Virtual Reality Glove for Hand and Arm Rehabilitation After Stroke
Phase: NA
Conditions: Stroke, Acute, Cerebral Infarction
Sponsor: Stanford University

 
 
 
 
Virtual Reality Glove for Hand and Arm Rehabilitation After Stroke 
Study Protocol and Statistical Analysis Plan 
NCT03741400 
December 6, 2021 

vREHAB - Virtual Reality Glove for Hand and Arm RehaBilitation 
Protocol V 3.0: 06DEC2021 
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PROTOCOL TITLE 
 
 
vREHAB 
 
Virtual Reality Glove for Hand and Arm RehaBilitation 
 
 
Protocol Version/Version Date 
 
Version 3.0 
 
December 6, 2021 
 
 
 
 
 
 
Protocol Directors 
 
 
Maarten Lansberg, MD, PhD 
 
Stanford University 
Stanford Stroke Center 
453 Quarry Rd. 
Palo Alto, CA 94304 
 
 
 
 
 

vREHAB - Virtual Reality Glove for Hand and Arm RehaBilitation 
Protocol V 3.0: 06DEC2021 
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vREHAB 
 
 
AGREEMENT ON THE PROTOCOL 
 
By signing below, I confirm that: 
 
1) I have read this protocol and it contains all necessary details for conducting this study 
 
AND 
 
2) I agree to conduct the trial in compliance with this protocol and to adhere to all 
regulations that govern the conduct of the study. 
 
 
 
 
_________________________________       ____________________ 
Principal Investigator’s Signature  
 
 
 
Date 
 
 
________________________________________________________ 
Principal Investigator’s Name 
 
 
_________________________________________________________ 
Site Name: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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The Virtual Reality Glove for Hand and Arm RehaBilitation (vREHAB) trial is a randomized, 
controlled, phase 2 trial aiming to evaluate the safety, usability, and efficacy of a virtual reality 
biofeedback system (Neofect RAPAEL Smart Glove) to promote recovery of distal arm and 
hand function after stroke, as compared to standard of care therapy. The purpose of the study is 
to demonstrate (a) the feasibility of increasing the dose of rehabilitation in acute stroke patients 
with the Smart Glove, (b) the effect of Smart Glove use on functional recovery, and (c) the effect 
of Smart Glove use on quality of life. 
 
Background 
 
Every year, over 700,000 patients in the US suffer from stroke. Upper extremity impairment is 
very common after stroke, with 15-30% of stroke survivors experiencing long-term arm 
weakness (1).  Distal upper extremity strength is required to complete a number of activities of 
daily living (ADLs), including feeding, grooming, dressing, writing, and typing.  As such, 
impairment of arm function limits patients’ ability to become independent in ADLs, resulting in 
significant costs, burden on caregivers, and a negative impact on patients’ quality of life (QOL) 
after stroke (2).  However, even after intensive rehabilitation of the upper extremity, only 5-20% 
of patients achieve complete functional recovery (3).   
 
Despite the major public health, as well as personal, costs resulting from impaired arm function 
after stroke, treatment options are limited.  The best evidence exists for constraint induced 
movement therapy (CIMT) and robotic therapy (4). Constraint induced movement therapy 
involves immobilization of the non-paretic arm for 90% of waking hours and high-repetition task-
oriented training for at least six hours per day. This therapy is not widely used due to its many 
limitations including the need for high intensity supervision by a therapist and patients’ 
frustration with the therapy.  Robot assisted arm training involves either passive movement of 
the affected arm or active movement with partial assistance. A meta-analysis has shown that 
robotic use leads to improvements in strength and ability to perform ADLs (4). Robots are, 
however, not widely used because they are expensive, large, not widely available, and need 
specific expertise to operate.   
 
