The Effect of the Self-empowered Upper Limb Repetitive Engagement (SURE) Program on Upper Limb Recovery Compared With Education in People With Stroke Undergoing Inpatient Rehabilitation
Phase: NA
Conditions: Stroke
Sponsor: Tan Tock Seng Hospital

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 1 of 23 
 
 
STUDY PROTOCOL 
 
PROTOCOL TITLE: 
Multimodal Imaging of Neuroplasticity in Upper Limb (UL) Recovery with Early Increased UL Practice 
after Stroke 
 
 
PROTOCOL NUMBER:  
2017/001 
 
PROTOCOL VERSION:  05 
PROTOCOL DATE:  
22 Jan 2018 
 
PRINCIPAL INVESTIGATOR:  
Clinical Principal Investigator (CPI) 
Ms Chin Lay Fong, Principal Physiotherapist, Tan Tock Seng Hospital Rehabilitation Centre (TTSHRC) 
 
Technical Principal Investigator (TPI) 
Dr Huang Weimin, Senior Scientist, Institute for Infocomm Research (I2R) 
 
SITE PRINCIPAL INVESTIGATOR:  
Clinical Principal Investigator (CPI) 
Ms Chin Lay Fong, Principal Physiotherapist, Tan Tock Seng Hospital Rehabilitation Centre (TTSHRC) 
 
 
STUDY SITE: 
Tan Tock Seng Hospital Rehabilitation Centre, 17 Ang Mo Kio Ave 9 Singapore 569766 
 
COLLABORATORS: 
Dr Mary Charlotte Stephenson, Senior Research Fellow, Clinical Imaging Research Centre (CIRC), Dr 
Effie Chew, National University Hosptial, (NUH) 
 
 
 
 
 
O F F I C I AL  U S E  O N L Y  
Doc Name : Protocol Template 
Doc Number : 207-002 
Doc Version : 03 
Date : 01 June  09 

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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ........................................................................................................................ 4 
1.1. 
GENERAL INTRODUCTION ........................................................................................................................................ 4 
1.2. 
RATIONALE AND JUSTIFICATION FOR THE STUDY ...................................................................................................... 7 
A. 
RATIONALE FOR THE STUDY PURPOSE ..................................................................................................................... 7 
B. 
RATIONALE FOR DOSES SELECTED ........................................................................................................................... 7 
C. 
RATIONALE FOR STUDY POPULATION ....................................................................................................................... 7 
D. 
RATIONALE FOR STUDY DESIGN .............................................................................................................................. 8 
2. 
HYPOTHESIS AND OBJECTIVES ......................................................................................................................... 8 
2.1. 
HYPOTHESIS ........................................................................................................................................................... 8 
2.4. 
POTENTIAL RISKS AND BENEFITS: ............................................................................................................................ 8 
A. 
END POINTS - EFFICACY ......................................................................................................................................... 8 
B. 
END POINTS - SAFETY ............................................................................................................................................ 9 
3. STUDY POPULATION..................................................................................................................................................5 
3.1. 
LIST THE NUMBER OF SUBJECTS TO BE ENROLLED. .................................................................................................. 10 
3.2. 
CRITERIA FOR RECRUITMENT ................................................................................................................................ 10 
3.3. 
INCLUSION CRITERIA ............................................................................................................................................ 10 
3.4. 
EXCLUSION CRITERIA ............................................................................................................................................ 10 
3.5. 
WITHDRAWAL CRITERIA ........................................................................................................................................ 11 
3.6. 
SUBJECT REPLACEMENT ......................................................................................................................................... 11 
4. 
TRIAL SCHEDULE ................................................................................................................................................... 11 
5. 
STUDY DESIGN ......................................................................................................................................................6 
5. 
STUDY DESIGN ................................................................................................................................................. 11 
5.1. 
SUMMARY OF STUDY DESIGN ................................................................................................................................ 12 
6. 
METHODS AND ASSESSMENTS ......................................................................................................................... 13 
6.1. 
RANDOMISATION AND BLINDING ........................................................................................................................... 15 
6.2. 
CONTRACEPTION AND PREGNANCY TESTING .......................................................................................................... 15 
6.3. 
STUDY VISITS AND PROCEDURES ........................................................................................................................... 15 
7. 
TRIAL MATERIALS ................................................................................................................................................. 17 
7.1. 
TRIAL PRODUCT (S) .............................................................................................................................................. 17 
7.2. 
STORAGE AND DRUG ACCOUNTABILITY .................................................................................................................. 17 
8. 
TREATMENT ............................................................................................................................................................. 17 
8.1. 
RATIONALE FOR SELECTION OF DOSE .................................................................................................................... 17 
8.2. 
STUDY DRUG FORMULATIONS ................................................................................................................................ 17 
8.3. 
STUDY DRUG ADMINISTRATION ............................................................................................................................. 18 
8.4. 
SPECIFIC RESTRICTIONS / REQUIREMENTS ............................................................................................................ 18 
8.5. 
BLINDING ............................................................................................................................................................. 18 
8.6. 
CONCOMITANT THERAPY........................................................................................................................................ 18 
9. 
SAFETY MEASUREMENTS .................................................................................................................................... 18 
9.1. 
DEFINITIONS ........................................................................................................................................................ 18 
9.2. 
COLLECTING, RECORDING AND REPORTING OF “UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR 
OTHERS” – UPIRTSO EVENTS TO THE NHG DOMAIN SPECIFIC REVIEW BOARDS (DSRB) ................................................... 18 
9.3. 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO THE HEALTH SCIENCE 
AUTHORITY (HSA) ....................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
9.4. 
SAFETY MONITORING PLAN ................................................................................................................................... 19 

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9.5. 
COMPLAINT HANDLING –....................................................................................................................................... 19 
10. DATA ANALYSIS ..................................................................................................................................................... 19 
10.1. 
DATA QUALITY ASSURANCE ................................................................................................................................... 19 
10.2. 
DATA ENTRY AND STORAGE .................................................................................................................................. 19 
11. SAMPLE SIZE AND STATISTICAL METHODS ................................................................................................ 19 
11.1. 
DETERMINATION OF SAMPLE SIZE ......................................................................................................................... 19 
11.2. 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................... 20 
12. ETHICAL CONSIDERATIONS .............................................................................................................................. 21 
12.1. 
INFORMED CONSENT ............................................................................................................................................. 21 
12.2. 
IRB REVIEW ......................................................................................................................................................... 21 
12.3. 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS .............................................................................................. 21 
13. PUBLICATIONS ....................................................................................................................................................... 21 
14. RETENTION OF TRIAL DOCUMENTS ............................................................................................................... 22 

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STUDY PROTOCOL 
 
1. 
BACKGROUND AND RATIONALE 
 
 
1.1. 
General Introduction 
 
Stroke is a significant cause of disability and the overall fourth-highest cause of disease burden in Singapore. 
Crude incidence of stroke in Singapore has increased from 187.9 (2008) to 196.7 (2012) per 100 000 
population1.The prevalence of stroke events is expected to increase worldwide due to the increase in the 
population aged above 65 years old. 
 
The mean annual direct medical cost of stroke in Singapore is S$12473.7, of which 93.6% of the cost comes 
from inpatient hospitalization. This amount is substantially higher than other prevalent inpatient 
hospitalization and other Asian countries. It does not account for outpatient rehabilitation services and direct 
non-medical cost such as out-of-pocket expenses and loss of work. It is important to bear in mind that the 
economic impact of stroke goes beyond acute care; it extends to costly prolonged institutional chronic care 
and rehabilitation. Therefore, it is important to maximize recovery after stroke to reduce disability and burden 
of care on individuals, within Singapore and worldwide.  
 
