exercise parameters which promote neuroplasticity are: 30 minutes of moderate-
intensity aerobic exercise per day, initiated 3 to 7 days post-stroke (25). In addition, aerobic 
exercise training initiated in the acute phase of stroke may induce neuroprotective effects. 
Aerobic exercise training interventions that start 24 to 48 hours after stroke have been 
shown to reduce biomarkers of inflammation, oxidative stress and cell death, promote 
angiogenesis and reduce lesion volume (24). Neuroprotective effects were most commonly 
found with interventions that started in the early acute phase (24 hours vs. 3 to 7 days) and 
were carried out at low to moderate intensity for 20 to 30 minutes (24). In light of the pre-
clinical evidence, it is plausible that a training intervention consisting of a daily 20 to 30 
minute bout of low- to moderate-intensity aerobic exercise for 5 days, initiated 1 to 7 days 
after stroke, may have neuroprotective and neuroplasticity-promoting effects in the clinical 
stroke population.  
 
4.3. Aerobic exercise training during acute stroke: clinical evidence overview 
 
To our knowledge, there is only one clinical study (44) that has investigated the use of 
aerobic exercise training initiated within the acute phase of stroke. The purpose of this study 
was to assess the feasibility of a task-specific walking exercise training programme, and to 
determine if participants could attain a sufficient exercise intensity to improve 
cardiorespiratory fitness. Of note, this study did not investigate mechanisms related to 
Adapted from Bernhardt et al. (2017). 

 
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neuroprotection or neuroplasticity. Strømmen et al., (44) recruited 20 acute stroke patients 
(41.5± 14 h post-stroke; mild to no disability) and implemented a 5-day intervention 
consisting of twice-daily 30-minute bouts of treadmill walking at a moderate exercise 
intensity (50% of heart rate reserve [HRR]) (45). Standing and sitting rest breaks were 
permitted as required. More than half of participants experienced at least 1 adverse event 
(AE) during exercise. Dizziness was the most frequent AE, occurring in 8.5% (19/224) of all 
exercise sessions, and 4 sessions ended prematurely due to dizziness. In addition, although 
not reported as an adverse event, 8 sessions were cancelled due to tiredness (5 
participants) and 28 sessions finished early due to exhaustion (number of participants not 
reported). Lastly, the target exercise intensity was only attained in 31% of sessions, and 8 
participants (40%) did not achieve the target exercise intensity in any exercise session. The 
authors attributed the low exercise intensity to lower limb motor deficit which limited step 
frequency. This suggests that walking may be an unsuitable mode of aerobic exercise 
training during the acute phase of stroke recovery. No serious adverse events (SAEs) (e.g. 
neurological deterioration) occurred in the 30-day follow-up period therefore the authors 
concluded that a 14.7% AE rate was acceptable (33 AEs in 224 exercise sessions). As this 
was a feasibility trial, clinical outcomes were not explored. The occurrence of dizziness 
suggests that frequent and prolonged upright standing and walking may induce orthostatic 
stress which could be detrimental, especially during the acute phase of stroke when blood-
brain barrier function is impaired (46). Indeed, standing upright has been shown to reduce 
CBF velocity by 13% relative to a supine position in chronic stroke (47). The landmark 
international AVERT trial found that very early (first mobilisation at a median of 18.5 hours 
post-stroke) and more frequent (3 additional bouts per day) mobilisation (out-of-bed sitting, 
standing or walking) was associated with a poorer functional outcome at 3 months post-
stroke compared to usual care (first mobilisation at a median of 22.4 hours post-stroke). The 
physiological mechanisms were not explored in the AVERT trial, but it is plausible that 
orthostatic stress was a contributing factor to the negative outcome (47,48).  
 
4.4. Aerobic exercise in clinical practice 
 
UK stroke rehabilitation guidelines recommend that walking-orientated activities should have 
a cardiorespiratory focus (49). In clinical practice, walking is undertaken at low intensities for 
very short periods of time. For example, Prajapati et al., (50) reported that in subacute stroke 
patients (mean 32 days post-stroke), over 80% of walking bouts were less than 1 minute 
long and mean walking intensity was 20% of HRR. Polese et al., (51) reported similar 
findings in chronic stroke survivors (mean 26 months post-stroke), where basic and 
advanced walking activities elicited intensities of 26% and 32% of HRR, respectively. The 
only study which has reported inpatient walking activity during the acute phase of stroke 

 
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found that elderly patients spend less than 1 minute per day walking (52) and time spent 
inactive was positively correlated with stroke severity (HR not reported). During the first 
week of stroke ~70% of patients have a lower limb motor deficit (53) and ~60% are unable to 
walk or require walking assistance (54,55). A more accessible and tolerable mode of aerobic 
exercise may therefore be necessary to achieve a cardiorespiratory stimulus of sufficient 
intensity (moderate) and duration (20 to 30 minutes) to elicit elevations in CBF and mBDNF. 
 
4.5. Accessibility of aerobic exercise 
 
Findings from patient and practitioner surveys (56,57) and our PPI events highlight that 
physical disability, lack of appropriate exercise equipment and fear of falling are key barriers 
to engagement in aerobic exercise during acute stroke. These barriers may exclude patients 
who have the most to gain from participating in aerobic exercise training. We will utilise a 
bedside cycle ergometer with a power assistance function (Figure 2; Letto 2,  Medimotion, 
Germany). This will enable participants to cycle even if they have hemiplegia or hemiparesis, 
without needing to be transferred out of their bed. Using a bedside cycle ergometer 
eliminates the risk of falling and enables people with lower limb motor deficits to participate 
in sustained aerobic exercise. Another benefit of using a bedside cycle ergometer is that 
participants exercise in a semi-recumbent position. In contrast to walking which may induce 
orthostatic stress (47), moderate-intensity semi-recumbent cycling is likely to preserve or 
increase cerebral perfusion (30). Our preliminary (ongoing) work supports this hypothesis; 
we have shown that in acute stroke patients (n=4), a single 30-minute bout of low- to 
moderate-intensity aerobic exercise is safe and tolerable, and increases CBF velocity by 9% 
above resting levels. We will build on this work by assessing the feasibility of an aerobic 
exercise training intervention versus standard care in the acute phase of stroke. 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. A bed-side power-assisted cycle ergometer (Medimotion, Letto 2). 

 
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5. Aims and objectives 
 
Aim 1: 
To assess the feasibility of conducting a RCT to assess the intervention. 
Objectives: 
 
1a)  
Assess the recruitment/consent and dropout rates 
1b) 
Assess the safety of the intervention via SAEs and AEs 
1c) 
Assess the completeness of planned data collection 
 
 
Aim 2:  
To assess the acceptability and feasibility of the intervention. 
Objectives: 
 
2a) 
Determine the retrospective acceptability of the intervention from the 
participant perspective using qualitative interviews and Likert scales. 
2b) 
Determine the retrospective acceptability of the intervention from the 
perspective of healthcare practitioners using qualitative interviews. 
2c) 
Determine the intervention fidelity by assessing the extent to which 
participants complete the prescribed exercise components (e.g. 
exercise intensity, duration and frequency). 
 
Aim 3:  
To develop mechanistic knowledge of the intervention. 
Objective: 
 
3a) 
Measure the acute physiological response to the intervention including 
CBF velocity and mBDNF. 
 
Aim 4:  
To identify potential primary outcomes for a subsequent definitive RCT. 
Objective:  
4a)  
Estimate the effect signal for potential primary outcome measures. 
The effect signal reflects the effectiveness of the intervention 
(difference between means of the groups) and the 'noise' (inter-
individual variability) in the measurement (i.e. precision of the 
measure) and will inform the selection of primary outcome for a 
subsequent definitive RCT. 
 
 
 
 
 

 
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6. Study overview 
 
6.1. Study design 
 
A phase II, single-centre, single-blinded, two-arm, parallel group, randomised, controlled 
feasibility trial. 
 
6.2. Study setting 
 
The study will be conducted at The Royal Hallamshire Hospital (RHH), Beech Hill 
Rehabilitation Unit (BHRU) and the Advanced Wellbeing Research Centre (AWRC), 
Sheffield. Most study activity (screening and intervention) will take place on the hyper acute 
stroke unit (HASU), the acute stroke unit (ASU) or the neurology day care unit at RHH. 
Follow-up visits will be conducted at either the RHH, BHRU or the AWRC. 
 
6.3. Success criteria 
 
Progression to a definitive trial will be considered if the following a priori success criteria are 
met: 
 
• 
Recruitment rate: ≥2 participants per month (30 participants recruited in 18 months) 
• 
Safety - The following traffic light-style system is proposed: 
o Red:  >10 adverse events related to the intervention – do not proceed. 
o Amber: 5-10 adverse events related to the intervention – review and revise 
protocol. 
o Green: <5 adverse events related to the intervention – proceed. 
• 
Acceptability: average comfort score > 3/5 Likert scale (1= very uncomfortable to      
5= very comfortable). 
• 
Completeness of data: >80% of planned measurements recorded. 
• 
Identification of an appropriate outcome measure. 
 
 
 
 
 
 
 
 

 
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6.4. Study flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. Recruitment 
 
Eligibility screening  
Informed consent 
Randomisation 
Excluded if ineligible. 
Study ends. 
Declines participation. 
Study ends. 
24-72h 
post-
stroke 
+5 
days 
+2 
weeks 
+3 
months 
Serious 
adverse event 
related to 
intervention, 
 or dropout.  
Study ends. 
Data analysis and 
study write-up 
Research 
dissemination 
+1 day 
Control group 
Baseline assessments 
Usual care 
Follow-up 
assessments 
Follow-up 
assessments 
Follow-up 
assessments 
Intervention group 
Baseline assessments 
Aerobic exercise training  
& usual care 
Follow-up  
assessments 
Follow-up  
assessments 
Follow-up  
assessments 
21 
month 
trial 
 
(n=30) 
9-12 
months 
Participant 
timeline 
Trial 
timeline 
Figure 3. Study flow chart 

 
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7.1. Patient throughput and planned recruitment 
 
According to NHS England figures, RHH HASU will receive approximately n=1335 stroke 
patient admissions in 2019/20 (58). 85% of these patients will have had an ischaemic stroke 
(6), thus, ~1135 ischaemic stroke survivors will potentially be eligible for our study per year 
(n=1700 in 18 months). A systematic review of recruitment rates in stroke rehabilitation trials 
suggests that 1.5 to 2 participants per month is a realistic target for a single site (59); hence, 
our recruitment target of 30 patients over 18 months.  
 
7.2. Recruitment strategy 
 
The Study Doctor will identify eligible patients located on the HASU, the ASU and the 
neurology day care unit. Eligibility will be determined in accordance with the inclusion and 
exclusion criteria. Daily ward rounds will be the primary means of identifying eligible patients.  
Once identified, the Study Doctor and an Investigator will greet eligible patients and inform 
them about the study. Patients will be informed about the potential risks, benefits and burden 
of participating, and will be made aware of the randomised group allocation procedure. 
Patients will be provided with a participant information sheet and will be politely asked to 
contemplate the information and make a decision within 48 hours of the initial discussion. 
This is due to the time-sensitive nature of the research. An aphasia-friendly version of the 
participant information sheet will be made available. A notepad and pen will be provided for 
patients with dysarthria (speech disorder). Where possible, family members and other 
supporting individuals will be informed about the study. At a later time point, an Investigator 
and the Study Doctor will revisit the patient at a mutually convenient time to answer any 
questions the patient, family member or supporting individual may have about the study. 
Patients will then be asked if they would like to participate. If they are willing to participate, 
informed consent will be taken. If the patient is undecided, the Investigator and the Study 
Doctor will return at a later time point (<48hrs of initial discussion) and repeat the process. 
 
7.3. Sample size 
 
A minimum of 24 participants (12 per arm) will be recruited. 12 has been recommended as a 
minimum number of participants per arm to be recruited for a clinical trial where there is no 
prior information to guide sample size (60). This figure is suggested to represent the lower 
threshold required to estimate the standard deviation of measures with adequate precision 
(60). Adjusting for a predicted 20% attrition rate, the target sample size is 30. 
 

 
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7.4. Inclusion criteria 
 
• 
Adult (age >18 years) patients diagnosed with acute ischaemic stroke 1-7 days 
previously. 
• 
Medically stable, assessed by a stroke physician. 
• 
Sufficient English language comprehension and cognitive ability to understand the 
study protocol, follow instructions, complete questionnaires and give informed 
consent. 
• 
Ability to mobilise lower body limbs in a cyclical manner (at least one leg). 
 
7.5. Exclusion criteria  
 
The following criteria are adapted from (45,61,62). 
 
• 
Haemorrhagic stroke. 
• 
<1 day or >7 days after onset of stroke symptoms. 
• 
Clinically unstable, assessed by stroke physician. 
• 
Disability preventing unipedal cycling. 
• 
New York Heart Failure Classification stage III/IV. 
• 
Terminal illness (life expectancy <6 months). 
• 
Resting blood pressure >180/110 mmHg. 
• 
Uncontrolled arrhythmia causing symptoms or haemodynamic compromise. 
• 
Unstable angina. 
• 
Uncontrolled diabetes mellitus. 
• 
Acute deep vein thrombosis, pulmonary embolism or pulmonary infection. 
• 
Already participating in a clinical research trial. 
• 
Pain during mobilisation of lower limbs. 
• 
Lower-limb spasticity or contracture which impairs ability to cycle. 
 
7.6. Patient screening 
 
The Study Doctor will review patients’ clinical data to determine eligibility in accordance with 
the inclusion and exclusion criteria. Patients will be screened for absolute and relative 
contraindications to aerobic exercise prior to participation (Table 1, section 8.1). Absolute 
contraindications will preclude individuals from undertaking aerobic exercise. The Study 
Doctor will use clinical judgment to determine if individuals with relative contraindications to 
aerobic exercise can participate. Established exercise termination criteria (Table 2, section 
8.2) will be used to minimise risk of harm during aerobic exercise.  

