Contralaterally Controlled FES Versus Cyclic NMES for Hand Function After Stroke
Phase: NA
Conditions: Stroke, Upper Extremity Paresis, Hemiplegia
Sponsor: MetroHealth Medical Center

 
 
Therapies for Recovery of Hand Function After Stroke 
 
 
NCT03574623 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
 
Note:  The text below was extracted from the IRB protocol for this study, which was first 
approved on January 22, 2018. The most recent amendment to the protocol was approved on: 
April 19, 2023 
 
 

Study Protocol 
 
Abstract 
This is the first multi-site clinical trial of contralaterally controlled functional electrical stimulation 
(CCFES). CCFES is an innovative technology and rehabilitation therapy for improving the recovery of 
hand function in patients with upper extremity hemiparesis. CCFES applies electrical stimulation to the 
paretic finger and thumb extensor muscles through surface electrodes, causing the weak hand to 
open, a function that is often lost in stroke survivors. The patient controls the intensity of stimulation 
to their paretic hand by wearing a glove with sensors on their unaffected contralateral hand. When the 
patient opens their unaffected hand, a proportional intensity of stimulation opens their paretic hand. 
CCFES puts the patient back in control of their paretic hand, and this may drive neuroplastic changes 
that lead to better recovery of hand function. The central hypothesis is that CCFES is more effective 
for recovery of hand function than conventional cyclic neuromuscular electrical stimulation (cNMES) 
therapy or task oriented training (TOT) without electrical stimulation. Stroke survivors between 6 and 
24 months post-stroke will be randomized to 12 weeks of CCFES, cNMES (which applies electrical 
stimulation to the hand extensors but with pre-set timing and intensity), or TOT without electrical 
stimulation. This study will determine if CCFES can be administered with positive results at other sites, 
will establish the clinical efficacy of CCFES (comparison with cNMES), and will generate initial 
estimates of effectiveness of CCFES (comparison with TOT). 
 
Specific Aims 
AIM 1. Compare the effects of CCFES and cNMES in improving hand function after stroke.  
Research Hypothesis: At 6 mo post-treatment, improvements in hand function will be significantly 
greater after CCFES than cNMES, and a greater proportion of participants will achieve clinically 
significant improvements after CCFES than cNMES. Outcomes will include measures of dexterity, 
upper extremity activity limitation and impairment, and patient-reported outcomes.  
 
AIM 2. Compare the effects of CCFES and TOT in improving hand function after stroke.  

Research Hypothesis: At 6 mo post-treatment, improvements in hand function will be significantly 
greater after CCFES than TOT, and a greater proportion of participants will achieve clinically significant 
improvements after CCFES than TOT.  
 
Methods and Procedures 
This is a 4-site, assessor-blinded Phase II randomized controlled trial to determine whether CCFES is 
superior to cNMES or TOT in improving hand function in patients with upper extremity hemiplegia who 
are between 6 and 24 months past their stroke. A target of 132 patients will be randomized to 
Contralaterally Controlled Functional Electrical Stimulation (CCFES), Cyclic Neuromuscular Electrical 
Stimulation(cNMES), or Task Oriented Training (TOT). Stratification factors include age, severity of 
hand impairment, months post-stroke, and treatment site.  
 
All groups will receive 12 weeks of upper limb rehabilitation treatment consisting of a home regimen 
and functional task practice in the lab. Treatment will include: 1) therapist-administered 90-min 
sessions of hand task practice twice a week in the lab, and 2) self-administered sessions lasting 
approximately 1 hour per session 10 times a week at home. 
• CCFES group: 90-min 2x/week CCFES therapy with therapist + 10x/week CCFES hand opening 
exercise self-administered at home. 
• cNMES group: 90-min 2x/week therapy with therapist + 10x/week cNMES hand opening exercise 
self-administered at home. 
• TOT group: 90-min 2x/week therapy with therapist + 10x/week home exercise program self-
administered at home.  
All subjects will be followed for 6 months post-treatment. Blinded assessments will take place at 
baseline, mid-treatment (6 wk), end-of-treatment (12 wk), and at 3- and 6-months post-treatment. 
 