Upper limb (UL) recovery after stroke has been found to be limited. Singapore data has revealed that less 
than one-third of the stroke patients regained UL dexterity one year after their strokes.  The remaining two-
third of the stroke population had to live and cope with enormous losses associated with their UL 
impairments for the rest of their lives. In view of the importance of hand dexterity for the performance of daily 
functional tasks, rehabilitation efforts should be channelled into facilitating UL recovery after stroke.  
 
The effects of rehabilitation on UL recovery after stroke appear to be more pronounced in the first six months 
post-stroke. It appears that there might be an optimal time window for gaining favourable rehabilitation 
outcome post-stroke. 
 
During this optimal time window, the use and the practice of the affected UL influence neuroplasticity and 
facilitate UL recovery after stroke. On the other hand, the lack of affected UL use leads to the “learned non-
use” phenomenon and the development of compensatory strategies (i.e. overuse of non-affected UL), which 
interfere and hinder the neuroplasticity process for recovery. Therefore, the use and practice of the affected 
UL at the early phase post-stroke is crucial and important. 
 
This can also be seen from the results of early intervention studies. These studies have shown that additional 
early UL practice resulted in better UL functional outcomes when compared with conventional/ traditional 
therapy alone. For patients with less severe UL impairment, early increased UL practice appeared to have 
pushed them to a higher level of UL functional outcomes. This higher level of UL functional outcomes was 
maintained even up to 9 to 12months post-stroke.  
 
Gap in the Knowledge of Optimal Effective Early UL Practice 
For early increased UL practice, “more” might not necessary mean better as seen in the early constrained-
induced movement therapy (CIMT) study results. In these studies, lower intensity CIMT intervention was 
found to be more beneficial when compared with higher intensity CIMT intervention during the early post-
stroke phase. A possible explanation for this result was that the subjects in the higher intensity group might 
have experienced fatigue. In addition, the requirement of the higher intensity UL practice might have resulted 
in “blocked” practice schedule rather than the desired “distributed” practice schedule throughout the day. 
Distributed learning schedules have been found to lead to better motor task learning and performance. It 
appeared that early increased UL practice after stroke might be more effective if it is incorporated into 
affected UL practice and use distributed throughout the day rather than concentrating all the intensive UL 
practice within one therapy session in a day. 
 
To date, there are still gaps in the knowledge of the optimal dosage intensity, optimal timeline to commence 

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UL practice and optimal effective mode of early UL practice after stroke. 
 
Gap in the Knowledge of Neuroplasticity During Early Post-Stroke 
To fill the gaps in knowledge of early UL practice, the understanding of the neuro-biological mechanism of 
recovery after stroke might be the key to answer these questions. In fact, it has been found that early 
increased UL practice does not necessarily mean better outcomes in neuroplasticity. In studies of rats, it was 
found that forced overuse of the affected limb 7 days (by casting the unaffected limb) after an induced stroke 
actually caused an expansion of the neural injury and interference in the restoration of affected limb function. 
Although it is always important to interpret results of animal studies with caution, the results show that there 
is a need for a greater understanding of the neuroplasticity mechanism behind early UL increased practice, 
otherwise we might possibly do more harm than good to stroke patients. 
 
There is still a lack of studies investigating the neuroplastic reorganisation of increased UL practice during 
early post-stroke. Only one study has been found, thus far, on investigating the effect of early increased UL 
practice on neuroplasticity after stroke in humans.  In this recent study by Hubbard et al, fMRI (functional 
magnetic resonance imaging) showed that stroke patients in the early increased training group showed 
increased activation in ipsilesional anterior cingulate and supplementary motor areas, and reduced activation 
in contralesional cerebellum, when compared to the standard care group. The increased activation of 
ipsilesional anterior cingulate and supplementary motor areas in the early increased training group was 
associated with early motor learning and attention, and the reduction in the activation of the contralesional 
cerebellum was interpreted as constituting better recovery in stroke patients. 
 
Most studies investigated the effect of additional UL practice on neuroplasticity on patients of more than 3-
months post-stroke and patients of chronic stroke (>6-months post-stroke).  These studies did not include 
control groups of stroke patients without UL additional practice to compare their outcomes. If there was a 
control group in these studies, the controls were normal healthy subjects. 
 
The results of these studies showed that for stroke patients who had undergone a period of increased UL 
practice, there was a trend towards a decreased activation of contralesional motor area and supplementary 
motor areas and an increased activation in the ipsilesional motor area. This trend was approaching towards 
the activation pattern of normal healthy controls in their studies. However for stroke patients who had lower 
UL baseline motor capability, the gain in UL recovery after UL practice corresponded to an increase in both 
the ipsilesional and contralesional motor areas and supplementary motor areas. The neural reorganisation 
after increased UL practice after stroke varied across different individuals. 
 
The complexity of neural reorganisation and the lack of studies on early increased UL practice on the 
neuroplasticity mechanism after stroke cause this important scientific area to be poorly understood. The 
understanding of this scientific gap is important because most rehabilitations occur early post-stroke and it is 
during this period that UL training can interact to support spontaneous recovery for optimal functional 
outcomes for patients. 
 
Importance of Identification of Potential Imaging Biomarkers for Recovery 
Another key to understanding the neurobiological mechanism of recovery is to identify potential biomarkers 
for recovery at early post-stroke and its interaction with UL practice. In a study by Marshall et al, it showed a 
correlation between the results of early task-related fMRI with the motor recovery. Marshall et al suggested 
that the recovery related activation pattern justified the investigation on early intervention to enhance the 
recovery process. In a study by Yin et al, it was reported that a biomarker can potentially be identified for UL 
recovery after stroke using volume-based measurement and diffusion tensor imaging (DTI) based FA 
(Fractional Anisotropy) analysis. 
 
In another study, Bylow used transcranial magnetic stimulation (TMS) and diffusion weighted image (DWI) 
and linear regression to predict the increase of UL Fugl-Meyer (FM) score with standardized and variable 
dosage of therapy in his study. The study showed that UL recovery could be predicted by presence of motor 
evoked potentials (MEP), FA analysis of the corticospinal tract but was insensitive to the dosage of UL 
practice. Deeper analysis of the study revealed that the variable therapy dosage which was defined as 
duration of time was not controlled in this study. To draw conclusion that therapy dose does not affect UL 
recovery might be premature. However, this showed that it is important to consider the interaction of both the 
neurobiology conditions and UL training in post-stroke recovery. 

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A potential biomarker to investigate in this study will be FA of the corticospinal tract and its interaction with 
increased UL practice during early post-stroke. FA of the corticospinal tract at early post-stroke has been 
found to correlate to later stage UL recovery. Interestingly, FA of the corticospinal tract has also been shown 
to increase significantly after training. Another potential biomarker to investigate in this study will be resting 
state fMRI, based on a previous A*STAR study which showed that individual gain in FM scores over 12 
weeks could be predicted from the resting state fMRI. 
 
Loss of Opportune Time During Early Post-Stroke To Influence Neuroplasticity  
A recent systematic review of stroke patients in hospitals has revealed that the mean duration of UL activity 
training during a physiotherapy (PT) session was 4.1 minutes to 5.7 minutes and 17 minutes during an 
occupational therapy (OT) session during the acute phase. The duration and repetitions in each UL training 
session in clinical practice are far below what are required for to effect a cortical re-organization in motor skill 
learning. With further reduction in manpower in healthcare due to rising healthcare needs, implies that 
employing more therapist manpower to increase current UL practice after stroke will be even more 
challenging.  
 