 
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The following routine medical examinations and clinical information will be used to determine 
eligibility and stratification: 
 
• 
Time and date of stroke onset. 
• 
Stroke treatments initiated. 
• 
Stroke severity. 
• 
Medication use. 
• 
Electrocardiography results. 
• 
Blood test results. 
• 
Neuroimaging results.  
• 
Carotid ultrasound imaging results. 
• 
Comorbidities. 
 
7.7. Consent and withdrawal 
 
Participants will only be enrolled in the study if they have capacity to understand the 
participant information sheet and give informed consent. An aphasia-friendly participant 
information sheet will be made available. All written material given to patients will have prior 
approval from a local NHS Research Ethics Committee (REC) and will comply with GCP, 
local regulatory requirements and legal requirements. Where participants have the capacity 
to understand the study and are willing to participate but cannot write due to motor 
impairment, a family member will be asked to sign on the patient’s behalf. All research team 
members involved in recruitment have received training in communication with people that 
have communication difficulties (e.g. aphasia). Participants will be informed that their 
participation is voluntary and that they may withdraw from the study at any time without 
giving a reason and without it affecting their clinical care or legal rights. Any data provided to 
that point will be used unless the patient requests otherwise. If the patient requests to have 
their data withdrawn, all data relating to that participant up until anonymisation of the final 
dataset will be destroyed. 
 
7.8. Randomisation  
 
A web-based permuted block randomisation procedure (sealedenvelope.com) will be used 
to allocate participants into one of the study arms: 1) usual care alone; 2) aerobic exercise 
training plus usual care. Participants will be stratified using the National Institutes of Health 
Stroke Scale (NIHSS): mild to moderate (0-15) and moderate to severe (>15) measured 
after reperfusion therapy or at a similar timepoint if not eligible for reperfusion therapy. Block 

 
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sizes of either 4 or 6 will be randomly chosen and block size will be masked from research 
team members involved in patient-facing research activities. An independent research team 
member will be responsible for the block randomisation procedure. They will be notified via 
email with participant ID numbers and a corresponding NIHSS score using a remote web-
based system. The independent research team member will publish the group allocation 
which will be remotely accessible only to authorised research team members.  
 
7.9. Blinding 
  
It is not possible to blind participants or on-site research team members to group allocation. 
Statistical analyses will be conducted by an independent research team member who is 
blinded to group allocation. 
 
7.10. 
Payment 
 
Reasonable travel expenses will be provided for follow-up appointments located at the 
AWRC or BHRU. This will cost approximately £600 (30 x £20) and will be funded by a PhD 
research budget. 
 
7.11. 
Physical accessibility 
 
 
Participants will be invited to attend routine follow-up clinics with Dr Ali at 2 weeks and 3 
months post-stroke. These will take place at the RHH, AWRC or BHRU. The location will 
depend upon where Dr Ali’s clinics are scheduled. The RHH, AWRC and BHRU are 
accessible for people with physical impairments; each building has ramps and elevators. 
The AWRC and BHRU have car parking facilities which are free of charge. Parking spaces 
will be reserved for participants and research team members attending the AWRC and 
BHRU. The RHH has a large pay-and-display car park. Each building has emergency 
evacuation strategies for people with physical disabilities. 
 
8. Safety  
 
8.1. Contraindications to aerobic exercise 
 
Patients’ medical notes will be reviewed by the Study Doctor to identify absolute and relative 
contraindications to aerobic exercise. Absolute contraindications are conditions or situations 
in which an intervention/procedure should not be performed due to a disproportionately high 

 
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risk of harm. Patients with absolute contraindications will be excluded from the study. 
Relative contraindications are conditions or situations in which an intervention/procedure 
should be used with caution if the benefits outweigh the risks (determined by the Study 
Doctor).  
 
Table 1. Contraindications to aerobic exercise.  
 
Absolute contraindications 
 
Relative contraindications 
Acute myocardial infarction (within 3–5 days)  
 
Left main coronary stenosis or its 
equivalent  
Resting ST segment displacement (>2 mm) 
 
Moderate stenotic valvular heart 
disease  
Significant aortic stenosis (aortic valve area <1.0 cm2) 
Tachyarrhythmia or bradyarrhythmia 
Uncontrolled sinus tachycardia (HR >120 bpm) 
High-degree atrioventricular block  
Third degree (complete) atrioventricular block without 
pacemaker 
Hypertrophic cardiomyopathy  
Active endocarditis  
Significant pulmonary hypertension  
Unstable angina  
Electrolyte abnormalities  
Uncontrolled hypertension:  
resting systolic blood pressure (SBP)  >180mmHg, or resting 
diastolic blood pressure (DBP) >110mmHg 
Use of insulin or insulin secretagogues 
Orthostatic blood pressure drop of >20 mmHg with symptoms 
Orthopaedic impairment 
Syncope  
Advanced or complicated pregnancy  
Uncontrolled arrhythmias causing symptoms or 
haemodynamic compromise  
Acute myocarditis or pericarditis  
 
Uncontrolled heart failure  
 
Severe grade 3 rejection (cardiac transplantation recipients) 
 
Acute pulmonary embolus or pulmonary infarction  
 
Thrombosis of lower extremities  
 
Suspected dissecting aneurysm  
 
Uncontrolled asthma  
 
Pulmonary oedema  
  
Room air desaturation at rest <85%  
  
Respiratory failure  
  
Acute noncardiopulmonary disorder that may affect exercise 
performance or be aggravated by exercise (i.e. infection, 
renal failure, thyrotoxicosis)  
  
Uncontrolled diabetes mellitus 
 
Other metabolic conditions, e.g. acute thyroiditis, 
hypokalaemia, hyperkalaemia or hypovolaemia (until 
adequately treated) 
 
Acute systemic illness or fever 
 
Medically unstable 
 
Cognitive impairment leading to inability to cooperate  
Note. Table adapted from (43,59,60). 

 
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8.2. Aerobic exercise termination criteria 
 
Table 2. Aerobic exercise termination criteria.  
 
Termination criteria 
 
†CBF velocity 30% below baseline 
Chest pain suggestive of ischaemia 
Fall in systolic blood pressure >20 mmHg from the highest value during exercise 
>225 mmHg systolic blood pressure 
>130 mmHg diastolic blood pressure 
Hypotension (<100 mmHg systolic) 
Severe desaturation: SpO2 ⩽ 80% when accompanied by symptoms and signs of severe hypoxaemia 
Sudden pallor 
Loss of coordination 
Mental confusion 
Dizziness or faintness 
Signs of respiratory failure 
 
Note. Table adapted from (45,61,62); † = Study Doctor’s clinical judgement. 
 
8.3. Safety of aerobic exercise  
 
Low- to moderate-intensity aerobic exercise is considered to be safe for medically stable 
acute ischaemic stroke patients without contraindications (44,63). The only study which has 
conducted a moderate-intensity aerobic exercise training intervention (five days of twice-
daily, 30-min bouts of moderate-intensity walking exercise) reported no SAEs but occasional 
dizziness (8.5%; 19/224 sessions) and exhaustion (44). Exhaustion is not classed as an AE 
but is an important outcome when considering exercise tolerability; 24 out of 224 (10.7%) 
exercise sessions ended early as a result of exhaustion (9/20 participants). In addition, 
Kramer et al., (64) investigated the energy cost of two different 6-minute fitness 
assessments in acute stroke patients (median 4 days post-stroke; mild to moderate stroke; 
n=21). Ambulatory participants (n=14) performed a 6-minute walk test, whereas non-
ambulatory participants (n=7) completed a 6-minute sit-to-stand test. The median rating of 
perceived exertion (RPE) reported at the end of each test was 12/20 and 13/20 for the walk 
and sit-to-stand tests, respectively (both moderate intensity). No SAEs or AEs were 
reported, and only one participant was unable to complete the walk test due to fatigue. 
Furthermore, Johnson et al., (65) demonstrated the safety of a graded exercise test in acute 

 
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and subacute stroke patients (n=28, days post-stroke: median = 9; range = 5-11), although 
the authors did not specify the proportion of participants that were in the acute (1-7 days 
post-stroke) or early subacute phase of stroke (7-30 days post-stroke). One of the exercise 
test termination criteria was reaching 85% of age-predicted maximum heart rate (HRmax), 
which is classed as vigorous exercise intensity (45). Over half of the participants exceeded 
this upper heart rate threshold and no SAEs or AEs were observed. Lastly, in our preliminary 
work (ESCAPE trial; STH20750), 4 acute stroke patients successfully completed a single 30-
minute moderate-intensity exercise session (13/20 RPE) and there were no AEs or SAEs. 
Importantly, none of the aforementioned studies reported follow-up safety outcomes. We 
can confirm that there have been no SAEs or AEs related to aerobic exercise in the 3 
months following our investigation. In summary, there have been approximately 276 
reported bouts of aerobic exercise conducted in the acute phase of stroke, ranging from 6 to 
30 minutes in duration and from moderate to vigorous intensity. No SAEs have been 
reported, whereas the AE rate ranged from 0-14.7% (mean 12%). The higher frequency of 
AEs appears to be related to high exercise volume and the mode of exercise training (e.g. 
treadmill exercise twice per day for 5 days). 
 
In our proposed aerobic exercise training intervention, participants will exercise at a 
moderate intensity (40-59% HRR; 12-13/20 RPE). Moderate-intensity aerobic exercise elicits 
a transient increase in cerebral perfusion and neurotrophin concentration (39,59) which may 
contribute to improved recovery after stroke (24–26). Exercise duration will gradually 
increase from 10 minutes in the first session (day 1) to 30 minutes in the fifth session (day 5) 
(5-minute increment per day). Heart rate (HR) will be monitored continuously during exercise 
to ensure that moderate intensity is not exceeded. Heart rate reserve – the difference 
between resting HR and HRmax – represents the capacity for the HR to increase under 
stress. Measurement of HRmax is not appropriate due to the required vigorous exercise 
intensity. Instead, age-predicted HRmax will be calculated using the Inbar equation which 
estimates HRmax with greater accuracy than the commonly used formula of 220-age (66).  
 
Inbar equation: 205.8 - (0.685 x age). 
 
To adjust for use of beta-blocker medication, age-predicted HRmax will be reduced by 30 
beats (62). The following Karvonen method will be applied to determine the target exercise 
HR (67). Importantly, this will enable the identification of the upper limit of the moderate 
exercise intensity domain (60% HRR). 
 
Karvonen method example: target HR = [(HRmax – resting HR) x 60%] + resting heart rate. 
 

 
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Peripheral oxygen saturation and brachial blood pressure will also be measured throughout 
exercise and during the recovery period. The recovery phase will be of sufficient duration 
(~10 minutes; minimum 5 minutes) to allow physiological measures to return to near 
baseline levels. If any physiological measures fall outside of pre-determined ranges (see 
Table 2, section 8.2), or symptoms of clinical worsening arise, exercise will be terminated 
and a medical professional will be notified immediately.  
 
8.4. Risk management  
 
 
Cardiovascular risk 
 
Participation in aerobic exercise may increase the risk of cardiovascular complications such 
as cardiac ischaemia, arrythmia or hypotension. The use of an appropriate warm-up and 
cool-down will minimise these risks (62). Participants’ physiological response to exercise will 
be closely monitored during and after exercise. Exercise will be stopped if any adverse signs 
or symptoms occur (see table 2, section 8.2). The research team are experienced in the 
supervision of exercise and are trained in cardiopulmonary resuscitation.  
 
Musculoskeletal risk 
 
Participation in aerobic exercise may increase the risk of musculoskeletal injury such as a 
muscle strain. This risk will be minimised by conducting a graduated warm-up (45) and by 
following the cycle ergometer manufacturer guidelines regarding correct positioning of 
participants.  
 
Blood glucose regulation risk 
 
Aerobic exercise has insulin sensitising effects, therefore it is important to consider the use 
of blood glucose-regulating medication. The prevalence of diabetes mellitus in the acute 
ischaemic stroke population is 28% (95% CI 26-31%) (68). It is unclear what proportion of 
this population require insulin or insulin secretagogues. Where patients are receiving insulin 
or insulin secretagogues (relative contraindications), the Study Doctor will decide if the 
patient may participate in aerobic exercise at that particular time. To minimise the risk of 
exercise-induced hypoglycaemia, patients receiving insulin or insulin secretagogues will 
have their capillary blood glucose levels assessed before and after exercise (69). If blood 
glucose level is below 4mmol/L prior to exercise, the planned exercise session will be 

 
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31 
delayed until euglycemia is achieved. Only clinical staff will be responsible for the provision 
of medication and carbohydrate. 
 
8.4.1. Risk categorisation 
 
Taking into account the absence of reported SAEs and our risk management procedures, 
we believe that this intervention is low risk. However, there is a lack of reported long-term 
follow-up outcomes. Due to this uncertainty, we propose that this intervention should be 
categorised as type B, that is, somewhat higher than the risk of standard medical care. 
 
8.5. Risks and benefits to be communicated to patients (lay summary): 
 
8.5.1. Potential benefits of aerobic exercise training 
 
• 
Aerobic exercise training may help the brain recover from injury (neuroprotection). 
However, this has only been shown in animal studies. 
• 
Aerobic exercise training may help the nervous system adapt after injury and 
improve learning (neuroplasticity). However, this has only been shown in animal 
studies. 
• 
Aerobic exercise may help to slow down the loss of fitness, muscle size and muscle 
strength whilst in hospital.  
• 
Aerobic exercise training may improve mood. 
 