With the increasing affordability and accessibility of virtual reality (VR) systems, VR has 
emerged as a new platform for stroke rehabilitation. VR therapy involves using computer-based 
programs to simulate daily tasks and events. VR has shown promise in both allowing patients to 
practice activities that directly translate to their ADLs, as well as motivating them by providing a 
novel and interesting virtual environment. A recent Cochrane Review of VR-based rehabilitation 
interventions concluded that it may be beneficial in improving upper limb function and ADL 
function, though it is unknown if these gains are sustained in the long term (5). 
 
The aim of this research is to test a novel VR-based rehabilitation method, Smart Glove therapy, 
for recovery of arm function.  Smart Glove therapy adopts the features that make constraint 
induced movement therapy and robotic therapy effective but does not have the same limitations.  
Specifically, the Neofect Smart Glove, like constraint induced movement and robotic therapy, 
promotes high frequency, intensive, repetitive movement therapy, features that have been 
shown to promote neuroplasticity and functional recovery (7). Unlike CIMT and robotic therapy, 
the Smart Glove is portable and therefore well-suited for home-use. It has an intuitive user 
interphase and therefore does not need supervision by an occupational therapist, uses games 
that can be played at different levels of complexity to keep patients engaged and motivated as 
their arm function improves, and is low-cost. 
 
 

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The Neofect Smart Glove is a commercially available, non-invasive biofeedback based system 
for distal upper extremity rehabilitation. The Smart Glove is very lightweight and allows for easy 
movement of all distal upper extremity joints. It consists of a glove-shaped sensor device and a 
software application which can be used with either a large screen or a portable tablet. It is made 
of an elastomer material that is simple to maintain and clean. The Bending Sensor, which 
consists of 3 acceleration channels, 3 angular rate channels, and 3 magnetic field channels, can 
detect wrist movement and position along 9 axes, and the amount of individual finger 
movements can also be precisely sensed by the glove (Figure 1-3).
Figure 1: The RAPAEL Smart Glove™system and the task-specific games of this system
The system includes multiple ADL-based training games, and the system tracks the motion and 
posture of the wearer’s distal limb as they participate. Games can be selected to focus on 
certain movements (such as forearm pronation/supination, wrist flexion/extension, finger 
flexion/extension, etc.) based on the needs of the wearer.  The software includes a smart 
learning algorithm, in which the computer automatically adjusts to the optimal level of difficulty to 
balance challenge and motivation. After initial set-up, the device requires no therapist 
supervision to use.
Figure 2: The Smart Glove
Figure 3: Using the Smart Glove in the VR 
environment
Preliminary data:  A meta-analysis of 72 VR-based stroke rehabilitation studies has shown that 
VR may be beneficial in improving upper limb function and activities of daily living when used in 

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combination with usual care.(4)  This analysis showed a trend towards better outcomes with a 
higher dose of VR therapy and with customized rehabilitation systems as opposed to systems 
primarily designed for gaming.  The study did not report specifically on the effect of VR therapy 
on wrist and hand function.   
A recent single-blinded, randomized controlled trial of 46 stroke survivors compared the Smart 
Glove combined with standard occupational therapy (OT) to dose-matched conventional upper 
extremity OT. Patients assigned to the Smart Glove used the Smart Glove in a rehabilitation 
facility under supervision of a therapist. The primary outcome was change in the Fugl-Meyer 
(FM) assessment, with secondary outcomes including fine motor tasks and quality of life (QOL). 
The study found an improvement of 5.3 points on the Upper Extremity Fugl-Meyer score in the 
active treatment group versus 1.3 points improvement in the control group (p<0.001) as well as 
greater improvements in fine motor tasks, assessed with the Jebsen Taylor Hand Function test, 
and QOL in the Smart Glove group.(6)   
 