It has been found that stroke patients spent most of their time in the hospital ward being inactive. Studies 
have shown that the use and practice of affected UL was also minimal in the ward. Bernhardt et al (2007) 
found that stroke patients only used their affected UL 1% out of the activities of the day in the ward. The time 
during which the stroke patients spend in the ward is an opportune time for them to increase their affected UL 
practice and use. It also captures the optimal time window for neuroplasticity, and thus should be fully utilised 
and not be wasted.  
 
The findings mentioned above showed that implementing therapy to increase UL practice in real clinical 
world is a challenge. The answers to the questions of neuroplasticity of early UL practice early post-stroke 
will only be meaningful if we can develop innovative ways to facilitate affected UL practice throughout the day 
in the ward to achieve the desired neuroplasticity for optimal recovery after stroke, even with reduced 
manpower. Hence, the purpose of this study is to develop and evaluate a new and innovative way of 
enhancing therapy to increase UL practice early post-stroke in the ward. 
 
Background on Preliminary Data/ Results  
Patients can be empowered to take ownership of their practice and recovery. This can be seen in a multi-site 
single blinded randomized controlled trial of GRASP (Graded Repetitive Arm Supplementary Program). 
GRASP is a self-administered graded program that incorporate additional complementary UL practice in the 
ward (on top of regular therapy sessions) by the patients without the direct involvement of therapists during 
practice.  This is made feasible by giving stroke patients and their caregiver instruction booklets (based on 
the level of the affected UL function) and teaching them on the self-administered exercises found in the 
booklet. This is followed by regular and consistent reviews by therapists to check and progress the exercises. 
The result of this trial showed that patients in GRASP group achieved better UL outcomes post treatment 
than the control. In addition, the gains in the GRASP group were sustained 5 months after the program. The 
program has also utilized an important source of manpower – patient and their caregiver, which has often 
been underutilized or sometimes even neglected.  
 
However, GRASP does not include the component of affected UL daily functional use. Affected UL daily 
functional use is important because from clinical experience, stroke patients often confine the practice of their 
affected UL to just during therapy sessions, as most of them do not know how to use their affected UL after 
stroke, especially for those with lower UL motor function. Reduced affected UL use perpetuates even to 
chronic phase as they have not learned how to incorporate the use of their affected UL in daily life, resulting 
in the phenomenon of “learned non-use”. 
 
In this new proposed program, Self-empowered Upper Limb Repetitive Engagement (SURE) program, 
specific instructions and guidance according to the level of their affected UL motor function will be given to 
guide and increase affected UL daily functional use in stroke patients in the ward. In addition, prescribed 
specific exercise according to the level of their affected UL motor function will also be given and guided to 
facilitate patients to exercise by themselves in the ward. The activity of the affected UL will be objectively and 
accurately monitored, reviewed and feedback to the patients to facilitate affected UL use and practice using 
accelerometers. Accelerometry has been found to be valid and reliable in the measurement of UL use in 

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stroke patients.  
 
To date, there is no therapy program that has specifically and systematically been introduced in Singapore to 
facilitate UL practice and use of the stroke patients in the ward. Taking into consideration the challenge of 
increased UL practice during early post-stroke in the real clinical world, it is, therefore, important to 
investigate the feasibility and effectiveness of SURE program and the potential imaging biomarkers to 
optimize the neuro-rehab 
 
1.2. 
Rationale and justification for the Study 
 
 
a. 
Rationale for the Study Purpose 
The recovery of affected UL is important both functionally and psychologically for the stroke patients. Less 
than one-third of the stroke population has return of dexterity of affected UL after stroke. More can be and 
should be done to facilitate recovery of affected UL after stroke. 
 
Early increase UL practice has been shown to improve UL recovery. However, there are still gaps in the 
knowledge of optimal dosage, optimal timeline of commencement and efficacious mode of UL practice. The 
understanding of neuroplasticity and identification of potential imaging biomarkers at early post-stroke stage 
might be the key to answer these questions in early UL practice.  
 
Stroke patients can be empowered to take ownership of their practice and recovery. The practice of affected 
UL in the ward and the patients/ their caregivers are underutilized resources that can be taped into to 
increase UL practice. SURE program is a new and innovative program that empower stroke patients to 
increase UL practice in the ward early post-stroke to influence neuroplasticity and improve functional 
outcomes.  
 
Therefore, the aims of this study are: 
 
1) To investigate the feasibility and effectiveness of SURE program to increase UL practice in the ward 
and improve UL functional outcomes after stroke.  To correlate the imaging biomarkers with the 
neuro-recovery outcomes under SURE and controlled program. 
2) To investigate the neuroplasticity in the brain through multiple neuro-imaging analysis 
(fMRI/MRI/DTI), with the goal to develop imaging biomarkers for image-guided neuro-rehabilitation 
framework so as to optimize early UL practice after stroke. 
 
 
b. 
Rationale for Doses Selected 
 
The subjects will perform the self-exercises for 60 minutes (3x 10-20minutes) and functional tasks (as and 
when is required in the daily function) per day for 6 days per week in the ward throughout the 4 weeks 
intervention period. These exercises are performed in addition to daily therapy. Additional period of self 
exercises and affected UL’s functional use are performed in the ward to increase the dosage of affected UL 
activity as studies have found that amount of affected UL activity during therapy session are limited. 
 
c. 
Rationale for Study Population 
 
20 eligible stroke subjects with positive motor evoked potential (MEP +ve) and with severe to moderate UL 
paresis (ULFM score below or equal to 50) admitted to TTSHRC will be selected. Subjects with severe and 
moderate UL paresis are selected because based on clinical observation subjects with this level severity 
require intensive UL practice to improve their UL functions, while subjects with mild paresis do not require 
such high intensity of UL practice for significant improvement. Investigation of motor evoked potential on 
extensor carpi radialis on the affected hand will be performed on stroke patients at NUH using a single 
Magstim 200 to prognosticate recovery. Subjects with MEP +ve will be selected to ensure that all the 
subjects chosen in this study have intact ipsilesional cortical spinal tract function to make comparison of UL 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
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recovery more consistent. 
 
 
 
d. 
Rationale for Study Design 
 
Randomized blinded controlled trial study design has been selected for this study to investigate whether if 
SURE program improves UL functional outcome and influences neuroplasticity positively to optimize UL 
recovery after stroke. This study design is chosen to prevent any bias in the assessment of outcomes. 
 
 
 
2. 
HYPOTHESIS AND OBJECTIVES 
 
 
2.1. Hypothesis 
 
1. SURE program increases UL practice in the ward and improves UL functional outcomes post-
stroke 
2. Increased UL practice early post-stroke period influences neuroplasticity positively to optimize 
UL recovery 
3. Imaging biomarkers are associated with rehab-methods and recovery of UL post-stroke 
 
 
2.2. Primary Objectives 
 
 
To investigate the effectiveness of SURE program to increase UL practice in the ward and improve UL 
functional outcomes after stroke.  To correlate the imaging biomarkers with the neuro-recovery outcomes 
under SURE and controlled program. 
 
2.3. Secondary Objectives 
 
To investigate the neuroplasticity in the brain through multiple neuro-imaging analysis (fMRI/MRI/DTI), with 
the goal to develop imaging biomarkers for image-guided neuro-rehabilitation framework so as to optimize 
early UL practice after stroke. 
 
 
2.4. Potential Risks and benefits:  
 
a. 
End Points - Efficacy 
SURE program improves UL functional outcome and influences neuroplasticity positively to optimize UL 
recovery after stroke. 

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b. 
End Points - Safety 
SURE Program 
Subjects might experience fatigue at the early part of the exercise program. 
 
The CPI will tailor and review subjects’ exercises and the use of stroke-affected hand in daily tasks according 
subjects’ stroke-affected hand’s capability.    
 