8.5.2. Risks of aerobic exercise training 
 
Previous studies have shown that aerobic exercise is safe for people to do in the first week 
after stroke. So far, 276 aerobic exercise bouts have been completed in the first week after 
stroke. 237 sessions (86%) involved walking, 32 sessions (12%) involved seated cycling or 
stepping, and 7 sessions (3%) involved sit-to-stand exercise. From these studies, we 
estimate that the risk of: 
 
• 
Cardiovascular, neurological, or musculoskeletal complications is less than 1%       
(no adverse events have happened so far). 
• 
Lower-limb pain is less than 2% (adverse events only happened in treadmill 
exercise). 

 
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32 
• 
Getting a blister or superficial wound on the foot is 1.1% (adverse events only 
happened in treadmill exercise. Cycling places less pressure on the feet than 
walking).  
• 
Dizziness is less than 7% (adverse events only happened in treadmill exercise which 
is possibly related to an upright head position. Cycling will be completed in bed with a 
reclined backrest). 
 
 
 
 
 
 
 
 
Figure 4. Pie charts displaying the risk of adverse events related to aerobic exercise. 

 
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33
9. Investigations 
 
Table 3. Schedule of investigations and outcome measures. Note: orange ticks indicate standard care. 
 
 
Study period 
 
Enrolment 
 
Allocation 
 
Post-allocation 
 
Post-stroke timeline 
24-72 h 
(study starts) 
≥48 h; 5-day intervention 
+1 day 
 
Follow-up 
 
+2 weeks 
 
+3 months 
(study ends) 
 
 
Study timeline 
t-1 
t0 
t1 
t2 
t3 
t4 
t5 
t6 
t7 
t8 
 
 
Group → 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
 
Eligibility screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age, sex, ethnicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time since stroke 
(hours) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stroke severity  
(NIHSS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular risk profile 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group allocation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thigh muscle morphology (ultrasound) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thigh accelerometer fitted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient physical activity levels (thigh 
accelerometer) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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34
 
 
Study period 
 
Enrolment 
 
Allocation 
 
Post-allocation 
 
Post-stroke timeline 
24-72 h 
(study starts) 
≥48 h; 5-day intervention 
+1 day 
 
Follow-up 
 
+2 weeks 
 
+3 months 
(study ends) 
 
 
Study timeline 
t-1 
t0 
t1 
t2 
t3 
t4 
t5 
t6 
t7 
t8 
 
 
Group → 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
Thigh accelerometer removed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical function                               
(SPPB, 10-m walk, handgrip strength) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activities of daily living (Barthel Index) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disability (mRS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute fatigue (RoFS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive function (MoCA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chronic fatigue (FSS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-morbid physical activity levels  
(GPAQ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anxiety and depression (GAD-7, PHQ-9) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Optimism (rLOT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health-related quality of life (EQ-5D) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exercise self-efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wrist accelerometer fitted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-discharge physical activity (wrist 
accelerometer returned) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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35
 
 
Study period 
 
Enrolment 
 
Allocation 
 
Post-allocation 
 
Post-stroke timeline 
24-72 h 
(study starts) 
≥48 h; 5-day intervention 
+1 day 
 
Follow-up 
 
+2 weeks 
 
+3 months 
(study ends) 
 
 
Study timeline 
t-1 
t0 
t1 
t2 
t3 
t4 
t5 
t6 
t7 
t8 
 
 
Group → 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
Post-discharge physical activity (GPAQ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resting cerebral blood flow velocity 
(transcranial Doppler ultrasound) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resting mature brain-derived neurotrophic 
factor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious/adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Length of stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualitative interviews   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aerobic exercise-specific investigations: 
 
 
Δ heart rate (telemetry or ECG) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Δ blood pressure (oscillometry) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Δ perceived exertion (RPE scale) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Δ oxygen saturation (pulse oximeter) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Δ cerebral blood flow velocity (transcranial 
Doppler ultrasound) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Δ mature brain-derived neurotrophic factor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Δ end-tidal CO2 and V̇ O2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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36 
9.1. Qualitative data  
 
 
One Co-Investigator (NK) will conduct semi-structured interviews with patients and 
healthcare professionals to assess the retrospective acceptability of the inpatient phase of 
the trial. If signs of emotional or cognitive issues or distress arise, the Study Doctor will be 
informed so that participants can be signposted to the appropriate services for longer term 
support if necessary. At the beginning of each interview participants will be assured that they 
can stop the interviews at any point should they become distressed. Further, participants will 
be able to withdraw their involvement in the study (including their transcribed interview data) 
at any point until anonymisation of the final data has occurred.  
 
All interviews will be audio-recorded and transcribed verbatim. A computer-assisted 
qualitative data analysis software package will be used to store, manage and code the 
interview transcripts. All transcripts will be checked for accuracy, with a sample being 
independently reviewed and coded by a Co-Investigator (HS). Interviews will be analysed 
inductively using thematic (framework) analysis, from a realist perspective (70). Briefly, 
framework analysis involves systematic management and mapping of textual data into a 
matrix consisting of rows (participants) and columns (labels/codes which describe relevant 
information/events such as behaviours, values, emotions etc.). The reduced textual data 
enables a comparison between data sets and facilitates the identification of themes across 
the data (70). A semantic approach will be used to identify themes, where the surface 
meaning of the data will interpreted, as opposed to a latent approach which finds deeper 
meanings from ‘between-the-lines’ (71). NK is trained in conducting semi-structured 
interviews and qualitative data analysis. HS has extensive experience in the field of 
qualitative research. 
 
The following definition of acceptability is used:  
 
“A multi-faceted construct that reflects the extent to which people delivering or receiving a 
healthcare intervention consider it to be appropriate, based on anticipated or experienced 
cognitive and emotional responses to the intervention” (72). 
 
9.1.1. Participant interviews 
 
At the point of group allocation, a sub-sample of participants from the intervention group 
(n=8) and the control group (n=8) will be randomly selected for interviews. Interviews will be 
held 1-3 days after completion of the intervention in a private clinical room (30-45 minutes). 

 
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37 
Using an intention-to-treat approach, individuals who drop out of the intervention will be 
asked to participate in an interview. Based on the positive feedback from our ongoing 
preliminary trial and our PPI events, we anticipate a low dropout rate. For this reason, all 
participants whom drop out will be asked to partake in an interview (non-randomly) to ensure 
that key information is not missed. 
 
Participant interviews will focus on: 
 
• 
Exercise equipment: comfort and ease of use. 
• 
Exercise components: mode, duration, intensity and frequency. 
• 
Perceived effectiveness of the intervention. 
• 
Intervention-related burden on participant. 
• 
Exercise self-efficacy, motivation and optimism. 
• 
Acceptability of the study procedures. 
 
At the 3-month follow-up appointment, a brief semi-structured interview (15-20 minutes) will 
be conducted with the same participants that were interviewed during their hospital stay 
(n=16) to gather information regarding the impact of hospital-based stroke rehabilitation on 
lasting exercise-related self-efficacy, motivation, optimism and emotional wellbeing.  
 
9.1.2. Healthcare professional interviews 
 
After the final participant has completed the trial, we aim to interview healthcare 
professionals to understand the retrospective acceptability of the study procedures and what 
impact the research had on clinical practice. We will recruit a convenience sample of 3-5 
healthcare professionals. We aim to select a range of practitioners from different disciplines 
with different levels of seniority. Each interview is estimated to last for up to 30 minutes. 
Healthcare professional interviews will focus on: 
 
• 
Attitude towards the intervention. 
• 
Intervention-related burden on staff and participants. 
• 
Perceived effectiveness of the intervention. 
 
9.1.3. Minimising bias 
 
The same Co-Investigator (NK) will supervise the intervention and undertake subsequent 
interviews. To reduce bias in favour of the intervention, NK will emphasise the importance of 
interviewees giving well-rounded feedback including positive and negative aspects. NK will 

 
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38 
frame the interview as a critical exercise that will help future participants to have a positive 
experience. The interviewer will ask broad, exploratory questions which do not restrict 
participants’ potential responses. For example, instead of asking the participant: “Did the 
exercise improve your mood?”, an unbiased question would be “How did the exercise 
intervention make you feel? This could be positive or negative”.  
 
9.2. Justification of investigations and outcome measures 
 
The proposed study activities, investigations and outcome measures aim to achieve a 
balance between scientific rigour, practicality and patient burden. Where possible, routine 
measures will be utilised to prevent duplication of work and to reduce patient burden. We 
acknowledge that the timing of routine assessments may vary depending on staff workload 
and patients’ health. If relevant assessments are missed or significantly delayed, where 
appropriate, the research team will conduct them. Follow-up assessments will be conducted 
at a 3-month follow-up appointment with the Study Doctor.  
 
Table 4. Justification of investigations and outcome measures 
 
Domain 
 
Outcome measure 
 
Justification 
 
Demographic  
 
Age, sex and ethnicity 
 
Description of demographic data will improve the 
generalisability of this work and may help us to identify 
demographic trends which otherwise may be masked by 
inclusion within a larger, more diverse group. 
 
Diagnostic 
 
Time since stroke 
 
 
 
 
 
Stroke aetiology 
 
 
 
 
Careful attention must be paid to the timing of the 
intervention relative to stroke onset. Distinct biological 
events occur within the first week of stroke. Intervening too 
early may exacerbate health, whereas intervening too late may 
miss a ‘window of neuroplasticity’ (see section 4, Rationale). 
 
This research builds on promising findings from pre-clinical 
studies utilising rodent models of ischaemic stroke. The 
effects of aerobic exercise early after haemorrhagic stroke are 
less clear. Patients with haemorrhagic stroke will be therefore 
excluded from the study.  
 
 
 
Pharmacological 
 
Use of medications 
which modify  
haemodynamics and 
psychoemotional state 
 
It is important to know if medications are likely to affect other 
outcome measures. For example, beta-blockers lower heart 
rate and blood pressure. The recommended method of 
prescribing exercise intensity relies on the estimation of peak 

 
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39 
 
heart rate (62). Without knowledge of beta-blocker use, there 
would be uncertainty around what exercise intensity an 
individual is exercising at. Further, beta-blockers reduce resting 
heart rate which may cause side effects including fatigue and 
dizziness (73). This may adversely affect exercise 
performance, fatigue, mood, cognition and HRQoL.  
 
Disability  
 
 
The National Institutes 
of Health Stroke Scale 
(NIHSS) (74) 
 
 
 
 
 
Modified Rankin Scale 
(mRS) (75) 
 
The NIHSS is a clinical measure of neurological disability 
which is routinely used in stroke medicine. We will use baseline 
NIHSS score to stratify participants into two subgroups: 1) 
minor to moderate stroke (NIHSS: ≤15), and 2) moderate to 
severe stroke (NIHSS: >15). Stratification by NIHSS score will 
ensure that each study arm contains an even balance of 
participants from across the stroke severity spectrum.  
 
The mRS is a questionnaire-based measure of stroke-induced 
disability which is commonly used in stroke research. We will 
use the mRS to assess the trajectory of stroke recovery. Using 
the mRS will enable follow-on research to be included in meta-
analyses.  
 
*The mRS is routinely used in the STH NHS acute stroke 
service. 
 
 
Cardiovascular 
risk 
 
 
 
Body mass index, 
cholesterol/HDL ratio, 
systolic blood 
pressure, smoking 
status, demographics, 
comorbidities 
 
It is of interest to understand how baseline cardiovascular risk 
factors relate to the incidence of cardiovascular events (e.g. 
stroke recurrence) throughout the study (76).  
 
*Cardiovascular risk factors are routinely measured in clinical 
practice, therefore no additional assessments will be 
undertaken by the research team. 
 
Length of hospital 
stay 
 
Number of days spent 
in hospital 
 
Length of stay (LoS) is a key NHS quality indicator. Longer 
LoS is associated with poorer medical outcomes and greater 
financial costs (77). Aerobic exercise may influence stroke 
recovery trajectory and thereby LoS. 
 
Psychoemotional 
state 
 
Health-related 
quality of life 
 
Depression 
 
Anxiety 
 
 
 
 
 
 
EuroQol Quality of 
Life Index (EQ-5D) 
(78) 
 
Patient Health 
Questionnaire (PHQ-
9) (79) 
 
Generalised Anxiety 
Disorder (GAD-7) (80) 
 
 
 
Health-related quality of life (HRQoL) and mood can be 
adversely affected after stroke (4,81,82). Exercise interventions 
improve mood and HRQoL (81,83). Measuring EQ-5D, PHQ-9 
and GAD-7 will enable the assessment of the effects of the 
intervention on HRQoL and mood. 
 
*PHQ-9 and GAD-7 are the only routine psychoemotional 
assessments used in the STH NHS acute stroke service.  

 
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40 
 
Optimism 
 
 
Revised Life 
Orientation Test 
(rLOT) (84) 
 
A higher level of optimism is associated with lower levels of 
inflammation and better health outcomes across a number of 
health conditions (85). An optimistic outlook may mitigate 
inflammation and in turn contribute to a better recovery after 
stroke. It is of interest to understand how the level of optimism 
at baseline may contribute to health outcomes. In addition, it is 
of interest to assess how the intervention may alter optimism. 
*Optimism is not routinely measured in the STH NHS acute 
stroke service. 
 
Exercise self-
efficacy 
 
Short Self-Efficacy for 
Exercise scale (86) 
 
Self-efficacy plays an influential role in the adoption and 
maintenance of exercise behaviour in older adults (87). Those 
with higher levels of exercise self-efficacy are better equipped 
to overcome barriers to exercise compared to those with low 
self-efficacy. Initiating an aerobic exercise intervention during 
the early stage of stroke rehabilitation may enhance self-
efficacy and result in higher levels of participation in exercise. 
*Self-efficacy is not routinely measured in the STH NHS acute 
stroke service. 
 