We recently concluded a 20-patient 
feasibility study at Stanford with the 
Smart Glove in subacute and 
chronic stroke patients who used the 
device at home without supervision.  
Patients were issued the device for 
an eight-week period and asked to 
use the device for 60 minutes per 
day for five days per week in their 
home environment.  We 
demonstrated that it is feasible for 
patients to use the Smart Glove 
without direct supervision and 
learned that 60 minutes of Smart 
Glove therapy per day was too long 
for most patients.  Based on these 
results, we feel comfortable that the 
current proposal, which specifies 
unsupervised home-use for 30 
minutes per day, is achievable.  The 
fact that the feasibility study was 
completed ahead of schedule and 
that all patients returned for their 
follow-up visits indicates that our 
study design does not place undue 
burden on the subjects or research 
coordinators. Importantly, we showed improvements in hand function (decrease in Jebsen 
Taylor Hand test times) and arm mobility (improvement in Fugl-Meyer score) after 8 weeks of 
use in our feasibility study (figure 4). These results are encouraging as these were chronic 
stroke patients who had plateaued in terms of their recovery prior to the Smart Glove 
intervention.   
 
While these preliminary studies show promising results, important questions remain 
unanswered.  These include: Can patients use self-guided Smart Glove therapy in their home or 
rehabilitation environment in addition to their routine rehabilitation therapy in the sub-acute 
 
Figure 4.  An 8-week therapy program with the Neofect 
Smart Glove in chronic stroke patients showed 
improvement in hand function on the Jebsen Taylor Hand 
Function (JTHF) test and in arm mobility on the Fugl 
Meyer Upper Extremity (FM-UE) score. 

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stroke period?   Is the addition of Smart Glove therapy to routine rehabilitation therapy beneficial 
for recovery of arm and hand function?  We will address these questions in the vREHAB study. 
 
Primary Hypothesis 
Our hypothesis is that self-directed use of the Smart Glove is feasible for subacute as well as 
chronic stroke patients, results in an increased dose of upper extremity rehabilitation, and leads 
to improved functional outcome and quality of life for stroke survivors. 
 
Specific Aims 
Aim 1: Demonstrate the feasibility of increasing the dose of rehabilitation in acute stroke 
patients with the Smart Glove.  We hypothesize that patients randomized to the Smart Glove will 
have more upper extremity therapy than patients randomized to standard of care therapy. 
Aim 2: Demonstrate the effect of Smart Glove use on functional recovery.  We hypothesize that 
patients randomized to Smart Glove will have a greater improvement in arm/hand function as 
assessed on the Jebsen Taylor Hand Function (primary efficacy outcome) and Fugl-Meyer tests 
at the end of the intervention period, and that this improvement is sustained 12 weeks after 
completion of the intervention. 
Aim 3: Demonstrate the effect of Smart Glove use on quality of life.  We hypothesize that, 
compared to controls, patients randomized to Smart Glove will have a greater improvement in 
self-rated stroke related disability and quality of life (assessed with the Stroke Impact Scale) at 
the end of the intervention period, and that this improvement is sustained 12 weeks after 
completion of the intervention. 
 
Relevance 
Regaining upper extremity function is very important for stroke survivors to increase their 
independence and ability to perform ADLs. The large majority of outpatient stroke rehabilitation 
currently takes place in a therapy clinic; however, access is often limited by resource allocation, 
financial hardship, and transportation difficulties. The Smart Glove is unique in its portability, 
ease of use, and low cost. It could easily be provided to stroke patients with limited financial 
resources and, because of its portability, can be shipped to patients in more geographically 
remote areas who have limited access to regular therapy services.  Thus, if successful, this 
research could lead to a novel rehabilitation method that provides value-based care to a large 
proportion of stroke patients with impaired arm function. 
 
Study Sites 
Stanford University will be the Coordinating Center for this study. Patients will be recruited from 
the Inpatient Stroke Unit, the Outpatient Stroke Clinic, or Stanford-affiliated Acute Rehabilitation 
Units.  Stanford’s CTRU and the Neurology Outpatient Clinic will be used for study visits and 
assessments.  Other non-Stanford affiliated sites will be invited to participate and will require 
separate IRB approval per their institution. A total of 80 patients will be included. 
 