Baseline characteristics will be collected, including demographic (e.g., sex, age, race, pre-morbid hand 
dominance), stroke-related (e.g., time post-stroke, hemorrhagic or ischemic, cortical or subcortical, 
right or left, Stroke Impact Scale score), and neurologic data (e.g., side of hemiparesis, cognition, 

depression, neglect, visual deficits, aphasia), as well as co-morbidities, and medications. The balance 
of these between the three groups and their effect on the outcomes will be evaluated.  
 
The stimulators used in this study for the CCFES and cNMES groups deliver biphasic rectangular 
current pulses at a pulse frequency of 35 Hz and pulse amplitude of 40 or 60mA. Up to 3 channels of 
stimulation will be used to produce hand opening. Surface electrodes will be positioned to activate the 
extensor digitorum communis (EDC) and extensor pollicis longus (EPL). Abductor pollicis brevis 
(AbPB), dorsal interossei (DI),or extensor indicis proprius (EIP) may also be targeted if they are 
necessary to achieve functional hand opening. A pulse amplitude (default, 40 mA) and maximum 
stimulus intensity (pulse duration) will be determined for each stimulus channel so as to achieve 
maximum finger and thumb extension without discomfort. For the CCFES group, each stimulus 
channel will be programmed so that stimulation intensities (pulse durations) change in proportion to 
the amount of opening of a CCFES glove worn on the unaffected hand. The CCFES glove is an 
assembly of bend sensors (Images SI, Inc., Staten Island, NY) attached to the fingers of an athletic 
batting glove. For the cNMES group, the stimulator will be set to automatically and repeatedly ramp 
on and off during an exercise session. After programming the stimulator (for CCFES and cNMES 
groups), the treating therapist will instruct and train the participants (and their caregivers if 
necessary), how to put on the components (i.e., electrodes, glove if applicable). The electrodes will be 
outlined on the skin and photographs of the electrodes correctly positioned will assist the subject in 
placing them correctly at home. An instruction manual will be reviewed with every participant, and 
each will be trained how to use their stimulator to complete their exercise sessions at home. 
Adherence to the home stimulation regimen will be collected with participant diaries and electronic 
data logging by the stimulator at every visit during the treatment period. From the stimulator's 
datalogger, the treating therapist will record the number of treatment sessions completed by the 
participant and the number of stimulated hand openings. 
 
For all groups, treatment will last 12 weeks and consist of: (a) 10 sessions per week of self-
administered exercises at home, and (b) 22 sessions of therapist-guided functional task practice in the 
lab (two per week except on weeks that include an assessment visit). Treatment regimens are: 

• CCFES group -- Lab: Observe home-based regimen (15 min). CCFES-mediated functional task 
practice (75 min). Home: CCFES-mediated cued hand opening exercise(1 session = 22-min set x 2). 
• cNMES group -- Lab: Observe home-based regimen (15 min). Functional task practice(75 min). 
Home: cNMES-mediated hand opening exercise (1 session = 29-min set x 2). 
• TOT group -- Lab: Review home exercise program (15 min). Functional task practice(75 min). 
Home: Home Exercise Program (1 session = 30-min set x 2). 
 
All groups will self-administer 10 exercise sessions per week at home. Each participant should do no 
more than 2 sessions per day separated by at least 2 hours; on days they come to the lab for a 
treatment session, they should do no more than one home session. The treating therapist and 
participant will create a schedule each week that helps the participant know when they should do their 
10 exercise sessions for that week. Each home exercise session will consist of 2 exercise sets 
separated by 3 min of rest. For CCFES and cNMES groups, each set consists of repeated stimulation-
mediated hand opening. For the CCFES group, the stimulation-mediated hand opening will be cued by 
audio and visual prompts. During the first two weeks, the cues will prompt the CCFES participants to 
open both hands at the same time and maintain hand opening for 6 seconds then rest for 14 seconds, 
repeating this for the duration of the set. At week 3, the treating therapist will change the cue timing 
to 8 sec open, 12 sec rest; at week 5 it will again be changed to 10 sec open, 10 sec rest. For the 
cNMES group, the stimulator will turn on and off automatically according to the same timing as the 
cues for the CCFES group; this will produce an automatic repetitive cycle of hand opening and resting 
for the cNMES group. For the TOT group, a home session will consist of practicing using the paretic 
hand to perform a list of tasks for several minutes each as instructed in the lab, and/or self-
administering active-assisted range of motion and activities in preparation for hand tasks.  
 