 
Fatigue & 
perceived 
exertion 
 
Fatigue Severity Scale 
(FSS) (88) 
 
 
 
 
 
 
 
Rating of Fatigue 
Scale (RoFS) (89) 
 
 
 
 
 
Rating of perceived 
exertion (RPE) (90) 
 
Post-stroke fatigue is a common, debilitating complication of 
stroke (91). The management and prevention of post-stroke 
fatigue was ranked 6th in the top 10 research priorities relating 
to life after stroke (agreed by stroke survivors, caregivers, and 
health professionals)(92). There is limited evidence regarding 
the effects of exercise interventions on post-stroke fatigue (93). 
Measuring this outcome using the FSS will help develop the 
evidence base. 
 
The RoFS will enable us to understand transient (acute) 
fatigue as opposed to generalised chronic fatigue. This is 
relevant because a patient may partake in various therapies 
and assessments throughout each day (differing in intensity 
and duration) which may adversely affect a their performance 
during a subsequent therapy or assessment. 
 
RPE is a subjective measure of exercise difficulty, from the 
participant’s perspective. We will utilise the RPE scale to guide 
exercise workload during each exercise session.  
 
RoFS and RPE are not routinely used in the STH NHS acute 
stroke service. FSS, is routinely used. 
 
Cognitive 
function 
 
Montreal Cognitive 
Assessment (MoCA) 
(94) 
 
 
 
Improvement of post-stroke cognition was ranked 1st amongst 
the top 10 research priorities relating to life after stroke (92). 
Aerobic exercise has positive effects on cognitive function 
after stroke (95). The MoCA is a simple assessment which will 

 
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41 
 
 
 
 
 
help elucidate the impact of the intervention on cognitive 
function.  
 
*The MoCA is routinely used in the STH NHS acute stroke 
service. 
 
 
Quadricep muscle 
morphology  
 
Muscle ultrasound 
(96,97): 
 
Rectus femoris cross 
sectional area and 
muscle thickness. 
 
Vastus lateralis 
muscle thickness and 
angle of pennation. 
 
Acute stroke patients spend 98% of their time physically 
inactive (52). Sedentary behaviour during hospitalisation 
causes accelerated muscle atrophy. This increases the risk of 
sarcopenia, disability and stroke recurrence (98,99). This issue 
is particularly important in stroke where recovery of motor 
function is dependent on intensity of rehabilitation, and fitness 
level represents a ‘neurorehabilitation ceiling’ (26). In non-
ambulatory acute stroke patients, a single week of immobility 
leads to 12.8% and 9.3% reductions in quadricep muscle 
thickness in the paretic and non-paretic limbs, respectively 
(100). Aerobic exercise may mitigate muscle atrophy therefore 
measurement of muscle morphology is of interest. 
Hypoallergenic ultrasound gel and nitrile gloves will be used. If 
a patient has a known allergy to ultrasound gel, this test will be 
excluded. 
  
*Muscle ultrasound is not routinely used in the STH NHS acute 
stroke service. 
 
Physical activity  
 
Accelerometers  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Global Physical 
Activity Questionnaire 
(GPAQ) (101) 
 
 
Total physical activity (i.e. rehabilitation) dose moderates 
change in motor function and level of disability (102). We will 
use therapist medical notes to quantify usual care therapy 
dose. However, patients only spend a minor proportion of their 
time with therapists. We will quantify physical activity levels for 
the remaining portion of each day using a light-weight 
accelerometer. This will be secured to the anterior thigh of the 
non-affected limb using a hypoallergenic adhesive dressing 
(103). The ActivPAL thigh-based accelerometer differentiates 
sitting, standing and walking postures, which wrist-based 
accelerometers cannot do. The device will be fitted immediately 
after the baseline thigh muscle ultrasound measurement, and 
retrieved immediately before the post-intervention thigh muscle 
ultrasound measurement. Participants will then be given a 
wrist-based accelerometer to wear until their post-discharge 2-
week follow-up appointment. This will record daily step count. 
The reason for switching to a wrist-based device is that the 
thigh-mounted device would need to have the adhesive 
dressing changed which would be impractical. The wrist-based 
accelerometer will be retrieved at the 2-week follow-up 
appointment. Due to limited availability of the wrist-based 
accelerometers, only the GPAQ will be conducted at the 3-
month follow-up appointment. 
 

 
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42 
In addition, the GPAQ will be used to estimate pre-stroke 
physical activity levels. This will be assessed the day after 
the intervention period. A higher level of physical activity pre-
stroke is associated with more favourable recovery after stroke 
(104,105), therefore it is important to account for this 
confounding variable.  
 
*Accelerometery and the GPAQ are not routinely used in the 
STH NHS acute stroke service. 
 
 
Activities of daily 
living & physical 
function 
 
 
 
 
 
 
 
 
Barthel Index (106) 
 
 
 
 
 
 
Short physical 
performance battery 
(SPPB) (107) 
 
 
 
 
10-metre walk test 
(108) 
 
 
 
 
 
 
Handgrip strength 
(109) 
 
 
 
Over half of stroke survivors live with a physical disability (2). 
Finding optimal strategies to improve post-stroke physical 
function is a research priority (92). Measurement of physical 
function is necessary to understand the effects of the aerobic 
exercise intervention compared to usual care alone.  
 
 
The Barthel Index is a simple measure of a person’s ability to 
undertake activities of daily living and to what degree 
assistance is needed. This assessment is routinely used by the 
STH NHS acute stroke service. 
 
 
 
The SPPB is short series of physical assessments that 
measure lower-extremity function. The test battery is 
designed for use in elderly and clinical populations and 
includes: a 3-metre walk, 5 sit-to-stand repetitions, and a 
set of standing balance tests. 
 
 
The 10-metre walk test will also be used in accordance with 
expert recommendations for core outcome measures in stroke 
recovery trials (110). Instead of testing 10-metre walk speed 
separately to the SPPB walk speed, we will extend the SPPB 
3-metre walkway by 7 metres and record the average walking 
speed at both distances. 
 
 
Handgrip strength is a simple measure of upper-limb function. 
 
*The Barthel Index is the only physical function assessment 
that the STH NHS acute stroke service use. 
 
 
 
 
 
 

 
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43 
 
Acute 
physiological 
response to 
aerobic exercise 
 
• 
Heart rate 
• 
Blood 
pressure 
• 
Oxygen 
saturation 
 
 
 
 
 
 
 
 
 
• 
Cerebral blood 
flow (CBF) 
velocity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Oxygen 
consumption 
(V̇ O2) 
 
Only one study has investigated the use of aerobic exercise in 
the acute phase of stroke (44). The only physiological variable 
reported was mean exercise heart rate. Collecting more in-
depth physiological data will improve the mechanistic 
knowledge of how aerobic exercise influences cerebral 
perfusion and recovery from injury. Furthermore, monitoring 
heart rate, blood pressure and oxygen saturation in real-
time will improve the safety of exercise prescription.  
 
Heart rate will be measured telemetrically via a chest strap or 
using wireless ECG; brachial blood pressure will be measured 
with an oscillatory monitor; and peripheral oxygen saturation 
will be measured with a fingertip pulse oximeter. 
 
CBF velocity is a non-invasive proxy measure of cerebral 
perfusion (111). Moderate-intensity aerobic exercise increases 
CBF velocity by 10-30% (30). Increasing blood flow to the peri-
infarct area may enhance reparative processes and promote 
neuroplasticity (24–26,30,31,36,37,95,112). We will use a 
transcranial Doppler (TCD) ultrasound device to determine 
changes in CBF velocity measured bilaterally at the middle 
cerebral arteries. A specially designed, comfortable headset 
will be used to fix the ultrasound probes in place during 
exercise sessions.  
 
To minimise time burden, CBF velocity will be measured a 
maximum of two times per participant. Both the control group 
and the intervention group will have resting CBF velocity 
measured on the second study day (t1) and the sixth study day 
(t5). For the intervention group only, we will record changes in 
CBF velocity throughout the exercise sessions immediately 
after resting measures. Measuring resting CBF velocity will 
enable us to understand how this variable changes in the first 
week of stroke under conditions of usual care and aerobic 
exercise training. Furthermore, as the aerobic exercise duration 
progresses throughout the 5-day intervention from 10 to 30 
minutes, a repeated measure (first vs. fifth exercise session) 
will help to identify if there is a dose-response relationship 
between exercise duration and change in CBF velocity 
(intervention group only). Hypoallergenic ultrasound gel and 
nitrile gloves will be used. If a patient has a known allergy to 
ultrasound gel, this test will be excluded. 
 
During moderate-intensity aerobic exercise, increased energy 
turnover within working muscle leads to increased V̇ O2 and 
CO2 production (30). CO2 is a potent vasodilator and is a key 
regulator of CBF (30). V̇ O2 can be used to estimate the energy 
expenditure of physical exercise. Combined measurement of 
V̇ O2 and end-tidal CO2 enables the estimation of the metabolic 

 
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44 
• 
End-tidal 
carbon dioxide 
(CO2) 
 
 
 
• 
Mature brain-
derived 
neurotrophic 
factor 
(mBDNF) 
 
 
• 
Platelet count 
 
 
 
 
 
 
 
 
 
 
• 
Plasma 
volume 
 
 
 
 
 
 
 
 
 
 
 
stress and thereby intensity of exercise (61). Both V̇ O2 and 
end-tidal CO2  can be measured concurrently using an expired 
gas analysis system. Expired gas will be collected via a non-
invasive face mask. V̇ O2 and end-tidal CO2 will be measured in 
the intervention group only during the fifth exercise session. 
 
mBDNF is a key mediator of neuroprotection, neuroplasticity, 
memory formation and learning (28). Aerobic exercise 
transiently increases the systemic production and secretion of 
mBDNF (29). Platelets are a primary storage site of mBDNF in 
the blood (29). Aerobic exercise stimulates the release of 
platelets from the spleen which increases the circulating level 
of mBDNF (29,37). To accurately determine exercise-induced 
changes in serum mBDNF independent of platelet count, 
mBDNF concentration will be calculated per platelet. In 
addition, blood plasma contains a freely circulating pool of 
mBDNF that is not bound to platelets. Possible sources of 
plasma BDNF include the brain, skeletal muscle, peripheral 
blood mononuclear cells and vascular endothelial cells (29). 
Measurement of plasma mBDNF is neccessary to determine if 
cellular sources of BDNF are secreted into circulation during 
exercise. However, during moderate-intensity exercise, water 
shifts from plasma into both the interstitial and intracellular fluid 
compartments of contracting skeletal muscle. Thus it is 
important to correct for changes in plasma volume to prevent 
erroneous interpretations of changes in mBDNF concentration 
(113). In sum, by assessing changes in the total mBDNF 
system (serum, volume-corrected plasma, platelets, and 
mBDNF per platelet), it is possible to quantify cellular sources 
of denovo mBDNF, and to differentiate this from changes in 
mBDNF that result from altered blood plasma volume and 
movement of mBDNF between plasma and platelet pools (29). 
 
Due to the invasive nature of venous blood sampling and the 
expense of analysing mBDNF, we have chosen to limit blood 
sample collection to a maximum of two timepoints per 
participant at t5: 1) baseline (both groups), and 2) post-exercise 
(intervention group only). We have chosen to measure mBDNF 
at the fifth aerobic exercise session which is 30 minutes in 
duration. This exercise duration has consistently been shown to 
increase circulating mBDNF (29). Hypoallergenic nitrile gloves, 
dressings and plasters will be used. 
 
 

 
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9.3.  Scheduling research activity 
 
Research team members will liaise with clinical staff to decide upon the most suitable times 
to conduct research activity. Key factors to consider will include patient clinical status, 
patient wellbeing and fatigue, and scheduled routine care.  
 
9.4. Participant food and drink consumption  
 
Participants will not be asked to alter their food intake. Participants will be politely asked to 
refrain from consuming caffeinated beverages prior to any research activity on the second 
and sixth study days, where CBF will be measured. Caffeine is a cardiovascular stimulant 
(114). In patients recovering from an acute ischaemic stroke, ingestion of 250 mg caffeine 
(approximately 2.5 cups of coffee) reduces CBF velocity and global blood flow by 13-30% 
(115). Restriction of caffeine intake will therefore improve the validity of CBF measurements. 
The research team will liaise with clinical and catering staff to ensure that this request is 
communicated. Alternative decaffeinated beverages will be offered instead. However, if 
participants refuse to restrict caffeine intake, they will not be excluded from the study. Data 
obtained from these participants will be interpreted with caution and this will be noted as a 
limitation of the study. 
 
9.5. Preparation, storage and analysis of blood samples 
 
Venous blood samples will be taken at t5 (6-8 days post-stroke). Baseline blood samples will 
be collected from control and intervention group participants in a resting state. Post-exercise 
blood samples will be taken from the intervention group participants during the recovery 
(passive cycling) phase following aerobic exercise.  
 
Blood samples will then be centrifuged and aliquoted at RHH. Processed samples will then 
either be stored in a designated -80°C freezer at RHH or put on ice (for up to 5 hours) and 
transferred to the AWRC and stored at stored at -80°C. mBDNF will be measured using an 
enzyme-linked immunosorbent assay (116). Platelet count will be measured using an 
automated haematology analyser. Blood plasma volume will be measured using the Dill and 
Costill method (117). Blood samples will be stored for 10 years to allow time to source 
additional funding and obtain ethical approval for further exploratory analyses that may 
improve mechanistic knowledge. 10 years after the trial end date samples will be destroyed 
in accordance with local laboratory procedures. Researchers are trained in venepuncture. 
 