Patient Population 
Patients will be eligible for the study if they (1) have a history of an ischemic or hemorrhagic 
stroke and (2) have impaired arm/hand function secondary to the stroke (see below for specific 
inclusion and exclusion criteria).  We will recruit 40 patients over a 4-year period at Stanford’s 
acute care hospitals, acute rehabilitation units, and outpatient facilities.  The doctor and/or 
research coordinator may introduce the study to potential candidates in-person in the 
aforementioned sites, and the research coordinator may contact potential candidates by phone 
after the doctor’s referral.  Enrolled patients will be randomized (1:1 ratio) to standard 

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rehabilitation therapy versus standard rehabilitation therapy plus Smart Glove use.  All patients 
will be allowed to participate in any scheduled outpatient rehabilitation during the study.  
Patients who are randomized to the Smart Glove treatment arm will take the Smart Glove with 
them if they transition between facilities; for example, if they transition from the acute hospital to 
an acute rehabilitation facility or to home.   
 
Inclusion Criteria: 
(1) a diagnosis of ischemic or hemorrhagic stroke  
(2) unilateral hand/arm weakness from stroke with indication for upper limb rehabilitation 
therapy. 
(3) ability to successfully play 2 out 4 pre-selected test games with the Smart Glove.  The test 
specific games and criteria for passing are as follows:  
• Pour the wine (Pronation/Supination): make 5 pours in first 1 minute 
• Snow Ball Fight (Wrist Flexion/Extension w/ gravity eliminated): take down 3 objects in 
first 1 minute 
• Scrub the Floor (Wrist Radial/Ulnar deviation w/ gravity eliminated): scrub the floor 5 
times in first 1 minute 
• Float the Fish (Finger Flexion/Extension): make 50 meters with 3 or less bumps in first 
3 minutes 
 
Exclusion Criteria: 
(1) Age <18 years 
(2) history of visually provoked seizures. 
(3) psychological disorder that could impede participation. 
(4) pre-existing neurologic disorder which causes significant deficits in arm/hand function (e.g. 
Parkinson’s disease, peripheral neuropathy, etc.). 
(5) severe receptive aphasia which results in inability to participate with the Smart Glove. 
(6) cognitive impairment which results in inability to participate with the Smart Glove. 
(7) severe pain impeding upper extremity rehabilitation and use of the Smart Glove. 
(8) limited life-expectancy which makes it unlikely that patient will be able to complete the 24-
week follow-up visit 
(9) any medical or other condition that, in the opinion of the investigator, makes the patient 
unsuitable for participation in this study. 
 
Randomization: Once the participant has given informed consent and enrolled in the study, 
they will be randomized in a 1:1 ratio to Smart Glove therapy plus usual care versus usual care 
alone.  A dynamic stratification system will ensure well-balanced subgroups. The randomization 
algorithm will employ biased-coin minimization and the variance method with stratification 
weights (8). The strategy is to balance treatment assignment along the marginal distribution of 
each stratification factor. The stratification factors used, will be: 1) age, 2) time from symptom 
onset to enrollment, 3) finger extension muscle testing score at enrollment, and 4) study site.  
Study Procedures: The study consists of a 12-week intervention period and a 12-week follow-
up period.  During the 12-week intervention period all patients will receive their usual 
rehabilitation therapy, with their therapists documenting rehabilitation dose in a journal provided 
at the start of the study.  In addition, subjects randomized to the Smart Glove therapy arm will 
be provided with a Smart Glove system, which includes the glove and tablet. The subjects will 
be trained on how to don and doff the glove, pair the glove and tablet, and start the smart 
algorithm to progress through games appropriate to the subject’s current functional status. 
Subjects will be instructed to use the system for at least one session per day for 5 days per 
week during the 12-week intervention period.  During this period, the device’s learning schedule 