Each of the twenty-two 90-min lab sessions will begin with 15 minutes of the treating therapist 
observing the participant performing the exercise they do at home, reinforcing instructions, and 
troubleshooting any problems, followed by 75 minutes of instructing and guiding the participants in 
practicing functional tasks with their paretic hand. Tasks will involve using the paretic hand to pick up, 
manipulate, and release objects commonly used in daily life. The treating therapist will adjust task 
difficulty from easy-to-acquire-and-manipulate tasks to tasks requiring wider hand opening, greater 

complexity and skill, graded hand opening (release), and coordination of hand function with proximal 
upper limb movement. The pace and content of the therapy will be standardized via study-specific 
protocols and task lists. The CCFES group will use CCFES to assist the paretic hand in performing 
tasks. The cNMES group will practice tasks using their paretic hand but without any stimulation 
because cNMES is not amenable to assisting with tasks since it is not controlled by the patient (one of 
the unique advantages of CCFES). Therefore, to ensure that both groups receive an equal weekly 
duration of electrical stimulation, the cNMES group will have longer home stimulation exercise 
sessions than the CCFES group (see treatment regimens above). The TOT group will receive the same 
task practice as the cNMES group (i.e., no stimulation). For subjects with severe hand impairment, 
early task practice sessions will focus on simpler tasks, such as opening the hand adequately to 
acquire a small object. If it is not possible to perform tasks, then the therapist will focus on passive 
and active-assisted range of motion, arm placement activities in preparation for hand tasks, and hand 
placement on target surfaces and objects.  
 
Adherence to the home stimulation regimen will be monitored with participant diaries and electronic 
data logging by the stimulator at every visit during the treatment period. The stimulator logs the date 
and time the unit is turned on and off and the start and completion of exercise periods. All participants 
will also be given a diary to log completion of sessions. The diaries will be reconciled with electronic 
data logs at every lab session, in the presence of the participant to encourage adherence. 
 
Outcome Measures 
Blinded assessments will take place at baseline, mid-treatment(6 wk), end-of-treatment (12 wk), and 
at 3- and 6-months post-treatment. All assessments will be done with no electrical stimulation. 
Subjects will refrain from using their stimulators for 24 hours prior to their 6-week and 12-week 
assessments in order to avoid any transient carry over effects or muscle fatigue.  
 
Box and Blocks Test (BBT): The primary endpoint is change in dexterity at 6-monthspost-treatment, 
as assessed by the BBT. The BBT is a measure of manual dexterity, which requires the subject to pick 
up one block at a time, move it over a partition, and release it in a target area as many times as 

possible in 60 seconds. Participants will perform the test first with the unaffected hand, and then with 
the affected hand. The BBT is classified as an activity (ICF domain) measure by the Rehabilitation 
Measures Database and the Evidence-Based Review of Stroke Rehabilitation. 
 
Upper Extremity Fugl-Meyer Assessment (UEFM). The UEFM is a measure of post-stroke upper limb 
motor impairment that takes into account synergy patterns, isolated strength, coordination, and 
hypertonia. Volitional movement of the upper limb (shoulder, elbow, forearm, wrist, and hand) is 
examined in and out of synergies. Each item is graded on a 3-point ordinal scale (0, cannot perform; 
1, perform partially; and 2, perform fully) and summed to provide a maximum score of 66. 
 
Action Research Arm Test, (ARAT): The ARAT is a measure of upper extremity functional ability. The 
ARAT is a 19-item test divided into four categories (grasp, grip, pinch, and gross movement), with 16 
of the 19 ARAT items measuring distal regions of the arm, making it an ideal and sensitive measure 
for this distally based intervention.  
 