The CPI will consult the treating rehabilitation team (including doctors, therapists, nurses) on the subjects’ 
medical and neurological stability before the commencement of teaching the exercises and each review. 
 
First session of teaching exercises 
CPI will pause, observe and ask each subject after teaching each exercise if they are tired. If they are tired, 
the CPI will stop teaching and let the subjects rest until they are not tired and ready to learn the next 
exercise. If the subjects are observed or express tiredness, the CPI will stop teaching the exercises for that 
session.  Subjects will be advised to stop doing their exercises if they feel tired or rest until they feel ready to 
continue to do the exercises. The caregivers who are assisting the subjects with self-exercises will be given 
the similar advice. Subjects will also be asked to record any pain or fatigue that they experience during 
performance of self-exercises in their Exercise Log. 
 
The next day after the first session 
CPI will check the subjects’ performance of their exercises and their level of tiredness, and also to reinforce 
the advice to rest if they are feeling tired. 
 
Subsequent reviews 
CPI will check the subjects’ performance of their exercises and their level of tiredness, and also to reinforce 
the advice to rest if they are feeling tired. 
 
Doctors, therapists and nurses who are taking care of the subjects in TTSHRC will be informed of the 
subjects’ participation in SURE program and will be kindly requested to keep a look out of any verbal and 
non-verbal expressions of fatigue by the subjects. They will be informed to give similar advice by CPI to stop 
exercise and rest before continually or stop the exercises entirely if the subjects are too tired on that 
particular day. CPI will be informed by the treating team of their findings and will continue to monitor the 
subjects’ suitability to continue with SURE program if there are reports of persistent fatigue due to self-
exercises in the ward. Additional monitoring of fatigue level will be performed at pre, 2 weeks of intervention, 
post-intervention assessment using the Stanford Fatigue Scale. 
 
A possible minimal risk is the development of allergy to the straps of the sensors. However, many research 
studies had used the sensors and there have been no reports of any adverse allergic reactions or problems 
reported with wearing the sensors. 
 
Transcranial Magnetic Stimulation (TMS) Screening 
TMS safety parameters have been documented and stimulation guidelines have been established 
(Wasserman, 1998). Seizures are the most important potential adverse event but are extremely rare. Mild 
headache, neck pain and discomfort from facial twitches are the most common and resolve spontaneously 
shortly after stimulation.  
 
Exclusion criteria include pregnancy, presence of cardiac pacemakers, orthodontics (braces), metal implant 
and intracranial implants such as ventriculoperitoneal shunts and clips. 
 
Functional Magnetic Resonance Imaging Investigation 
Magnetic Resonance Imaging use radio waves similar to those used in radio and TV transmission. These 
have a much lower energy than X rays and are considered biologically safe. We follow strict safety guidelines 
which are designed to prevent the possible hazards of MRI: burns and electric shocks. The main risk in MRI 
is injury or death arising from the action of the strong magnetic field on any metal objects on or within the 
body. This may result in flying metal objects or damage to tissue. Strict screening procedures to remove 
external metal objects and exclude unsuitable volunteers will be carried out.  
 

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Exclusion criteria include prior history of central nervous system disorders, significant head trauma, structural 
brain lesions and psychiatric disturbance.  In addition, subjects shall be excluded if they have pacemakers, 
metallic foreign bodies in the brain or eye, claustrophobia, tattoo, work with metal, or are pregnant. 
 
Other potential issues include (i) Excessive heating of tissue due to absorption of RF energy, (ii) peripheral 
nerve stimulation (PNS) that may cause an uncomfortable but not harmful tingling sensation in the limbs and 
(iii) acoustic noise generated during the scanning. Excess power deposition will be avoided by hardware and 
software controls that limit this to well within FDA limits of 3.2W/kg, and the scanner has in-built warnings that 
let the operator know when a given sequence may cause PNS, so that he/she may adjust the sequence 
accordingly. Such accidents have never occurred at CIRC and have only very rarely occurred elsewhere in 
the world. 
 
 
3. 
STUDY POPULATION 
 
3.1. List the number of subjects to be enrolled.  
20 subjects will be randomly assigned to a control (N=10) and experimental group (N=10). 4 normal healthy 
subjects will also be recruited for fMRI investigations. 
 
 
3.2. Criteria for Recruitment 
 
CPI will identify patients that will be admitted to TTSHRC based on their medical records.  CPI will then 
approach the patients’ therapist to confirm their eligibility for the recruitment to the study.   
 
3.3. Inclusion Criteria 
 
All patient subjects have to fit in the following Inclusion criteria to be included in the study: diagnosis of stroke 
due to infarct resulting in UL hemiparesis (with confirmation from MRI and Computed axial tomography (CT) 
scans); and admitted within first 21days post-stroke in TTSHRC with Montreal Cognitive Assessment (MoCA) 
score >=19. In addition, stroke subjects with positive motor evoked potential (MEP +ve) and with severe to 
moderate UL paresis (Upper Limb Fugl Meyer (ULFM) score below or equal to 50) admitted to TTSHRC will 
be selected. Subjects with severe and moderate UL paresis are selected because based on clinical 
observation subjects with this level severity require intensive UL practice to improve their UL functions, while 
subjects with mild paresis do not require such high intensity of UL practice for significant improvement. 
Investigation of motor evoked potential on extensor carpi radialis on the affected hand will be performed in 
NUH on stroke patients using a single Magstim 200 to prognosticate recovery. Subjects with MEP +ve will be 
selected to ensure that all the subjects chosen in this study have intact ipsilesional cortical spinal tract 
function to make comparison of UL recovery more consistent. 
 
All normal healthy subjects aged 21 years old and above who are able to give informed consent and follow 
commands will be recruited. 
 
 
3.4. Exclusion Criteria 
 
All subjects (includes the normal healthy subjects and patient subjects) meeting any of the following 
exclusion criteria at baseline will be excluded from participation. 
 
Exclusion criteria for subjects are:  
1. recurrent stroke or previous history of brain injury  
2. bilateral stroke 
3. cardiac disease that limit function by exertional dyspnea, angina or severe fatigue 
4. hemiplegic shoulder pain – visual analogue scale (VAS) >5/10 
5. previous orthopaedic conditions on affected UL such as frozen shoulder and fracture that interfere 

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Page 11 of 23 
with affected UL movement 
6. existing peripheral nerve or orthopaedic conditions that interfere with affected UL movement 
7. severe aphasia, neglect, agitation, or depression that can limit participation 
8. Additional exclusion criteria for TMS screening (Refer to Section 2.4b Endpoints Safety- TMS 
screening). 
9. Additional exclusion criteria for fMRI investigations are inability to follow the fMRI instructions, 
claustrophobia, and MRI safety concerns (Refer to Section 2.4b Endpoints Safety- fMRI 
investigations). 
 
3.5. Withdrawal Criteria  
 
Subject will be withdrawn from the study if the subject is unable to tolerate the SURE program 
 
 
3.6. Subject Replacement 
Subjects who drop out will be replaced 
 
4. 
TRIAL SCHEDULE 
 
 
 
Clinical Assessments 
(TTSHRC)/ no. of visit 
TMS Screening 
(NUH)/ no. of 
visit 
fMRI Investigations 
(CIRC@NUS)/no. of 
visit 
Pre-Intervention 
1 (Inpatient) 
1 (Inpatient) 
1 (Inpatient) 
Two 
weeks 
after 
start 
of 
Intervention 
1 (Inpatient) 
NIL 
NIL 
Post-Intervention 
1 (In/ Outpatient) 
NIL 
1 (In/ Outpatient) 
One Month Post-Intervention 
1 (Outpatient) 
NIL 
NIL 
Three Months Post-Intervention 
1 (Outpatient) 
NIL 
1 (Outpatient) 
 
SURE program intervention will start after pre-intervention TMS screening, clinical assessment and fMRI 
investigations. It consists of 4 weeks of additional 1 hour daily self-exercise and functional use of affected 
UL in the hospital ward 6 days a week. The subjects will require to wear an accelerometer on unaffected 
wrist for 3 weekdays of first week to establish baseline of use, and wear an accelerometer on affected wrist 
3 weekdays (8am -8pm each day) per week so that the actual affected UL use can be feedback to subjects 
during review. Please see attached file: Patient's_Involvement_In_Study_15_April_2017 for summary of 
each subject’s involvement in the study. 
 