 
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10. COVID-19 contingency plan 
 
Currently, non-essential face-to-face research is suspended due to the COVID-19 pandemic. 
A restart date has not yet been announced, however it is unlikely that the proposed study 
will be able to take place before the end of 2020 due to the combination of winter pressures 
and a second wave of COVID-19-related hospital cases. If the proposed study is approved 
and is able to commence in the early months of 2021, we anticipate that patient follow-up 
appointments will be conducted virtually (via video call or telephone) for a transitional period 
of an unknown duration. Thus, the research activities that are planned to be conducted at 
follow-up appointments may be adapted or omitted. Table 5 outlines our contingency 
planning for research-related activities. In line with STH procedures, participants will be 
given an information leaflet providing technical support with regards to video call and 
telephone consultations. All face-to-face research activities will be conducted in accordance 
with STH risk management policy. 
 
 
Table 5. COVID-19 contingency plan 
Activity/measure 
Plan A 
(no face-to-face research restrictions) 
Plan B 
(COVID-19 restrictions) 
 
National Institutes of 
Health 
Stroke Scale 
(NIHSS) 
 
 
Face-to-face assessment conducted at 
the 3-month follow-up appointment by Dr 
Ali Ali. 
 
Only possible to conduct via high-quality 
video call. This will be dependent on if 
the participant has access to a device 
with high-quality video calling function. 
This assessment will be conducted by Dr 
Ali Ali. 
 
If the video quality is deemed to be poor, 
this assessment will be omitted. 
 
 
 
Barthel Index 
 
Conducted at the 2-week and 3-month 
follow-up appointments via face-to-face 
interview by Dr Ali Ali. 
 
 
Conducted at the 2-week and 3-month 
follow-up appointments via telephone or 
video call interview by Dr Ali Ali. 
 
 
Thigh muscle 
ultrasound 
 
 
 
 
 
 
Conducted at the 3-month follow-up 
appointment. Requires physical contact. 
 
 
Omitted. 
 
Physical function 
assessments (SPPB, 
 
Conducted at the 3-month follow-up 
appointment. Requires direct 
 
 
Omitted. 

 
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47 
10-m walk, handgrip 
strength) 
supervision and in some cases, 
physical assistance.  
 
 
Acute fatigue (RoFS) 
 
Simple visual analogue scale conducted 
before and after physical function 
assessments at the 3-month follow-up 
appointment. 
 
 
Omitted. 
 
Modified Rankin 
Scale 
 
Conducted at the 2-week and 3-month 
follow-up appointments via face-to-face 
interview by Dr Ali Ali. 
 
 
Conducted at the 2-week and 3-month 
follow-up appointments via telephone or 
video call interview by Dr Ali Ali. 
 
 
Cognitive function 
(MoCA) 
 
Conducted at the 3-month follow-up 
appointment. Requires direct 
supervision. 
 
 
Omitted. 
 
Chronic fatigue (FSS) 
 
Anxiety and 
depression (GAD-7, 
PHQ-9) 
 
 
Conducted at the 3-month follow-up 
appointment via face-to-face interview by 
Dr Ali Ali. 
 
Conducted at the 3-month follow-up 
appointment via telephone or video call 
interview by Dr Ali Ali. 
 
 
Optimism (rLOT) 
 
Health-related quality 
of life (EQ-5D) 
 
Exercise self-efficacy 
 
Post-discharge 
physical activity 
(GPAQ) 
 
 
Conducted at the 3-month follow-up 
appointment via face-to-face interview by 
Mr Nik Kudiersky. 
 
 
Conducted at the 3-month follow-up 
appointment via telephone or video call 
interview by Mr Nik Kudiersky. 
 
 
 
Wrist-based 
accelerometer 
 
Participant to bring activity monitor to 2-
week appointment and hand over to Dr Ali 
Ali. 
 
 
Participant will be provided with a pre-
paid envelope to post the activity 
monitor back to the research team. 
 
Qualitative interview 
 
Face-to-face interview to be conducted 
by Mr Nik Kudiersky at the 3-month follow-
up appointment. 
 
 
Conducted at the 3-month follow-up 
appointment via telephone or video call 
interview by Mr Nik Kudiersky. 
 
 
 
 
 
 

 
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48 
11. Feasibility outcome measures 
 
Table 6. Feasibility outcome measures 
 
Outcome 
 
 
Description 
 
Recruitment rate 
 
Number of participants recruited per month of the 
recruitment period. 
 
Exclusion rate 
Number of ineligible patients divided by the total 
number of patients admitted to the RHH stroke service 
during the recruitment period. 
 
Consent rate 
 
Percentage of eligible patients who consent to 
participate. 
 
Dropout rate 
 
Percentage of individuals that discontinue 
participation after the study has commenced. 
Voluntary reasons for dropout will be recorded. Early 
discharge from hospital will not count as a dropout. 
 
Participant fidelity 
 
Completion of key exercise components in 
accordance with the exercise protocol including: 
percentage of planned exercise session duration 
completed, percentage of target exercise intensity per 
session attained, and percentage of total planned 
exercise sessions completed. 
 
Completeness of data 
 
Percentage of planned measurements completed and 
recorded. 
 
Safety 
 
Number of SAE and AEs related to the intervention. 
 
Acceptability of intervention (participant interview) 
 
Comfort and ease of using cycling apparatus. 
 
Acceptability of study procedures (healthcare 
professional interview) 
 
• 
Attitudes towards the intervention 
• 
Burden on staff and participants 
• 
Perceived effectiveness of the intervention 
 
 
 
 
 
 
 

 
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49 
12. Intervention 
 
12.1. 
 Usual care 
 
Participants randomised to the control group will receive usual care according to guidance 
from the National Institute for Health and Care Excellence (19) and the Royal College of 
Physicians (49). Briefly, it is recommended that patients complete at least 45 minutes of 
each appropriate therapy per day (physiotherapy, occupational therapy and or speech and 
language therapy) for five days per week. Patients should be mobilised (out-of-bed sitting, 
standing or walking) within the first 48 hours of stroke onset, or if physically capable, as soon 
as possible post-stroke. 
 
12.2. 
Usual care therapy dose 
 
Adequate reporting of therapy dose and timing of initiation is essential to understand the 
effectiveness of therapeutic interventions, and enables replication (118). This is particularly 
important in complex interventions such as stroke rehabilitation which involves a variety of 
active ingredients. The Stroke Recovery and Rehabilitation Roundtable recently highlighted 
the lack of consideration of dose complexity as a potential reason for neutral findings in 
stroke recovery and rehabilitation trials (119). Clinical trials tend to quantify therapy dose 
using duration (minutes/hours) only, which masks important variables such as the relative 
intensity of activities and number of repetitions – both of which moderate neuroplasticity and 
neurological recovery (120). In addition to a lack of clarity regarding therapy components, 
UK audit data from the 2018/19 Sentinel Stroke National Audit Programme (121) 
demonstrates that a large proportion of UK stroke units do not meet the minimum 
recommendation for therapy duration. Observations of UK stroke units have highlighted 
various organisational (e.g. staffing levels and time spent in information exchange) and 
patient (e.g. fatigue and therapy tolerance) factors that reduce therapy duration (122).  
 
In recognition of the widespread underreporting of therapy composition and the reported 
variability in therapy duration and content across NHS sites, we aim to capture detailed 
information pertaining to therapy dose using therapy records and overall physical activity 
levels using accelerometer-based motion sensors. Timing of therapy initiation (hours/days 
post-stroke) will also be recorded.  
 

 
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12.3. 
Aerobic exercise training protocol 
 
Detailed reporting of the intervention will align with the Consensus on Exercise Reporting 
Template (123). 
 
12.3.1. Exercise equipment 
 
A bedside cycle ergometer (MOTOmed Letto 2, Medimotion, Reck, Germany) will be 
positioned at the foot of the participant’s bed. Both the bed and the cycle ergometer will be 
positioned at their lowest height which orientates the lower limbs at approximately chest 
height. The MOTOmed Letto2 detects asymmetrical force distribution and provides motor 
assistance to compensate for hemiparesis or hemiplegia. The bed backrest angle will be 
elevated to 45° and the participant will be positioned so that the lumbar spine is supported 
by the backrest. The participant’s feet will be inserted onto the foot pedals which contain 
heel cups to prevent the feet from slipping downwards. To prevent knee hyperextension, 
support frames, which extend from each crank arm, will be positioned underneath the 
superior region of each shank. Flexible rubber straps will be fastened around the feet and 
shanks for stability. The foot pedals and support frames will fixate the lower limbs in a 
comfortable position, enabling a smooth cycling motion in the sagittal plane. The knee angle 
at the end of the pedal stroke will be 25°, which is considered to be optimal for both 
movement economy and injury prevention (124). Knee angle will be measured using a 
goniometer centred on the lateral epicondyle with each measuring arm aligned to the centre 
point of the corresponding greater trochanter and lateral malleolus (125). All equipment used 
in the study will have a CE mark for European use and will meet European safety 
regulations. 
 
12.3.2. Exercise supervision 
 
All exercise sessions will be supervised by the Principal Investigator (SN) or a Co-
Investigator (NK) on a one-to-one basis. Dr Simon Nichols (SN) is a senior research fellow in 
clinical exercise physiology with expertise in conducting exercise-based cardiovascular 
rehabilitation trials in clinical populations. The assigned Co-Investigator (NK) is undertaking 
a PhD in Clinical Exercise Physiology, holds an MSc in Clinical Exercise Physiology, has 
extensive experience supervising exercise in healthy (>400 hours) and clinical (>50 hours) 
populations, and is trained in basic life support. A medical doctor will be readily available to 
intervene in the case of an adverse event. 
 

 
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12.3.3. Aerobic exercise 
 
The exercise protocol will begin with a 5-minute passive cycling period (20 revolutions per 
minute [rpm]), where the participant will be relaxed (no exertion) and the bike will rotate the 
participant’s legs to mobilise the lower limb joints and increase venous return. Subsequently, 
the participant will complete a low- to moderate-intensity warm-up phase. Starting in the 
lowest gear, the participant will be instructed to cycle a self-selected cadence aiming for an 
intensity equivalent to ‘light’ (11/20) on the RPE scale (90). At 60s and at each subsequent 
minute, the operator will increase the cycle gear by one level until a target RPE of 13 
(‘somewhat hard’) is achieved. The warm-up duration will be individualised for each 
participant based on time taken to reach RPE 13. When RPE 13 is reached, the conditioning 
phase will commence and the participant will be instructed to maintain a consistent cadence 
(10%) for 5-min. After which, passive mode (20 rpm) will be activated and the participant 
will be asked to rest for 1-min. The number of 5-min conditioning bouts will increase by one 
bout per session. The first session will contain 2 bouts (total = 10 mins), and the fifth session 
will contain 6 bouts (total = 30 mins). The rationale for this progressive design was 
developed with input from researchers, healthcare practitioners and people affected by 
stroke (see PPI section, 13.2.). Briefly, it was considered that starting with 30-min of aerobic 
exercise in session 1 may be too difficult for some patients due to fatigue, whereas a gradual 
progression in exercise duration would be more tolerable. Throughout the warm-up and 
conditioning phases, RPE will be measured in the last 15s of each minute, and the cycle 
gear will be adjusted accordingly if RPE deviates away from target. The target exercise 
intensity (moderate) will remain constant during the work intervals of the conditioning phase. 
To ensure that the intervention is tolerable (i.e. the conditioning phase can be completed), 
the cycling gear (resistance) will be adjusted according to the participant’s level of function 
and RPE at that particular time. All performance metrics displayed on the MOTOmed 
interface (Watts, gear, left-to-right symmetry and distance) will be concealed from the 
participant with the exception of cadence (rpm). After the conditioning phase, the participant 
will undertake a graduated cool-down for 5 minutes and then will be instructed to relax whilst 
a final 2-min passive cycling recovery phase is completed.   
 
The day after completing the first exercise bout, participants will undertake a single aerobic 
exercise session per day for 4 days (5 exercise sessions in total). If patients are discharged 
earlier, study participation will terminate on the day of discharge. The workload that elicited 
an RPE of 13 at the start of the conditioning phase in the first aerobic exercise session will 
be used to guide the initial workload for the conditioning phase in subsequent sessions. 
Number of repetitions (rpm multiplied by minutes) completed during the warm-up, 

 
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conditioning phase and cool-down will be included within therapy dose calculations. Verbal 
communication provided by the operator will be standardised (detailed in Table 6, 
Appendix).   
 
Through consultations with stroke survivors and healthcare practitioners we acknowledge 
the need for a flexible exercise protocol. It was expressed to us that patients’ level of fatigue 
and physical function may fluctuate throughout the duration of hospital stay depending on 
various intrinsic and extrinsic factors. Thus, the workload used for each exercise session will 
be a collaborative choice made between the researcher and the participant. 
 
 
 
 
 
 
 
 
 
Note: Blue = passive cycling (no exertion) = 5 minutes; brown = warm up/cool down; pink = 
active cycling (moderate intensity). Active cycling duration = 5 minutes per bout. Passive 
recovery intervals = 1 minute (blue). 
 
 
 
 
 
1 
 
 
2 
 
 
3 
 
 
 
4 
 
 
 
5 
Exercise 
session 
number 
Duration (minutes) 
5         10         15         20         25         30         35         40         45         50         60 
Moderate 
 
 
Low 
Figure 5. Schematic diagram of 5-day exercise protocol.  

 
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12.4. 
Operational definitions for (S)AEs 
 
Adverse events 
 
Any untoward medical or psychological occurrence in a patient or trial subject involved in a 
trial intervention and which does not necessarily have a causal relationship with this 
intervention. An adverse event can therefore be any unfavourable and unintended sign, 
symptom, or disease (including abnormal lab results or a traffic accident) in any subject in a 
trial (including those in an untreated control group), whether or not considered related to the 
investigational intervention.  
 
Serious adverse events 
 
Unless exempted by the approved protocol, any untoward medical or psychological 
occurrence that:  
• 
results in death 
• 
is life-threatening* 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity  
• 
requires intervention to prevent one of the above occurrences 
 
*Life-threatening in the definition of a SAE refers to an event in which the subject 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. 
 