Stroke Upper Limb Capacity Scale (SULCS). The SULCS is a 10-item test in which stroke patients are 
rated using a 2-point ordinal scale on their performance of upper limb tasks ranging from reaching 
forward to manipulating coins. It is a valid and reliable measure of upper limb capacity that is suitable 
for a wide range of patients including those with poor hand-related upper limb capacity.  
 
Questionnaires. The subjects’ impressions of the effectiveness of the intervention, the dose, and the 
ease of using the device/equipment will be captured with questionnaires including the Stroke Impact 
Scale Hand Section, the Neuro-QOL Upper Extremity Function Fine Motor ADL from the Patient 
Reported Outcomes Measurement Information System (PROMIS) Neuro-QOL Bank, and an end-of-
treatment questionnaire. The purpose is to gain insight into how well the device and dosage are 
tolerated and the subjects’ perception of effectiveness. The questionnaires will be administered at end 
of treatment by a staff member who will have no other interaction with the subjects.  
 
Other Measures. Additional secondary measures include changes in muscle tone (modified Ashworth 
scale) and finger flexion and extension strength (dynamometry).These outcomes along with the 

baseline characteristics collected and treatment adherence may provide insight into mechanisms of 
action and interpretation of the main findings.  
 
Experimental Flow 
Participation time for each subject will be ~9.5 months (inc. 3 months treatment, 6months follow-up). 
There are a total of 29 visits involved in this study. 
 
Visit 1. Consent and eligibility (2 hrs) 
Visit 2. Baseline Assessment (2 hrs) 
Visit 3. Randomization, Device Setup and Training (2 hrs) 
Visits 4-14. Therapy Visits (1.5 hrs) 
Visit 15. Mid-Treatment Outcome Assessment (2 hrs) 
Visits 16-26. Therapy Visits (1.5 hrs) 
Visit 27. End of Treatment Outcome Assessment (2 hrs) 
Visit 28. 3-mo post-Treatment Outcome Assessment (2 hrs) 
Visit 29. 6-mo post-Treatment Outcome Assessment (2 hrs) 
 
Selection Criteria 
Inclusion Criteria 
• Age 21 to 90 years old at time of randomization 
• 6 to 24 months since a first clinical cortical or subcortical, ischemic or hemorrhagic stroke 
• unilateral upper limb hemiparesis with finger extensor strength of ≤ grade 4/5 on the Medical 
Research Council (MRC) scale 
• score of ≥1/14 and ≤ 11/14 on the hand section of the upper extremity Fugl-Meyer Assessment 
• adequate active movement of shoulder and elbow to position the paretic hand in the workspace for 
table-top task practice 
• able to follow 3-stage commands 
• able to recall at least 2 of a list of 3 items after 30 minutes 
• skin intact on hemiparetic arm 

• surface electrical stimulation of the paretic finger and thumb extensors produces functional hand 
opening without pain (this will exclude patients who have too much flexor spasticity) 
• able to hear and respond to cues from stimulator 
• not receiving occupational therapy (no concomitant OT) 
• full volitional hand opening/closing of contralateral hand 
• demonstrates ability to follow instructions for putting on and operating the assigned stimulator or 
has caregiver to assist 
 
Exclusion Criteria 
• co-existing neurologic diagnosis of peripheral nerve injury, Parkinson’s disease, spinal cord injury, 
traumatic brain injury, or multiple sclerosis 
• uncontrolled seizure disorder, defined as having a seizure within the previous 3months 
• brainstem stroke 
• uncompensated hemi-neglect (extinguishing to double simultaneous stimulation) 
• severe shoulder or hand pain, i.e., unable to position hand in the workspace without pain 
• insensate to touch on forearm or hand 
• history of potentially fatal cardiac arrhythmias with hemodynamic instability 
• cardiac pacemaker or other implanted electronic system 
• botulinum toxin injections to any upper extremity muscle within 3 months of enrolling 
• pregnancy (unknown risks of surface NMES during pregnancy) 
• lack of functional passive range of motion of the wrist or fingers of affected side 
• diagnosis (apart from stroke) that substantially affects paretic arm and hand function 
• deficits in communication that interfere with reasonable study participation 
• lacking sufficient visual acuity to see the stimulator’s display 
• concurrent enrollment in another investigational study. 
 