 
5. 
STUDY DESIGN 
 
Experimental procedure 
 
The subjects will be randomly assigned to a control (N=10) and experimental group (N=10). 
 
Experimental Group 
The experimental group will receive one SURE program booklet with specific instructions and pictorial 
illustrations of each exercise and functional use according to their affected ULFM score. There are 3 booklets 
available (Level 1A for patients with affected ULFM score from 0 to 10; Level 1B for patients with affected 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 12 of 23 
ULFM score from 11 to 22; Level 2 for patients with affected ULFM score from 23 to 50). Each SURE 
program booklet consists of stretching exercises, strengthening exercises and performance of simple motor 
tasks such as reaching, picking up cubes etc. Each exercise will be graded and progressed according to the 
subjects’ affected UL capability by the Clinical Principal Investigator (CPI) who is an experienced principal 
physiotherapist. The SURE program booklet also consists of selected motor tasks to be performed by the 
subjects using their affected UL. Functional activities such as subjects will be using their affected UL to wipe 
their faces; wiping the table after eating; applying lotion by the affected hand along the unaffected arm and 
legs after shower; drinking water from cup/ bottle; lifting and placing affected hand on table top; etc. Each 
functional motor task will be selected, graded and progressed by the PI according to the subjects’ affected 
UL motor capability during the reviews. The subjects will be taught how to perform the exercises and 
functional tasks during the first session. The performance of the exercises and functional motor tasks will be 
reviewed by the CPI three times per week for the first 2 weeks, two times for the third week and one time for 
the fourth week of intervention period. 
 
The subjects will be asked to perform the exercises 60 minutes (3x 10- 20 minutes) distributed across 
morning, afternoon, and evening per day for 6 days per week during the 4-week intervention period. They will 
also be asked to perform the functional tasks as and when is required for their daily function for 6 days per 
week during the 4-week intervention period. The subjects will be given an Exercise Log to tick and track 
number of repetitions of the exercises and functional activities each day, the number of days the protocol is 
completed, and the level of fatigue and pain experienced.  If the subject is discharged from the hospital 
before the 4 weeks of intervention period, he/ she has to carry on with the protocol till the intervention period 
ends. The CPI will continue to review exercises and the amount of affected UL use with the subjects at home 
if the subjects are discharged till the intervention period ends.  
 
Control Group 
The control group will receive an education booklet with 10 modules. The education booklet will contain 
information on stroke, recovery and management strategies after stroke. Subjects are to complete 2-3 
modules per week and answer 1-2 simple questions after each module. Each module including answering 
questions takes approximately 5-10 minutes to complete. The CPI will review the information with the 
subjects 3 times per week for the first 2 weeks, two times for the third week and one time for the fourth week 
of intervention period. 
 
Both groups will continue with their daily routine therapy sessions in the hospital. The treating therapists will 
record the duration of therapy of each subject per day.  
 
UL functional outcome measures- ULFM and ARAT will be assessed pre-intervention, 2 weeks after start of 
intervention, post-intervention, 1month and 3months post-intervention. Measures of SURE program’s 
feasibility such as VAS pain score, fatigue level, and MAS of biceps and finger flexors will be measured pre-
intervention, 2 weeks after start of intervention and post-intervention. A team member who is blinded to which 
group the subjects are in will perform the outcome measure assessments. 
 
Multimodal imaging for the normal healthy control will be performed once to establish the activation pattern in 
normal. Multimodal imaging assessment for the patient subjects will be done pre-intervention, post-
intervention, and 3months post-intervention. 
 
 
5.1. 
Summary of Study Design 
 
The subjects will be randomly assigned to a control (N=10) and experimental group (N=10). The control 
group will undergo an education program while the experimental group will undergo the SURE program. 
Clinical assessments for both groups will be performed by a blinded assessor at pre, two weeks after start of 
intervention, immediate post intervention, 1 and 3months post-intervention to determine if the SURE program 
improve affected UL functional outcomes compared with the control group. fMRI investigations will be 
performed at pre-intervention, post- intervention and 3months post-intervention to determine if the increased 
UL activity in the SURE program influences brain neuroplasticity positively early post-stroke.  
 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 13 of 23 
6. 
METHODS AND ASSESSMENTS 
 
Outcome Measures 
UL functional outcome measures 
UL Fugl Meyer Scale (ULFM) 
UL Fugl Meyer Scale will be used to stratify subjects to their level of UL severity and assessment of UL 
impairment. ULFM score can be subdivided into 3 categories to define the different level of severity of 
paresis (severe= 0 to 22; moderate=23 to 50; mild>= 51). ULFM will be one of the primary outcome 
measures to determine UL recovery. 
 
Action Research Arm Test (ARAT) 
ARAT will be used as the primary outcome measure of UL functional outcome. ARAT will be one of the 
primary outcome measures to determine UL recovery. 
 
Measure of UL practice and use  
Rating of Everyday Arm-use in the Community and Home (REACH Scale) 
The REACH scale is a self-report measure that captures how much an individual with stroke use affected UL 
outside clinical setting. It has one scale for subjects whose dominant UL is affected and another scale for 
subjects whose non-dominant UL is affected. It will be used to rate patients’ affected UL use after discharge. 
 
Measure of UL practice and use using accelerometry 
One tri-axial accelerometer (ActiGraph GT3X+, ActiGraph LLC, Pensacola, Florida) will be placed on 
subject’s unaffected wrist to establish the duration of unaffected UL use in the ward for 3 days in the first 
week. Another tri-axial accelerometer will be placed on subject’s affected wrist for 3 weekdays each week of 
the 4-week intervention period to assess the amount of affected UL use. The accelerometers will be worn by 
all subjects (both experimental and control groups) from 8am to 8 pm on the day of donning. 
 
Measures of feasibility of accelerometry in measuring affected UL use 
The compliance rate of wearing the accelerometers during the 4 weeks of intervention period will be used to 
assess compliance. Subjects will also be asked to fill a questionnaire to rate the acceptance, ease, comfort, 
discomfort, benefits, and problems of wearing the accelerometers in the ward. 
 
Measures of SURE program’s feasibility 
The key measure of SURE program’s feasibility will be the additional affected UL practice and use per day as 
measured by the accelerometers. 
 
Subjects’ fatigue levels will be assessed using 0-10 point Stanford Fatigue Visual Numeric Scale (Stanford 
Patient Education Research Centre, n.d). Subjects’ level of affected UL pain will be assessed using 0-10 
rating Visual Analogue Scale (VAS). Subjects’ UL spasticity level for biceps and finger flexors will be 
assessed using Modified Ashworth Scale (MAS). These assessments will be performed pre, 2 weeks in 
training, and post-training. 
 
SURE program feasibility is also assessed by the compliance rate, dropout rate and any adverse events 
reported during the intervention period. 
 
Subjects and their caregiver will be asked to fill up a questionnaire to rate on SURE program’s ease, benefit 
and overall satisfaction based on VAS (rating 0 -10). In addition, 10 nurses in the ward who have taken care 
of the stroke patients undergoing the SURE program in the ward will also be asked to fill up a questionnaire 
to rate the ease, difficulty, advantages and disadvantages on SURE program implementation in the ward. 
 