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algorithm will automatically adjust the daily therapy sessions to the optimal level of difficulty to 
balance challenge and motivation.  Each session typically takes 20-30 minutes depending on 
the patient’s speed.  Study coordinators will be readily available for any technical 
troubleshooting needs.  Participants will all receive phone calls by coordinators during weeks 1-
5, and 7-11, to ensure compliance and troubleshoot as needed, and will present for in-person 
visits on weeks 6, 12, and 24 for blinded assessments by study coordinators.  Smart Glove 
usage data from participants in the intervention arm will be monitored and dose of rehabilitation 
as recorded on the PT/OT rehabilitation log will be reviewed and documented on CRFs during 
in-person visits. 
At the completion of the intervention period, subjects will return the Smart Glove and subjects in 
both arms of the study will only receive usual care during the 12-week follow-up period.  They 
will continue to record any rehabilitation they receive during this time period. Participants will 
continue to receive phone calls by coordinators during weeks 13-24 to ensure compliance with 
rehabilitation logging.  Subjects will have a final assessment at week 24 (12 weeks after 
completing the intervention) to assess for persistence of effect.  After the final assessment, at 
study completion, all individuals who were randomized to the standard therapy arm will be 
offered use of the Smart Glove, at no cost to the patient, for a period of 6 weeks. 
An overview of the study assessments is described below and summarized in table 1.  
Day 0, baseline visit: 
• 
Research coordinator will review the research consent form in detail with the participant 
and answer any questions about the study. After informed consent, the participant will be 
enrolled in the study, and baseline demographics will be collected. 
• 
Smart Glove training for patient and caregiver 
• 
Issuance of Smart Glove and tablet with preloaded software 
• 
Modified Rankin Scale and NIHSS scoring 
• 
Baseline testing of the affected extremity: 
o Jebsen-Taylor hand function test (JTHFT) 
o Upper Extremity Fugl-Meyer assessment (FM) 
o Manual muscle testing (MMT)  
o Shoulder Abduction/Finger Extension (SAFE) score of Predicting Recovery 
Potential (PREP) algorithm  72h post-stroke (retrospective) and at enrollment 
 
Day 7, 14, 21, 28 and 35: 
• 
Phone call for patient compliance and troubleshooting 
 
Day 42, follow-up visit #1 (mid-intervention): 
• 
Discussion regarding patient compliance and troubleshooting 
• 
Document amount of rehabilitation from PT/OT session log 
• 
Testing of the affected extremity: 
o Fugl-Meyer assessment (FM) 
o Jebsen-Taylor hand function test (JTT) 
• 
Download of patient use data from tablet (SmartGlove arm only) 
 
Day 49, 56, 63, 70 and 77: 
• 
Phone call for patient compliance and troubleshooting 
 
Day 84 follow-up visit #2 after routine clinical follow-up appointment (end-intervention): 
• 
Assess amount of rehabilitation from PT/OT session log 
• 
Modified Rankin Scale  

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• 
Testing of the affected extremity and quality of life: 
o Jebsen-Taylor hand function test (JTHFT) 
o Fugl-Meyer assessment (FM) 
o Manual muscle testing (MMT)  
• 
Stroke Impact Scale (SIS) 
• 
Download of patient use data from tablet (SmartGlove arm only) 
• 
User experience survey (SmartGlove arm only) 
 
Day 91, 98, 105, 112, 119, 126, 133, 140, 147, 154, 161: 
• 
Phone call for patient compliance and troubleshooting 
 
Day 168 follow-up visit #3 (end-study): 
• 
Assess amount of rehabilitation from PT/OT session log 
• 
Modified Rankin Scale  
• 
Testing of the affected extremity and quality of life: 
o Jebsen-Taylor hand function test (JTHFT) 
o Fugl-Meyer assessment (FM) 
o Manual muscle testing (MMT)  
• 
Stroke Impact Scale (SIS) 
 
 
Table 1.  Schedule of Events 
Time-point 
Week 
0 
Weeks 
1 –  5 
Week 
6 
Weeks  
7 – 11 
Week 
12 
Weeks 
13 – 23 
Week 
24 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Compliance Phone-Calls 
 
X 
 
X 
 
X 
 
SAFE score (at 72h and at 
enrollment) 
X 
 
 
 
 
 
 
Modified Rankin Scale (mRS) 
X 
 
 
 
X 
 
X 
NIHSS assessment 
X 
 
 
 
 
 