12.5. 
Recording and reporting of serious adverse events 
 
All SAEs occurring from the time of start of the intervention until 3 months post cessation of 
trial intervention will be recorded on a STH-approved form and faxed/emailed to the Sponsor 
within 24 hours of the research staff becoming aware of the event. Once all resulting queries 
have been resolved, the Sponsor will request that the original form should also be posted to 
the Sponsor and a copy to be retained on site. 
 
For each SAEs the following information will be collected: 
 
• 
Full details in medical terms and case description. 
• 
Event duration (start and end dates, if applicable). 

 
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54 
• 
Action taken. 
• 
Outcome. 
• 
Seriousness criteria. 
• 
Causality (i.e. relatedness to intervention), in the opinion of the Investigator. 
• 
Whether the event would be considered anticipated. 
 
Any change of condition or other follow-up information should be emailed/faxed to the 
Sponsor as soon as it is available or at least within 24 hours of the information becoming 
available. Events will be followed up until the event has resolved or a final outcome has 
been reached. 
 
12.6. 
Responsibilities 
 
Principal Investigator:  
 
1. Ensuring that all AEs related to the intervention are recorded and reported to the 
sponsor in line with the requirements of the protocol.  
2. Ensuring that all SAEs related to the intervention are recorded and reported to the 
sponsor within 24 hours of becoming aware of the event and provide further follow-
up information as soon as available.  
3. Ensuring that SAEs are chased with Sponsor if a record of receipt is not received 
within 2 working days of initial reporting.  
4. Central data collection and verification of AEs and SAEs according to the trial 
protocol onto a database.  
5. Reporting safety information to the Sponsor for the ongoing assessment of the 
risk/benefit. 
6. Adhering to all aspects of the study protocol in accordance with GCP guidance. 
 
Study Doctor: 
 
1. Clinical oversight of the safety of patients participating in the trial, including an 
ongoing review of the risk/benefit. 
2. Using medical judgement in assigning the SAEs seriousness, causality and whether 
the event was anticipated (in line with data from previous studies) where it has not 
been possible to obtain local medical assessment. 
3. Review of specific SAEs in accordance with the trial risk assessment and protocol. 

 
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4. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System 
coding to all SAEs. 
5. Adhering to all aspects of the study protocol in accordance with GCP guidance. 
 
Co-Investigators: 
 
1. Adhering to all aspects of the study protocol in accordance with GCP guidance. 
 
13.  Data management 
 
Where possible, all participant data will be coded using unique reference numbers (pseudo-
anonymised). All hard copy data will be stored securely in the site file located in a locked 
office. The location of the site file will be specified to the Sponsor and regulatory bodies. 
The site file will be accessible to authorised individuals upon request. Scanned copies of 
hard copy data will be saved as encrypted PDFs and stored in the university SHU 
Research Store. Qualitative data will be recorded on encrypted Dictaphones and 
downloaded in either MP3. or WAV format as soon as possible after data collection. 
Audio recordings of interviews will be destroyed after they have been transcribed. Digital 
data will be transferred between devices using https://zendto.shu.ac.uk, which is an 
encrypted platform that enables users to upload and download data. If the internet is 
inaccessible, an encrypted external hard drive will be used to transfer data instead. Data 
will be transferred as soon as possible form the external hard drive to the relevant device 
and will be deleted from the hard drive after being transferred. Relevant data will be input 
into encrypted Microsoft Excel spreadsheets and saved in XLS format. Data will be 
analysed in SPSS version 24.0 according to established statistical principles. All data will 
be saved on the SHU Research Store with a file name corresponding to the study title 
e.g. ‘Q:\RESEARCH\ATAS’. With the exception of participant personal data, data relating 
to the trial will be archived for 10 years in line with the Sponsor’s requirements. 
Participant personal data (e.g. phone number, email address and home address) will be 
archived for 2 years after the end of the study so that participants can be contacted 
regarding research dissemination. An anonymised description the available data 
(metadata), including a list of key variables will be placed on University open-access 
repository (SHURDA).  
 
The data collected from this project will be suitable for sharing on request because of the 
broad academic interest in stroke rehabilitation. Other researchers should have the 

 
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opportunity to explore this dataset to develop the field of research without having to 
repeat the same investigations, and expose patients to unnecessary risk. Original data 
will be provided on application rather than be offered open access. This is because it 
may not be possible to ensure that data is completely anonymised. We can only 
guarantee that data will be pseudo-anonymised. All external users of our data will be 
bound by a data sharing agreement between the research team and SHU, and the user 
themselves. Data will be supplied on the condition that their research is non-profit, and 
that their findings will be published in an open access domain. Data users will not be 
permitted to share the data with anyone outside of their immediate research team. 
 
SHU storage arrangements conform to GDPR and NHS standards. The Principal 
Investigator (Dr Simon Nichols) will be the custodian of the data and the data processor. 
 
14.  Ethical and regulatory considerations 
 
14.1. 
Research Ethics Committee review and reports 
 
Before the start of the trial, approval will be sought from a REC for the trial protocol, 
informed consent forms and other relevant documents. Substantial amendments that require 
review by REC will not be implemented until the REC grants a favourable opinion for the 
trial. All correspondence with the REC will be retained in the site file. An annual progress 
report will be submitted to the REC within 30 days of the anniversary date on which the 
favourable opinion was given, and annually until the trial is declared ended. It is the Principal 
Investigator’s responsibility to produce the annual reports as required. The Principal 
Investigator will notify the REC of the end of the trial if the trial is ended prematurely, 
including the reasons for the premature termination within one year after the end of the trial. 
The Principal Investigator will submit a final report with the results, including any 
publications/abstracts to the REC. 
  
14.2. 
Patient and public involvement  
 
In January 2020, two PPI events were held at Graves Health and Sports Centre in Sheffield 
to gather ideas from key stakeholders regarding the use of aerobic exercise training early 
after stroke. The events were advertised on Twitter and at local organisations including 
health, leisure and rehabilitation centres. Attendees included five people affected by stroke, 
two physiotherapists, one stroke physician, one speech and language therapist, one fitness 

 
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instructor, two senior research fellows and two PhD students. People affected by stroke and 
practitioners participated in separate events that contained identical content. Researchers 
played a passive role by facilitating discussions and scribing. Discussions were transcribed 
and common themes were identified. Protocol amendments were made based on these PPI 
events. In October 2020, we hosted an online PPI event which was attended by people 
affected by stroke. The purpose of this PPI event was to obtain feedback regarding the 
design of participant information resources. At the end of the study, participants will be 
invited to a workshop where the research findings will be presented in a lay format. Using 
consensus-based methods, we will collaborate with participants to design an infographic 
which depicts the key findings in a meaningful way.  
 
14.2.1.      Protocol amendments based on patient and public involvement  
 
We initially proposed a fixed 30-minute bout of aerobic exercise per session. However, the 
PPI consensus was that this duration may be too long for some individuals due to severe 
fatigue and disability after stroke. We responded to this issue with two solutions: 1) by 
adopting an interval training design consisting of shorter moderate-intensity aerobic exercise 
bouts interspersed with rest intervals; and 2) by gradually increasing the total exercise 
duration per session over 5 days. It was also noted that NHS staff capacity is reduced at 
weekends, therefore the intervention should be delivered over 5 working days. A key point 
raised at the PPI events was that aphasia may be a barrier to participation due to issues with 
reading and speech comprehension. We will therefore use aphasia-friendly design and 
communication techniques wherever possible to increase the accessibility of our study 
information and intervention protocol. In addition, discussions from the PPI events inspired 
the idea of assessing exercise self-efficacy and optimism. A summary of the PPI events is 
attached to the IRAS form. 
 
14.3. 
Financial and other competing interests 
 
None disclosed. 
 
 
14.4. 
Notification of serious breaches to GCP and/or the protocol 
 
A “serious breach” is a breach which is likely to affect to a significant degree: 
 
a) The safety or physical or mental integrity of the participants of the trial; or 
b) The scientific value of the trial. 
 

 
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The Sponsor of a clinical trial shall notify the licensing authority in writing of any serious 
breach of: 
 
a) The conditions and principles of GCP in connection with that trial; or 
b) The protocol relating to that trial, as amended from time to time, within 7 days of 
becoming aware of that breach. 
 
The Sponsor will be notified immediately of any case where the above definition applies 
during the trial conduct phase. The Sponsor’s standard operating procedure on ‘serious 
breaches’ will be followed. 
 
 
14.5. 
Data protection and patient confidentiality  
 
All data will be collected, stored, analysed and reported in accordance with General Data 
Protection Regulation guidelines. Where possible, identifiable information will be replaced 
with unique identification codes. 
 
14.6. 
Access to the final dataset 
 
A summary of the final dataset will be anonymised and made publicly available via an open 
access publication. The full dataset will be made available upon request and under the 
conditions of a shared data sharing agreement between the research team and SHU, and 
the individual requesting the data. 
 
15.  Dissemination  
 
We will seek the support of stroke survivors to determine the most appropriate ways to 
translate and disseminate our findings to the general public. 
 
Publication definition: “Any activity that discloses, outside of the circle of trial investigators, 
any final or interim data or results of the Trial, or any details of the Trial methodology that 
have not been made public by the Sponsor including, for example, presentations at 
symposia, national or regional professional meetings, publications in journals, theses or 
dissertations.” 
 
All scientific contributors to the Trial have a responsibility to ensure that results of scientific 

 
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interest arising from Trial are appropriately published and disseminated. The Sponsor has a 
firm commitment to publish the results of the Trial in a transparent and unbiased manner 
without consideration for commercial objectives. To maximise the impact and scientific 
validity of the Trial, data shall be consolidated over the duration of the trial, reviewed 
internally among all Investigators and not be submitted for publication prematurely.  
 
15.1. 
Lay summaries 
 
Plain English research summaries will be produced in collaboration with PPI attendees. 
These will be written clearly and simply, without jargon and with an explanation of any 
technical terms that have been used. The summaries will answer the following questions: 
Why did we do this study?; How did we do it?; What did we find?; What does this mean? 
Research summaries will be sent to all participants and PPI attendees that provided consent 
to do so. In addition, copies will be sent to charities (e.g. Stroke Association, SameYou, 
British Heart Foundation) with the intention of publicising research summaries on their 
websites and social media platforms. Infographics will also be produced to aid research 
dissemination on social media platforms. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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16.   References  
 
1.  Feigin Valery L., Norrving Bo, Mensah George A. Global Burden of Stroke. Circ 
Res. 2017 Feb 3;120(3):439–48.  
2.  D’Alessandro G, Gallo F, Vitaliano A, Del Col P, Gorraz F, De Cristofaro R, et 
al. Prevalence of stroke and stroke-related disability in Valle d’Aosta, Italy. 
Neurol Sci. 2010 Apr 1;31(2):137–41.  
3.  Adamson J, Beswick A, Ebrahim S. Is stroke the most common cause of 
disability? J Stroke Cerebrovasc Dis. 2004 Jul 1;13(4):171–7.  
4.  Knapp P, Dunn-Roberts A, Sahib N, Cook L, Astin F, Kontou E, et al. Frequency 
of anxiety after stroke: An updated systematic review and meta-analysis of 
observational studies. Int J Stroke. 2020 Jan 24;1747493019896958.  
5.  Patel A, Berdunov V, King D, Quayyum Z, Wittenberg R, Knapp M. Stroke 
Association: Current, future and avoidable costs of stroke in the UK. 2018;  
6.  Johnson CO, Nguyen M, Roth GA, Nichols E, Alam T, Abate D, et al. Global, 
regional, and national burden of stroke, 1990–2016: a systematic analysis for 
the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):439–
58.  
7.  Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ (Buddy), Culebras 
A, et al. An Updated Definition of Stroke for the 21st Century: A Statement for 
Healthcare Professionals From the American Heart Association/American 
Stroke Association. Stroke. 2013 Jul;44(7):2064–89.  
8.  Xing C, Arai K, Lo EH, Hommel M. Pathophysiologic cascades in ischemic 
stroke. Int J Stroke Off J Int Stroke Soc. 2012 Jul;7(5):378–85.  
9.  Campbell, De Silva DA, Macleod MR, Coutts SB, Schwamm LH, Davis SM, et 
al. Ischaemic stroke. Nat Rev Dis Primer. 2019 Dec;5(1):70.  
10.  Davis S, Donnan GA. Time Is Penumbra: Imaging, Selection and Outcome. 
Cerebrovasc Dis. 2014;38(1):59–72.  
11.  Vagal A, Aviv R, Sucharew H, Reddy M, Hou Q, Michel P, et al. Collateral clock 
is more important than time clock for tissue fate: A Natural History Study of 
Acute Ischemic Strokes. Stroke. 2018 Sep;49(9):2102–7.  
12.  Wheeler HM, Mlynash M, Inoue M, Tipirnini A, Liggins J, Bammer R, et al. The 
growth rate of early DWI lesions is highly variable and associated with 
penumbral salvage and clinical outcomes following endovascular reperfusion. 
Int J Stroke. 2015;10(5):723–9.  
13.  Jung S, Wiest R, Gralla J, McKinley R, Mattle H, Liebeskind D. Relevance of the 
cerebral collateral circulation in ischaemic stroke: time is brain, but collaterals 
set the pace. Swiss Med Wkly. 2017;147(14538).  