TMS Screening  
A research staff will apply TMS to the subject. The subject will be seated comfortably and instructed to 
remain as still as he/ she can. A tight swim cap will be worn by the subject. The vertex will be marked on the 
cap. Singe pulse TMS was delivered using a single Magstim 200 via the coil of figure of eight. The coil 
position was maintained manually by the assistant and the handle of the coil point to posterior with an angel 
of 45 degree to the sagittal plane. Surface electromyography (EMG) electrodes are attached to the extensor 
carpi radialis (ECR) for EMG recording. The “hot spot” of the motor evoked potential (MEP) from ECR is first 
identified and marked for affected side. This spot will be used for all recordings on that side. The subject will 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 14 of 23 
be considered MEP positive if more than or equal 50µV amplitude can be elicited in 50% of 10 successive 
trials while the muscle is at rest. If this criterion is not met with stimuli delivered at maximal intensity, the 
subject will be considered MEP negative.  
 
 
Multimodal MRI imaging and Analysis 
MRI data acquisition 
Multimodal MRI data (T1, T2-flair, PCASL, DTI, MRS, resting-state fMRI and task-based fMRI) will be 
collected immediately pre-, post-, and 3months post treatment using a 3T Siemens MR system at the Clinical 
Imaging Research Centre using a 32 channel receive array head coil. Measurements will be made to assess 
changes in brain structure, metabolic status and connectivity as follows: 
 
For anatomical delineation of the stroke lesion, and for normalization of functional data, a T1 weighted 
MPRAGE image (1mm3 isotropic voxels, 176 sagittal slices, TI/TE/TR=900/3/1950ms) and a T2 weighted 
FLAIR image (1x0.5x2mm, TI/TE/TR= 2500/78/2500ms) will be acquired. 
 
To investigate changes in metabolic status of the tissue, a pseudo-continuous arterial spin labelled 
acquisition (PCASL) will be used to assess brain perfusion (3mm isotropic voxels). In addition, magnetic 
resonance spectroscopy will be used to measure concentrations of gamma-amino butyric acid (GABA, the 
main inhibitory neurotransmitter) and Glx (glutamate plus glutamine concentrations, the main excitatory 
neurotransmitter and its cycling intermediate) from a MEGA-PRESS localized volume in primary motor cortex 
(2x2x2cm volume) 
 
For assessment of changes in neuronal connectivity, Diffusion Tensor Images (68 directions, b=1000, 
TE/TR=98/9100ms, plus 6 b=0 scans, 2mm isotropic voxels) will be collected to assess changes in fractional 
anisotropy related to structural connectivity. To investigate changes in functional connectivity, resting state 
connectivity data will be collected, as well as assessing changes in activation induced fMRI BOLD responses 
during an elbow extension task. 
 
fMRI Activation paradigm 
Subjects will be asked to extend their elbow to push against a bulb distally in a self-directed comfortable pace 
on a wooden/plastic board secured on their abdomen during fMRI investigation. All subjects will practice 
outside the scanner to reduce the mirror movements from the unaffected UL. For the task based acquisition, 
12s of active task will be followed by 16s of resting (to allow the hemodynamic response to return to 
baseline). This will be repeated 9 times. 
 
Neuroplasticity Investigation 
fMRI imaging and image Analysis 
Imaging is performed as above. Blood oxygenation level dependent (BOLD) images will be acquired to study 
the dynamic changes in brain activation in subjects during the investigation. The semi-automatic 
segmentation of the brain and atlas registration using FSL with the standard human brain atlas will be used 
to map the fMRI to atlas. Group analysis used in FSL will be applied to identify the functional activation and 
changes. 
 
Multi-modality longitudinal brain function analysis 
The modalities include T1, T2-flair, event-based fMRI BOLD, resting-state fMRI BOLD and DTI, as shown in 
Fig. 1. T1 image provides the anatomical structural information of the subject’s brain. Haemorrhagic lesion 
also can be observed in T1 image. T2-flair provides the ischemic stroke lesion information. Event-based fMRI 
BOLD images will be used to find out the cortical activities that relate to subject’s movement. The difference 
between pre- and pro- retaliation will be analysed to verify the retaliation performance. The difference 
between resting-state fMRI BOLD and event-based fMRI BOLD imaging is that the subject is requested to 
keep conscious but don’t do any activity. It is used to recover functional connectivity inside subject’s brain. In 
this study, the change of functional connectivity between pre- and pro- retaliation will be analysed as well. 
Diffusion-tensor magnetic resonance imaging, or DTI, is to map white matter tractography in subject’s brain. 
The longitudinal changes of patients’ white matter connectivity will be analysed during rehabilitation. 
 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 15 of 23 
T1 image
T2-flair image
fMRI images
DTI images
fMRI resting 
state images
Brain 
extraction
Stroke lesion 
labeling
EPI/Motion 
correction
EPI/Motion 
correction
CSF 
contamination
/EPI/Motion/
Eddy current 
correction
Longitudinal 
cortical 
thickness 
analysis
longitudinal 
lesion 
development 
analysis
Lesion 
excluded co-
registration
Longitudinal 
function shift 
analysis
Lesion 
excluded co-
registration
Longitudinal 
functional 
connectivity 
analysis
Lesion 
excluded co-
registration
Longitudinal 
brain 
connectivity 
analysis
 
 
Figure 1. Multimodal MRI analysis diagram for early increased UL practice 
 
The processing of the acquired multi-modality data is shown in Fig. 1. As the stroke may destroy part of 
patient’s brain tissues, the stroke lesion(s) should be labelled using T2-flair image then convert to T1 image 
space. The brain structure should be accurately extracted from T1 structural image as it will be used as a 
middle point in fMRI-template, DTI-template co-registration and cortical thickness estimation as well. In the 
co-registration process, lesion areas should be excluded to prevent miss-alignment on the remaining healthy 
structures. 
 
MRS data will be analysed using in-house based matlab scripts (GABA) and LCModel software (NAA, Cr, 
Cho, Glx). For LCModel an 18 metabolite basis dataset (TE appropriate) will be used. Concentrations will be 
corrected to absolute values using water referencing and, additionally, GABA concentrations will be provided 
relative to Cr.  To account for tissue losses, concentrations will be corrected for tissue fraction based on the 
T1 weighted image (assuming concentrations are constant across tissue, no WM/GM differences). 
Concentrations of Lactate will not be tissue corrected as it exists in significant concentrations in CSF. 
 
6.1. 
Randomisation and Blinding 
 
Random assignment of subjects will be done using the randomizer found in the web (www.Randomizer. 
org/form.htm). A non-team member will generate the randomized allocation sequence, seal the group 
numbers in individual envelopes, and arrange them according to the randomized allocated sequence. These 
envelopes will be kept under lock and key in TTSHRC. The same non-team member will pass these sealed 
envelopes in accordance to the randomized allocated sequence one at a time to the CPI who will enrol and 
assign the eligible subjects to their groups. The unmasking of the randomization will be at the end of data 
collection and fMRI analysis. A blinded assessor will perform all the clinical assessments. The I2R who will 
be performing the fMRI analysis will be blinded to the group which the subjects are in. 
  
6.2. 
Contraception and Pregnancy Testing 
 
Although MRI is a non-invasive and non-radioactive imaging technology and is not known to affect baby’s 
development, it is prudent to exclude pregnant women. If the subject become pregnant during this study, she 
must stop participating and call your doctor or the Principal Investigator immediately. 
 