 
Jebsen Taylor Hand Test (JTHT) 
X 
 
X 
 
X 
 
X 
Upper Extremity Fugl-Meyer (FM) 
X 
 
X 
 
X 
 
X 
Manual Muscle Testing (MMT) 
X 
 
 
 
X 
 
X 
Stroke Impact Scale (SIS) 
 
 
 
 
X 
 
X 
Assess amount of rehabilitation 
 
 
X 
 
X 
 
X 
User Survey (Smart Glove arm) 
 
 
 
 
X 
 
 
 
Data analyses:  All efficacy analyses are analyzed under the intention to treat principle. The 
primary efficacy outcome is the change in score on the Jebsen Taylor Hand Test between 
baseline and week 12.  Secondary efficacy endpoints are changes in scores on the upper 
extremity Fugl-Meyer Scale, modified Rankin Score, total NIHSS score, Manual Muscle testing 
(of the biceps, triceps, wrist extensors, finger flexors, and finger abductors), Stroke Impact 
Scale, and total dose of rehabilitation received during the 12-week intervention period.  
Persistence of the treatment effect will be tested by comparing changes in scores on the Jebsen 
Taylor Hand Test and Fugl-Meyer upper extremity score at 24 weeks between treatment 
groups.  Differences between treatment groups will be assessed using a generalized linear 
model (GLM) that accounts for repeated measures (assessments at baseline, 6 and 12 weeks 
for primary outcome, as well as 24 weeks for secondary outcome) and will be adjusted for 
imbalances in baseline variables.  We will use a two-sided test with an alpha of 0.05 to declare 
significance.  Based on prior studies we assume to see an 11.0-point improvement on the JTHF 

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test in patients who use the glove, a 3.0-point improvement in control subjects, and a standard 
deviation of the change score of 2.0.(1)  Based on these assumptions we will have more than 
90% power to show a significant effect of the use of the Smart Glove on our primary efficacy 
outcome. 
 
Risks 
Potential risks and inconveniences include that the participant will need to travel to Stanford for 
3 follow-up visits over the course of the study. One may also experience technical difficulties in 
using the Smart Glove system.  There is a low likelihood of one having a skin reaction to the 
material used to make the Smart Glove. 
 
Benefits 
While there is no definitive evidence that SmartGlove therapy will benefit patients, a potential 
benefit is that the participant may experience improvement in the function of their affected upper 
extremity as a result of study participation. 
 
Withdrawal 
Each subject and the investigator reserve the right at any time to terminate a subject’s 
participation in the clinical investigation. Possible reasons for study withdrawal:  
1) Subject voluntarily withdraws consent 
2) Subject develops an adverse event that would not allow him or her to continue in the 
study 
3) Subject has an adverse event which, in the opinion of the investigator, warrants 
withdrawal from the study. The sponsor or its designee must be notified within 2 
business days 
4) A decision is made by the subject and/or investigator that the subject should be 
withdrawn from the study 
 
Alternative to Participation: 
There are several alternatives to participation that each potential study candidate should 
discuss with their physician. The alternatives include not participating and seeking no other 
treatment, or not participating and seeking a standard-practice treatment which is outpatient 
occupational therapy. Candidates should understand that choosing to participate is not mutually 
exclusive with receiving outpatient occupational therapy. 
 
Data Collection, Transfer, and Storage 
Clinical assessments (UE-FM, MMT and JTHT) will be done by an investigator blinded to 
treatment assignment.  All study data (including patient demographics, previous medical 
conditions, mRS, NIHSS, MMT, FM, JTHT, and SIS scores) will be entered directly on electronic 
case report forms (eCRFs) programmed in RedCap, a HIPAA compliant electronic clinical trial 
database.  For patients randomized to the Smart Glove arm, time of use of the device and 
performance on the VR games will be collected automatically by the device and downloaded at 
the aforementioned time points during the intervention period.  Screening logs will be kept of 
patients who are considered but not enrolled in this trial and the reason for exclusion will be 
recorded.  
References 
1. 
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