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
61 
14.  Heiss W-D. Malignant MCA Infarction: Pathophysiology and Imaging for Early 
Diagnosis and Management Decisions. Cerebrovasc Dis. 2016;41(1–2):1–7.  
15.  Lansberg MG, O’Brien MW, Tong DC, Moseley ME, Albers GW. Evolution of 
Cerebral Infarct Volume Assessed by Diffusion-Weighted Magnetic Resonance 
Imaging. Arch Neurol. 2001 Apr 1;58(4):613–7.  
16.  Moretti A, Ferrari F, Villa RF. Neuroprotection for ischaemic stroke: Current 
status and challenges. Pharmacol Ther. 2015 Feb 1;146:23–34.  
17.  Xiong X-Y, Liu L, Yang Q-W. Refocusing Neuroprotection in Cerebral 
Reperfusion Era: New Challenges and Strategies. Front Neurol. 2018 Apr 
23;9(249).  
18.  Schmidt‐Pogoda A, Bonberg N, Koecke MHM, Strecker J-K, Wellmann J, 
Bruckmann N-M, et al. Why Most Acute Stroke Studies Are Positive in Animals 
but Not in Patients: A Systematic Comparison of Preclinical, Early Phase, and 
Phase 3 Clinical Trials of Neuroprotective Agents. Ann Neurol. 2020;87(1):40–
51.  
19.  NICE. NICE clinical guideline (NG128). Stroke and transient ischaemic attack in 
over 16s: diagnosis and initial management. Natl Inst Health Care Excell 
[Internet]. 2019 [cited 2020 Jan 16]; Available from: 
https://www.nice.org.uk/guidance/ng128/resources/stroke-and-transient-
ischaemic-attack-in-over-16s-diagnosis-and-initial-management-pdf-
66141665603269 
20.  Campbell. Advances in stroke medicine. Med J Aust. 2019 May;210(8):367–74.  
21.  SSNAP. Royal College of Physicians Sentinel Stroke National Audit Programme 
(SSNAP). National clinical audit annual results portfolio. [Internet]. 2018 [cited 
2020 Dec 14]. Available from: http://bit.ly/1NHYlqH 
22.  Nour M, Scalzo F, Liebeskind DS. Ischemia-Reperfusion Injury in Stroke. Interv 
Neurol. 2012;1(3–4):185–99.  
23.  Bai J, Lyden PD. Revisiting Cerebral Postischemic Reperfusion Injury: New 
Insights in Understanding Reperfusion Failure, Hemorrhage, and Edema. Int J 
Stroke. 2015 Feb 1;10(2):143–52.  
24.  Austin MW, Ploughman M, Glynn L, Corbett D. Aerobic exercise effects on 
neuroprotection and brain repair following stroke: A systematic review and 
perspective. Neurosci Res. 2014 Oct;87:8–15.  
25.  Ploughman M, Austin MW, Glynn L, Corbett D. The Effects of Poststroke 
Aerobic Exercise on Neuroplasticity: A Systematic Review of Animal and 
Clinical Studies. Transl Stroke Res. 2015 Feb;6(1):13–28.  
26.  Ploughman M, Kelly LP. Four birds with one stone? Reparative, neuroplastic, 
cardiorespiratory, and metabolic benefits of aerobic exercise poststroke: Curr 
Opin Neurol. 2016 Dec;29(6):684–92.  

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
62 
27.  Marzolini S, Robertson AD, Oh P, Goodman JM, Corbett D, Du X, et al. Aerobic 
Training and Mobilization Early Post-stroke: Cautions and Considerations. Front 
Neurol. 2019;10(1187).  
28.  Woo NH, Lu B. Regulation of Cortical Interneurons by Neurotrophins: From 
Development to Cognitive Disorders. The Neuroscientist. 2006 Feb 1;12(1):43–
56.  
29.  Walsh JJ, Tschakovsky ME. Exercise and circulating BDNF: Mechanisms of 
release and implications for the design of exercise interventions. Appl Physiol 
Nutr Metab. 2018 Nov;43(11):1095–104.  
30.  Smith KJ, Ainslie PN. Regulation of cerebral blood flow and metabolism during 
exercise. Exp Physiol. 2017;102(11):1356–71.  
31.  Steventon J, Foster C, Furby H, Helme D, Wise RG, Murphy K. Hippocampal 
Blood Flow Is Increased After 20 min of Moderate-Intensity Exercise. Cereb 
Cortex. 2019;1–9.  
32.  Baptista P, Andrade JP. Adult Hippocampal Neurogenesis: Regulation and 
Possible Functional and Clinical Correlates. Front Neuroanat. 2018 Jun 
5;12(64).  
33.  Webster MJ, Herman MM, Kleinman JE, Shannon Weickert C. BDNF and trkB 
mRNA expression in the hippocampus and temporal cortex during the human 
lifespan. Gene Expr Patterns. 2006 Oct 2;6(8):941–51.  
34.  Drake CT, Milner TA, Patterson SL. Ultrastructural Localization of Full-Length 
trkB Immunoreactivity in Rat Hippocampus Suggests Multiple Roles in 
Modulating Activity-Dependent Synaptic Plasticity. J Neurosci. 1999 Sep 
15;19(18):8009–26.  
35.  Marie C, Pedard M, Quirié A, Tessier A, Garnier P, Totoson P, et al. Brain-
derived neurotrophic factor secreted by the cerebral endothelium: A new actor 
of brain function? J Cereb Blood Flow Metab. 2018 Jun;38(6):935–49.  
36.  Serra-Millàs M. Are the changes in the peripheral brain-derived neurotrophic 
factor levels due to platelet activation? World J Psychiatry. 2016 Mar 
22;6(1):84–101.  
37.  Beck WR, Scariot PPM, Gobatto CA. Primary and secondary thrombocytosis 
induced by exercise and environmental luminosity. Bratisl Lek Listy. 
2014;115(10):607–10.  
38.  Bernhardt J, Hayward KS, Kwakkel G, Ward NS, Wolf SL, Borschmann K, et al. 
Agreed definitions and a shared vision for new standards in stroke recovery 
research: The Stroke Recovery and Rehabilitation Roundtable taskforce. Int J 
Stroke. 2017 Jul;12(5):444–50.  
39.  Shen J, Huber M, Zhao EY, Peng C, Li F, Li X, et al. Early rehabilitation 
aggravates brain damage after stroke via enhanced activation of nicotinamide 

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
63 
adenine dinucleotide phosphate oxidase (NOX). Brain Res. 2016 Oct 
1;1648:266–76.  
40.  Li F, Shi W, Zhao EY, Geng X, Li X, Peng C, et al. Enhanced apoptosis from 
early physical exercise rehabilitation following ischemic stroke. J Neurosci Res. 
2017;95(4):1017–24.  
41.  Li F, Jr JTP, Ding JN, Peng C, Li X, Shen J, et al. Exercise rehabilitation 
immediately following ischemic stroke exacerbates inflammatory injury. Neurol 
Res. 2017 Jun 3;39(6):530–7.  
42.  Carmichael ST, Archibeque I, Luke L, Nolan T, Momiy J, Li S. Growth-
associated gene expression after stroke: evidence for a growth-promoting 
region in peri-infarct cortex. Exp Neurol. 2005 Jun 1;193(2):291–311.  
43.  Biernaskie J, Chernenko G, Corbett D. Efficacy of Rehabilitative Experience 
Declines with Time after Focal Ischemic Brain Injury. J Neurosci. 2004 Feb 
4;24(5):1245–54.  
44.  Strømmen AM, Christensen T, Jensen K. Intensive treadmill training in the 
acute phase after ischemic stroke: Int J Rehabil Res. 2016 Jun;39(2):145–52.  
45.  Pescatello L, Riebe D, Thompson P. ACSM’s Guidelines for Exercise Testing 
and Prescription. 9th ed. Lippincott Williams & Wilkins; 2014.  
46.  Abdullahi W, Tripathi D, Ronaldson PT. Blood-brain barrier dysfunction in 
ischemic stroke: targeting tight junctions and transporters for vascular 
protection. Am J Physiol - Cell Physiol. 2018 Sep 1;315(3):C343–56.  
47.  Novak Vera, Hu Kun, Desrochers Laura, Novak Peter, Caplan Louis, Lipsitz 
Lewis, et al. Cerebral Flow Velocities During Daily Activities Depend on Blood 
Pressure in Patients With Chronic Ischemic Infarctions. Stroke. 2010 Jan 
1;41(1):61–6.  
48.  Langhorne P, Wu O, Rodgers H, Ashburn A, Bernhardt J. A Very Early 
Rehabilitation Trial after stroke (AVERT): a Phase III, multicentre, randomised 
controlled trial. Health Technol Assess. 2017 Sep;21(54):1–120.  
49.  Intercollegiate Stroke Working Party. National Clinical Guidelines for Stroke. 
2016 [cited 2020 Jan 16];5. Available from: 
https://www.strokeaudit.org/SupportFiles/Documents/Guidelines/2016-National-
Clinical-Guideline-for-Stroke-5t-(1).aspx 
50.  Prajapati SK, Mansfield A, Gage WH, Brooks D, McIlroy WE. Cardiovascular 
Responses Associated with Daily Walking in Subacute Stroke. Stroke Res 
Treat. 2013;2013:1–7.  
51.  Cunha Polese J. Cardiorespiratory Stress is not Achieved During Routine 
Physiotherapy in Chronic Stroke. Int J Phys Med Rehabil. 2014;2(4).  

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
64 
52.  Sheedy R, Kramer SF, Johnson L, Shields N, Churilov L, Cadilhac DA, et al. 
Acute Hospital Admission for Stroke Is Characterised by Inactivity. Naess H, 
editor. Stroke Res Treat. 2020 Feb 11;2020:1–8.  
53.  Lawrence Enas S., Coshall Catherine, Dundas Ruth, Stewart Judy, Rudd 
Anthony G., Howard Robin, et al. Estimates of the Prevalence of Acute Stroke 
Impairments and Disability in a Multiethnic Population. Stroke. 2001 Jun 
1;32(6):1279–84.  
54.  Jørgensen HS, Nakayama H, Raaschou HO, Olsen TS. Recovery of walking 
function in stroke patients: The copenhagen stroke study. Arch Phys Med 
Rehabil. 1995 Jan;76(1):27–32.  
55.  Scrivener K, Sherrington C, Schurr K. Amount of Exercise in the First Week 
After Stroke Predicts Walking Speed and Unassisted Walking. Neurorehabil 
Neural Repair. 2012 Oct 1;26(8):932–8.  
56.  Prout EC, Mansfield A, McIlroy WE, Brooks D. Patients’ perspectives on aerobic 
exercise early after stroke. Disabil Rehabil. 2017 Mar 27;39(7):684–90.  
57.  Gaskins NJ, Bray E, Hill JE, Doherty PJ, Harrison A, Connell LA. Factors 
influencing implementation of aerobic exercise after stroke: a systematic review. 
Disabil Rehabil. 2019 Dec 25;0(0):1–15.  
58.  Hargreaves M, Wilkins L, Cook J. Decision Making Business Case for the 
Reconfiguration of Hyper Acute Stroke Services [Internet]. Joint Commitee of 
Clinical Commisioning Groups; 2017. Available from: 
https://smybndccgs.nhs.uk/application/files/8415/1074/0095/Decision_making_b
usiness_case_-_Hyper_acute_stroke.pdf 
59.  McGill K, Sackley CM, Godwin J, McGarry J, Brady MC. A systematic review of 
the efficiency of recruitment to stroke rehabilitation randomised controlled trials. 
Trials. 2020 Jan 10;21(1):68.  
60.  Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharm 
Stat. 2005;4(4):287–91.  
61.  ATS/ACCP Statement on Cardiopulmonary Exercise Testing. Am J Respir Crit 
Care Med. 2003 Jan 15;167(2):211–77.  
62.  Association of Chartered Physiotherapists in Cardiac Rehabilitation. Standards 
for Physical Activity and Exercise in the Cardiovascular Population. 2015;3.  
63.  MacKay-Lyons M, Billinger SA, Eng JJ, Dromerick A, Giacomantonio N, Hafer-
Macko C, et al. Aerobic Exercise Recommendations to Optimize Best Practices 
in Care After Stroke: AEROBICS 2019 Update. Phys Ther. 2020 Jan 
23;100(1):149–56.  
64.  Kramer SF, Cumming T, Bernhardt J, Johnson L. The Energy Cost of Steady 
State Physical Activity in Acute Stroke. J Stroke Cerebrovasc Dis. 2018 Apr 
1;27(4):1047–54.  

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
65 
65.  Johnson L, Kramer SF, Catanzariti G, Kaffenberger T, Cumming T, Bernhardt J. 
Safety of Performing a Graded Exercise Test Early after Stroke and Transient 
Ischemic Attack. Am Acad Phys Med Rehabil. 2019;1–8.  
66.  Robergs RA, Landwehr R. The surprising history of the “HRmax=220-age” 
equation. Off J Am Soc Exerc Physiol ASEP. 2002;5(2):10.  
67.  Karvonen MJ. Problems of training of the cardiovascular system. Ergonomics. 
1959;2(2):207–15.  
68.  Lau L, Lew J, Borschmann K, Thijs V, Ekinci EI. Prevalence of diabetes and its 
effects on stroke outcomes: A meta‐analysis and literature review. J Diabetes 
Investig. 2019 May;10(3):780–92.  
69.  Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et 
al. Physical Activity/Exercise and Diabetes: A Position Statement of the 
American Diabetes Association. Diabetes Care. 2016 Nov 1;39(11):2065–79.  
70.  Gale NK, Heath G, Cameron E, Rashid S, Redwood S. Using the framework 
method for the analysis of qualitative data in multi-disciplinary health research. 
BMC Med Res Methodol. 2013 Dec;13(1):117.  
71.  Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 
2006 Jan;3(2):77–101.  
72.  Sekhon M, Cartwright M, Francis JJ. Acceptability of healthcare interventions: 
Following considerable development in the field since 2006, MRC and NIHR 
have jointly commissioned an update of this guidance to be published in 2019. 
BMC Health Serv Res. 2017 Dec;17(1):88.  
73.  Steinman MA, Zullo AR, Lee Y, Daiello LA, Boscardin WJ, Dore DD, et al. 
Association of β-Blockers With Functional Outcomes, Death, and 
Rehospitalization in Older Nursing Home Residents After Acute Myocardial 
Infarction. JAMA Intern Med. 2017 Feb 1;177(2):254–62.  
74.  Ortiz GA, Sacco RL. National Institutes of Health Stroke Scale (NIHSS). Wiley 
Encycl Clin Trials. 2008;9.  
75.  van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA, van Gijn J. 
Interobserver agreement for the assessment of handicap in stroke patients. 
Stroke. 1988;19(5):604–7.  
76.  Mohan Keerthi M., Wolfe Charles D.A., Rudd Anthony G., Heuschmann Peter 
U., Kolominsky-Rabas Peter L., Grieve Andrew P. Risk and Cumulative Risk of 
Stroke Recurrence. Stroke. 2011 May 1;42(5):1489–94.  
77.  Ingeman Annette, Andersen Grethe, Hundborg Heidi H., Svendsen Marie L., 
Johnsen Søren P. In-Hospital Medical Complications, Length of Stay, and 
Mortality Among Stroke Unit Patients. Stroke. 2011 Nov 1;42(11):3214–8.  
78.  Rabin R, Charro F de. EQ-SD: a measure of health status from the EuroQol 
Group. Ann Med. 2001;33(5):337–43.  