6.3. 
Study Visits and Procedures 
 
 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 16 of 23 
a. 
Screening Visits and Procedures 
CPI will identify patients that will be admitted to TTSHRC based on their medical records based on the 
study’s patients’ inclusion and exclusion criteria. Once the CPI check that the particular patient meets all the 
inclusion’s criteria, she will then approach the patients’ therapist to confirm that patient’s eligibility for the 
recruitment to the study. In addition, the CPI will also check with the treating doctor to find out if that patient is 
medically fit and stable to travel to CIRC and back. Once the treating therapist confirms that that particular 
patient meets the study inclusion’s criteria and the treating doctor confirms that the patient is medically fit and 
stable for the travel, the patient will then be approached to invite to participate in the study. If that patient 
agrees to participate in the study, he/ she will have to sign informed consent, and complete a pre-intervention 
clinical assessment and a fMRI investigation before the commencement of the study’s intervention. 
 
b. 
Study Visits and Procedures 
 
 
Clinical Assessments 
(TTSHRC)/ no. of visit 
TMS Screening 
(NUH)/ no. of 
visit 
fMRI Investigations 
(CIRC@NUS)/no. of 
visit 
Pre-Intervention 
1 (Inpatient) 
1 (Inpatient) 
1 (Inpatient) 
Two 
weeks 
after 
start 
of 
Intervention 
1 (Inpatient) 
NIL 
NIL 
Post-Intervention 
1 (In/ Outpatient) 
NIL 
1 (In/ Outpatient) 
One Month Post-Intervention 
1 (Outpatient) 
NIL 
NIL 
Three Months Post-Intervention 
1 (Outpatient) 
NIL 
1 
(Outpatient) 
 
4 weeks of SURE program intervention will start continuously after pre-intervention TMS screening, clinical 
assessment and fMRI investigation.  
 
The CPI who has successfully completed all the prescribed requirements of the CPR + AED Course will 
accompany the inpatient subjects to NUH and CIRC at NUS for TMS screening and fMRI scanning in 
ambulance from TTSHRC and back to TTSHRC to ensure safety of the subjects during transit for TMS 
screening and fMRI scanning.  
 
The CPI following the subjects to and back from NUH and CIRC will follow the routine inter-institution 
transportation protocol for patients with AWAS 0- 1 (see attached document: JCI-ACC-HAP-008.doc).  
 
Before any TMS and fMRI appointment is made, the CPI will check with the treating doctor if the subject is 
clinical fit to travel, if the doctor deems the subject clinically unfit to travel, no TMS or fMRI appointment will 
be made. 
 
On the day of travel, the CPI will check with the treating doctor if the subject is clinical fit to travel, if the 
doctor deems the subject clinically unfit to travel, the ambulance services and TMS/ fMRI will be cancelled for 
that day and the subject will remain in the ward and not travel. If the doctor deems the subject clinically stable 
to travel, the subject will be accompanied by CPI and paramedic in the ambulance service to NUH and CIRC. 
 
In the process of transportation, if the subject suffers any adverse events or re-stroke, the paramedic 
accompanying the subject in the ambulance will manage the emergency situations and send the subject to 
the nearest hospital Emergency Department. The CPI will call the treating doctor in TTSHRC to inform and 
update on the emergency situation and subject’s location. The CPI will stay with the subject until further 
instructions has been given by the treating doctor in TTSHRC. 
 
 

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c. 
Final Study Visit: 
 
The final study visit will be either the three-months post-intervention clinical assessment or fMRI 
investigation. 
 
d. 
Post Study Follow up and Procedures 
 
CPI will check on all clinical assessments and TPI will check on all fMRI investigations to ensure that all the 
assessments and investigations are done accurately and the results obtained are accurately. CPI and TPI 
will also check and monitor for any adverse events occurring during SURE program and fMRI investigations. 
 
e. 
Discontinuation Visit and Procedures 
 
All clinical assessments and fMRI investigations should be done until the subject indicate to the CPI that he/ 
she want to withdraw voluntarily from participation in the study at any time. Subjects may also withdraw 
voluntarily from receiving the SURE program for any reason. All the withdrawals and reasons for withdrawal 
will be evaluated to gain an insight to the feasibility of SURE program. As SURE program is a safe exercise 
program, no efforts will be made to follow-up if the subject chooses to withdraw from the program, unless 
subject has specifically requested for follow-up. 
 
 
7. 
TRIAL MATERIALS 
 
NIL 
 
7.1. 
Trial Product (s) 
 
NIL 
 
7.2. 
Storage and Drug Accountability 
 
NIL 
 
 
8. 
TREATMENT 
8.1. 
Rationale for Selection of Dose 
 
Exercise Dosage of SURE Program 
The subjects will perform the self-exercises for 60 minutes (3x 10-20 minutes) and functional tasks  (as and 
when it is required in the subjects’ daily function) per day for 6 days per week in the ward throughout the 4 
weeks intervention period. These exercises are performed in addition to daily therapy. Additional period of 
self exercises and affected UL’s functional use are performed in the ward to increase the dosage of affected 
UL activity as studies have found that amount of affected UL activity during therapy session are limited. 
Additional of 1 hour of affected UL activity (total of additional of 24 hours for intervention period) was chosen 
to enhance affected UL recovery 
 
See Appendix 1 to see details of SURE program booklet 
 
8.2. 
Study Drug Formulations 
 
NIL. 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 18 of 23 
8.3. 
Study Drug Administration 
 
NIL. 
 
8.4. 
Specific Restrictions / Requirements  
 
NIL 
 
8.5. 
Blinding 
 
The therapists performing the clinical assessments, the I2R and CIRC scientists performing the fMRI 
investigations and analysis will be blinded to which group the subjects are in. Only the CPI and another team 
member who will be carrying out the SURE program when PI is unavailable will know which group the 
subjects are in. The subjects will not be told which group they are in as well.  The SURE program and 
education program will be delivered to them without disclosing which group they are in. The unblinding is 
expected and will only occurs after all the clinical assessments and fMRI investigations are completed for 
individual subjects.  
 
8.6. 
Concomitant therapy 
 
Conventional therapy which occurs from Monday to Friday which includes approximately 45 minutes of 
physiotherapy and 45 minutes of occupational therapy daily in TTSHRC. 
 
 
9. 
SAFETY MEASUREMENTS 
9.1. 
Definitions 
 
UPIRTSO Events 
Occurrence of epileptic seizures during fMRI investigations 
 
 
Serious Adverse Events  
MRI related injury or death arising from the action of the strong magnetic field on any metal objects 
on or within the body 
 
 
Other adverse Events 
MRI related burns and electric shocks 
Development of allergy to the straps of the accelerometers 
 
9.2. 
Collecting, Recording and Reporting of “Unanticipated Problems Involving Risk 
to Subjects or Others” – UPIRTSO events and “Serious Adverse Events” (SAEs) 
to the NHG Domain Specific Review Boards (DSRB) 
 
Reporting Timeline for UPIRTSO Events and SAE to the NHG DSRB:  
 
1. Urgent Reporting: All problems involving local deaths, whether related or not, should be 
reported immediately – within 24 hours after first knowledge by CPI. 
 
2. Expedited Reporting: All other problems must be reported as soon as possible but not later 
than 7 calendar days after first knowledge by CPI. 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 19 of 23 
 
9.3. 
Collecting, Recording and Reporting of “Serious Adverse Events” (SAEs) to the 
Health Science Authority (HSA) 
NA 
 
 
9.4. 
Safety Monitoring Plan 
 
CPI will perform the clinical data and safety monitoring. TPI from I2R will perform the fMRI data and safety 
monitoring. Daily review of any possible adverse events such as medical adverse events, allergic reactions to 
the accelerometers' straps, adverse events of fMRI investigations. 
 
Refer to Section 9 Safety Measurement to understand the plan in place to ensure the safety and well-being 
of the subjects.  
 
Refer to 10.1 Data Quality Assurance to understand how integrity of data collected will be ensured. 
  
9.5. 
Complaint Handling  
 
CPI will handle complaints in consultation with TPI. If the data of complainants will still be used for analysis 
unless specified by the complainants not to be included in this study. 
 
 
10. 
DATA ANALYSIS 
10.1. Data Quality Assurance 
 
CPI will check the data of all clinical assessments and TPI will check on the data of fMRI investigations to 
ensure that the data obtained from this research is accurate, complete and reliable. Reviews will be 
performed daily. 
 
10.2. Data Entry and Storage 
 
Data from clinical assessments will be entered on paper. Soft copy of the research data will be stored in 
research staff's computers, laptops and portable hard disks. All the research staff involved in the investigation 
will use password protected laptops and PCs for development and study. The subjects' identifiers will be 
coded and be stored separately from the research data. The original personal data will only be accessed by 
the CPI. The data can only be accessed with the permission from the CPI. The CPI's personal computer and 
laptop are protected by password. The hard disk and hard copy of the data will be kept in a secure cupboard 
in TTSHRC. The anonymized data will only be available to CO-Is and related research personnel involved in 
the study. 
 
Data from fMRI investigations will be entered electronically. CPI, TPI,  I2R scientists, CIRC scientists will 
have accessed to fMRI data.  The data will be stored in a secured server (I2R), which is in a locked room and 
the data can only be accessed by password. 
 
 
11. 
SAMPLE SIZE AND STATISTICAL METHODS 
 
11.1. Determination of Sample Size  
 
Since this study is a pilot exploratory trial, results of individual subjects from each group will be analysed in 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 20 of 23 
detail to determine the difference in brain neuroplasticity between the control and experimental groups. N=10 
from each group is chosen because it is deemed feasible to recruit stroke patients who will be willing to 
participate in this study clinically in the period of 2 years (the time period of the funding). 
    
11.2. Statistical and Analytical Plans 
a. 
Study Statistical Analysis 
Statistical analysis will be performed using STATA version 10.0 for Windows (StataCorp, TX, USA). 
Descriptive statistics will be used to describe subjects’ demographics in each group.  
 
Analysis of UL Functional Outcome  
Wilcoxon signed-ranked tests will be used at each time points (pre, 2 weeks after start of intervention, post, 
1month post-intervention, 3months post-intervention) to compare UL functional outcomes between the 
experimental and control groups. The significance level for all statistical tests will be set at p<0.05 levels. All 
data will be analysed by intention to treat. 
 
Analysis of feasibility of accelerometers to measure affected UL use 
Analysis of the compliance rate and responses from the questionnaire will be used to determine the feasibility 
and acceptance of using accelerometers to measure affected UL use after stroke. 
 
Analysis of SURE Program’s feasibility 
Wilcoxon signed-rank test will also be used to compare outcomes of pain, fatigue and spasticity pre-and 
post-intervention period.  The differences in the duration of affected UL use per day and the ratio of affected 
UL use/ non-affected UL use between the experimental group and control group (from the accelerometer 
recordings), the rate of compliance, the proportion of subjects who successfully complete the whole training, 
and the dropout rate will be calculated to assess the feasibility of SURE Program.  
 
Analysis of fMRI investigation 
Comparison of activation in primary motor cortex, secondary motor cortex and cerebellar hemisphere for 
bilateral sides will be done by comparing mean percentage signal change (%SC), absolute voxel counts (VC) 
and changes in geometric centers of these areas on both sides17.  In addition, a laterality index (LI) will also 
be calculated to determine the relative cortical activity. Asymmetry has been found to restore to normal 
(L=1.0) when the affected hand movement improved after rehabilitation41. 
 
Analysis of resting state fMRI/DTI 
Functional connectivity and tract integrity32,38 will be studied by FSL with the normalization method39,40. The 
secondary degeneration of the brain in the remote region to the primary lesion will also be studied for the 
sub-groups of subjects with less motor recovery30. 
 
MRS analysis 
A one-way ANOVA test will be performed to assess differences across the visits (pre, post, and 3months 
post intervention). Provided a significant difference is found, a paired t-test will be used. Due to an 
abundance of measurable metabolites, metabolite analysis will be limited to those defined by our hypothesis 
(changes in GABA and Glx) to minimise multiple comparisons.  
 
b. 
Safety Analysis 
Safety analysis will be done by monitoring the adverse events and complaints of the study daily. 
 
c. 
Interim Analysis 
Interim analysis of the data and study’s safety and complaints will be performed every quarterly. If the 
analysis of study’s safety shows that the subjects’ safety is compromised because of the study procedures, 
the study will stop.  
 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 21 of 23 
 
12. 
ETHICAL CONSIDERATIONS 
12.1. Informed Consent 
 
CPI will explain to TTSHRC therapists of the study and the subjects' inclusion and exclusion criteria. CPI will 
check through the admission list to check for patients who meet the study’s inclusion criteria. When a patient 
is fit the study’s inclusion criteria and does not have any of the exclusion criteria, the CPI will approach the 
treating therapists to verify. Once the TTSHRC treating therapists have confirmed the patient’s suitability for 
the study, TTSHRC therapists will speak to that particular patient about the study. If that patient expresses 
interest in the study, the therapists will notify the CPI. The CPI will then approach the patient in the ward/ gym 
to explain the study in detail and give him/ her a Patient Information Sheet to consider. If the patient is willing 
to participate in the study, CPI will ask him/ her to sign the informed consent form.  
 
The consent process will take place in the ward when the patients are resting or in the gym when the patients 
are waiting for their therapy sessions. At the time of approach, patients should be calm. 
 
CPI who is currently doing her PhD study and not involve in direct patients' care will be the one doing 
informed consent for all the subjects. The CPI will speak in a soft and gentle voice so that the attention of the 
conversation by others will be minimal. 
 
For patients who cannot speak English/ cannot read English/ cannot sign on the informed consent form, 
translation in Chinese will be provided by the CPI. A witness will be present to witness the translation and will 
sign on the informed consent form as a witness. 
 
12.2. IRB review 
 
This study will gain IRB / NHG DSRB approval before commencement.  
 
12.3. Confidentiality of Data and Patient Records 
 
Information collected for this study will be kept confidential. Subjects’ records, to the extent of the applicable 
laws and regulations, will not be made publicly available.  
However, NHG Domain-Specific Review Board and Ministry of Health will be granted direct access to the 
original medical records to check study procedures and data, without making any of subjects’ information 
public.  
Refer to Section 10.2 Data Entry and Storage to understand how data will be entered and stored to ensure 
confidentiality of data and patient records 
 
13. 
PUBLICATIONS 
 
The study findings will be published in established Scientific journals without revealing subjects’ identities. 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 22 of 23 
 
14. 
RETENTION OF TRIAL DOCUMENTS 
 
Records for all participants, including CRFs, all source documentation (containing evidence to study 
eligibility, history and physical findings, laboratory data, results of consultations, etc.) as well as IRB records 
and other regulatory documentation will be retained by the CPI in a secure storage facility. Refer to Section 
10.2 Data Entry and Storage to understand how data will be stored securely. 
 
The records will be accessible for inspection and copying by authorized authorities. The data will be kept for 
minimum of 6 years in TTSHRC. I2R will use the anonymized data as specified by the research agreement. 
 

Study Protocol Number 2017/001, Version 05, Dated 22 Jan2018 
Page 23 of 23 
 
List of Attachments 
 
Appendix 1 
Please see attached SURE Program Booklets in the DSRB Application: 
 
SURE Program Booklet 1A 
SURE Program Booklet 1B 
SURE Program Booklet 2