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
66 
79.  Kroenke K, Spitzer RL. The PHQ-9: A New Depression Diagnostic and Severity 
Measure. Psychiatr Ann. 2002;32(9):509–15.  
80.  Spitzer RL, Kroenke K, Williams JBW, Löwe B. A Brief Measure for Assessing 
Generalized Anxiety Disorder: The GAD-7. Arch Intern Med. 2006 May 
22;166(10):1092–7.  
81.  Chen Ming-De, Rimmer James H. Effects of Exercise on Quality of Life in 
Stroke Survivors. Stroke. 2011 Mar 1;42(3):832–7.  
82.  Eng JJ, Reime B. Exercise for Depressive Symptoms in Stroke Patients: A 
Systematic Review and Meta-Analysis. Clin Rehabil. 2014 Aug;28(8):731–9.  
83.  Wegner M, Helmich I, Machado S, Nardi A, Arias-Carrion O, Budde H. Effects 
of Exercise on Anxiety and Depression Disorders: Review of Meta- Analyses 
and Neurobiological Mechanisms. CNS Neurol Disord - Drug Targets. 2014 Jun 
12;13(6):1002–14.  
84.  Scheier MF, Carver CS, Bridges MW. Distinguishing optimism from neuroticism 
(and trait anxiety, self-mastery, and self-esteem): A reevaluation of the Life 
Orientation Test. J Pers Soc Psychol. 1994;67(6):1063–78.  
85.  Rasmussen HN, Scheier MF, Greenhouse JB. Optimism and Physical Health: A 
Meta-analytic Review. Ann Behav Med Publ Soc Behav Med. 2009 
Jun;37(3):239–56.  
86.  Resnick B, Jenkins LS. Testing the Reliability and Validity of the Self-Efficacy 
for Exercise Scale. Nurs Res. 2000 Jun;49(3):154–159.  
87.  Korpershoek C, Bijl J van der, Hafsteinsdóttir TB. Self-efficacy and its influence 
on recovery of patients with stroke: a systematic review. J Adv Nurs. 
2011;67(9):1876–94.  
88.  Ozyemisci-Taskiran O, Batur EB, Yuksel S, Cengiz M, Karatas GK. Validity and 
reliability of fatigue severity scale in stroke. Top Stroke Rehabil. 2019 Feb 
17;26(2):122–7.  
89.  Micklewright D, St Clair Gibson A, Gladwell V, Al Salman A. Development and 
Validity of the Rating-of-Fatigue Scale. Sports Med Auckl Nz. 
2017;47(11):2375–93.  
90.  Borg G. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 
1982;14(5):377–81.  
91.  Thomas K, Hjalmarsson C, Mullis R, Mant J. Conceptualising post-stroke 
fatigue: a cross-sectional survey of UK-based physiotherapists and occupational 
therapists. BMJ Open. 2019 Dec 1;9(12).  
92.  Pollock A, St George B, Fenton M, Firkins L. Top 10 research priorities relating 
to life after stroke--consensus from stroke survivors, caregivers, and health 
professionals. Int J Stroke Off J Int Stroke Soc. 2014 Apr;9(3):313–20.  

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
67 
93.  Kennedy C, Kidd L. Interventions for post-stroke fatigue: A Cochrane review 
summary. Int J Nurs Stud. 2018 Sep;85:136–7.  
94.  Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, 
et al. The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For 
Mild Cognitive Impairment. J Am Geriatr Soc. 2005;53(4):695–9.  
95.  Oberlin LE, Waiwood AM, Cumming TB, Marsland AL, Bernhardt J, Erickson KI. 
Effects of Physical Activity on Poststroke Cognitive Function: A Meta-Analysis of 
Randomized Controlled Trials. Stroke. 2017 Nov;48(11):3093–100.  
96.  Toledo DO, Silva DC de L e, dos Santos DM, de Freitas BJ, Dib R, Cordioli RL, 
et al. Bedside ultrasound is a practical measurement tool for assessing muscle 
mass. Rev Bras Ter Intensiva. 2017;29(4):476–80.  
97.  Strasser EM, Draskovits T, Praschak M, Quittan M, Graf A. Association 
between ultrasound measurements of muscle thickness, pennation angle, 
echogenicity and skeletal muscle strength in the elderly. Age. 2013 
Dec;35(6):2377–88.  
98.  Scherbakov N, von Haehling S, Anker SD, Dirnagl U, Doehner W. Stroke 
induced Sarcopenia: Muscle wasting and disability after stroke. Int J Cardiol. 
2013 Dec 10;170(2):89–94.  
99.  English C, McLennan H, Thoirs K, Coates A, Bernhardt J. Loss of Skeletal 
Muscle Mass after Stroke: a Systematic Review. Int J Stroke. 2010 Oct 
1;5(5):395–402.  
100.  Nozoe M, Kanai M, Kubo H, Kitamura Y, Shimada S, Mase K. Changes in 
quadriceps muscle thickness in acute non-ambulatory stroke survivors. Top 
Stroke Rehabil. 2016 Jan 2;23(1):8–14.  
101.  Bull FC, Maslin TS, Armstrong T. Global Physical Activity Questionnaire 
(GPAQ): Nine Country Reliability and Validity Study. J Phys Act Health. 2009 
Nov;6(6):790–804.  
102.  Lang CE, Lohse KR, Birkenmeier RL. Dose and timing in neurorehabilitation: 
Prescribing motor therapy after stroke. Curr Opin Neurol. 2015 Dec;28(6):549–
55.  
103.  Edwardson CL, Winkler EAH, Bodicoat DH, Yates T, Davies MJ, Dunstan 
DW, et al. Considerations when using the activPAL monitor in field-based 
research with adult populations. J Sport Health Sci. 2017 Jun 1;6(2):162–78.  
104.  López-Cancio E, Ricciardi AC, Sobrino T, Cortés J, de la Ossa NP, Millán M, 
et al. Reported Prestroke Physical Activity Is Associated with Vascular 
Endothelial Growth Factor Expression and Good Outcomes after Stroke. J 
Stroke Cerebrovasc Dis. 2017 Feb 1;26(2):425–30.  
105.  Reinholdsson M, Palstam A, Sunnerhagen KS. Prestroke physical activity 
could influence acute stroke severity (part of PAPSIGOT). Neurology. 2018 Oct 
16;91(16):e1461–7.  

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
68 
106.  Mahoney F, Barthel D. Functional Evaluation: The Barthel Index. Md State 
Med J. 1965;14:56–61.  
107.  Stookey AD, Katzel LI, Steinbrenner G, Shaughnessy M, Ivey FM. The Short 
Physical Performance Battery as a Predictor of Functional Capacity after 
Stroke. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc. 2014 Jan;23(1).  
108.  Watson M. Refining the Ten-metre Walking Test for Use with Neurologically 
Impaired People. Physiotherapy. 2002;88(7):386–97.  
109.  Basílio ML, de Faria-Fortini I, Polese JC, Scianni AA, Faria CD, Teixeira-
Salmela LF. Handgrip strength deficits best explain limitations in performing 
bimanual activities after stroke. J Phys Ther Sci. 2016;28(4):1161–5.  
110.  Kwakkel G, Lannin NA, Borschmann K, English C, Ali M, Churilov L, et al. 
Standardized measurement of sensorimotor recovery in stroke trials: 
Consensus-based core recommendations from the Stroke Recovery and 
Rehabilitation Roundtable. Int J Stroke. 2017 Jul 1;12(5):451–61.  
111.  Bathala L, Mehndiratta MM, Sharma VK. Transcranial doppler: Technique and 
common findings (Part 1). Ann Indian Acad Neurol. 2013;16(2):174–9.  
112.  Boyne P, Meyrose C, Westover J, Whitesel D, Hatter K, Reisman DS, et al. 
Exercise intensity affects acute neurotrophic and neurophysiological responses 
poststroke. J Appl Physiol. 2018 Dec 20;126(2):431–43.  
113.  Kargotich S, Goodman C, Keast D, Morton AR. The Influence of Exercise-
Induced Plasma Volume Changes on the Interpretation of Biochemical 
Parameters Used for Monitoring Exercise, Training and Sport: Sports Med. 
1998;26(2):101–17.  
114.  Voskoboinik A, Koh Y, Kistler PM. Cardiovascular effects of caffeinated 
beverages. Trends Cardiovasc Med. 2019 Aug 1;29(6):345–50.  
115.  Ragab S. Caffeine reduces cerebral blood flow in patients recovering from an 
ischaemic stroke. Age Ageing. 2004 May 1;33(3):299–303.  
116.  Gejl AK, Enevold C, Bugge A, Andersen MS, Nielsen CH, Andersen LB. 
Associations between serum and plasma brain-derived neurotrophic factor and 
influence of storage time and centrifugation strategy. Sci Rep. 2019 Jul 
4;9(1):1–9.  
117.  Dill DB, Costill DL. Calculation of percentage changes in volumes of blood, 
plasma, and red cells in dehydration. J Appl Physiol. 1974 Aug;37(2):247–8.  
118.  Page P, Hoogenboom B, Voight M. Improving the Reporting of Therapeutic 
Exercise Interventions in Rehabilitation Research. Int J Sports Phys Ther. 2017 
Apr;12(2):297–304.  
119.  Bernhardt J, Hayward KS, Dancause N, Lannin NA, Ward NS, Nudo RJ, et al. 
A stroke recovery trial development framework: Consensus-based core 

 
ATAS Protocol. V3 – 14.12.2020               STH:21298                       IRAS: 280320
 
                
69 
recommendations from the Second Stroke Recovery and Rehabilitation 
Roundtable: Int J Stroke. 2019 Oct 29;14(8):792–802.  
120.  Lohse Keith R., Lang Catherine E., Boyd Lara A. Is More Better? Using 
Metadata to Explore Dose–Response Relationships in Stroke Rehabilitation. 
Stroke. 2014 Jul 1;45(7):2053–8.  
121.  Sentinel Stroke Audit Programme. Sixth Annual Report: Stroke care received 
for patients admitted to hospital between April 2018 to March 2019. 2019;6. 
Available from: https://www.hqip.org.uk/resource/sentinel-stroke-national-audit-
programme-sixth-annual-report/#.Xj13jBP7RPN 
122.  Clarke DJ, Burton L-J, Tyson SF, Rodgers H, Drummond A, Palmer R, et al. 
Why do stroke survivors not receive recommended amounts of active therapy? 
Findings from the ReAcT study, a mixed-methods case-study evaluation in eight 
stroke units. Clin Rehabil. 2018 Aug;32(8):1119–32.  
123.  Slade SC, Dionne CE, Underwood M, Buchbinder R. Consensus on Exercise 
Reporting Template (CERT): Explanation and Elaboration Statement. Br J 
Sports Med. 2016 Dec;50(23):1428–37.  
124.  Peveler WW, Shew B, Johnson S, Palmer TG. A Kinematic Comparison of 
Alterations to Knee and Ankle Angles from Resting Measures to Active Pedaling 
During a Graded Exercise Protocol. J Strength Cond Res. 2012 
Nov;26(11):3004.  
125.  Jones A, Sealey R, Crowe M, Gordon S. Concurrent validity and reliability of 
the Simple Goniometer iPhone app compared with the Universal Goniometer. 
Physiother Theory Pract. 2014 Oct;30(7):512–6.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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17.   Appendix 
 
 
Table 7. Standardised verbal communication during aerobic exercise 
 
Scenario 
 
Verbal communication 
 
Cadence drops below 10% of initial self-
selected cadence. 
 
Can you go a little bit faster?  Aim for 
around ‘x’ rpm. Let me know if it feels too 
hard and I will change the resistance. 
 
Cadence exceeds 10% of initial self-
selected cadence. 
 
Can you slow it down a little bit? Aim for 
around ‘x’ rpm. Let me know if it feels too 
easy and I will change the resistance. 
 
Inconsistent cadence. 
 
Try and stick to around ‘x’ rpm. 
 
RPE drops below 13 but at target cadence. 
 
Maintain your speed at ‘x’ rpm, I’m going to 
increase the resistance a little bit. 
 
RPE exceeds 13 but at target cadence. 
 
Maintain your speed at ‘x’ rpm, I’m going to 
reduce the resistance a little bit. 
 
Beginning of each 5-min work phase. 
 
You have five minutes of work at this 
intensity.  
 
Fourth minute of each 5-min work phase. 
 
One minute left, you’re doing really well. 
 
End of 5-min work phase. 
 
Well done, you now have one minute of 
rest. Relax, the bike will move your legs for 
you. 
 
End of conditioning phase. 
 
Great effort, you have done really well 
today.