Potential Risks 
Neuromuscular Electrical Stimulation Risks (pertain to CCFES and cNMES groups) 
 

* Skin Irritation – When surface electrodes are used, it is possible that the subject will experience a 
temporary redness of the skin from either the electrodes, the conductive gel used with them, or any 
adhesive used to secure them. This risk is common. Skin irritation and redness from the electrical 
stimulation is also possible, but this possibility is rare and minimized by the type and intensity of 
stimulation that will be used. Participants will be instructed that redness should fade within an hour 
and that if redness persists, they should contact study staff. If necessary, electrodes or adhesives will 
be replaced with an alternative. 
 
* Uncomfortable Sensation – Electrical stimulation of a muscle may be perceived as a twitching or 
vibrating sensation and may be uncomfortable. Electrical stimulation of a nerve may be perceived as a 
strong but short shock and may be uncomfortable. Electrical stimulation of the skin may be perceived 
as a “pins and needles” sensation and may be uncomfortable. Discomfort is common but stimulus 
parameters will be adjusted to the subject’s comfort. 
 
* Electrical Hazards – There is a possibility of an electrical shock hazard whenever electrical 
stimulation is used or whenever electrical equipment is used to make measurements. There is a 
possibility of an electrical burn whenever electrical stimulation with surface electrodes is used. The 
equipment to be used has been designed and tested to minimize these risks. Subjects will be trained 
how to use the stimulator safely and will be asked to adhere to a list of safety precautions. With these 
precautions, electrical hazards are rare. 
 
* Stimulator Malfunction – There is a rare possibility that the stimulator may malfunction and produce 
painful stimulation after it has been programmed in the laboratory. The subject could feel a sudden 
burning sensation, which can damage the skin if it does not stop. The equipment to be used has been 
designed and tested to minimize this risk. If the subject experiences pain from the stimulation, they 
will be told to turn off the stimulator and/or unplug the electrode cables, stop using it, and contact 
study personnel. 
 
* Unknown Effect of Stimulation on Pregnancy – The effect of electrical stimulation on a fetus is not 
known. If the subject is pregnant or is planning to become pregnant they may not participate in this 

study. Subjects will be told to notify study personnel if they suspect that they become pregnant during 
the study.  
 
All Groups 
 
* Fatigue – During the treatment and assessment sessions, participants will practice several motor 
control tasks repeatedly or will be tested on how well they can move their arm and hand and perform 
specific tasks. These tasks involve concentration and repetition and may induce “mental fatigue” from 
the intensity of concentration required during these tasks or soreness from the repetition. Fatigue is 
common. Participants in previous similar studies have reported feeling very tired, needing to nap 
when they go home, or experiencing headaches following lab sessions. This is similar to what one 
might experience after working hard in a traditional occupational therapy session. Participants will be 
given rest breaks as needed during the treatment sessions. Additionally, participants will be 
encouraged to plan time to rest at home after their lab sessions until they know the effect the 
sessions will have on them. 
 
* Breach of Confidentiality – When PHI is involved there is the rare risk of a privacy breach. 
 
* Unknown Risks – There may be unknown or unforeseen risks associated with study participation.  
 
Risk Management 
If a subject experiences any of the risks described above, they will be asked to report it as soon as 
possible to the research team. Skin irritations, electrical burns, and electrical shocks will be assessed 
and treated by the study physiatrist if necessary. In the event of skin irritations associated with the 
electrodes, alternative electrodes may be used and/or the use of the stimulator may be temporarily 
suspended. In the event of uncomfortable sensations associated with the electrical stimulation, the 
stimulus parameters will be readjusted to the subjects’ comfort. In the event of electrical burns, the 
subject will be retrained in the procedures necessary to guard against their occurrence. In the event of 
electrical shocks, the equipment will be assessed for faults. All equipment has been designed to 

minimize the possibility of electrical hazards. To help prevent "mental fatigue", physical fatigue, pain 
and related issues, subjects will be provided with a five-minute rest break as needed during the lab 
session. Additionally, they will be advised to plan some time for rest or relaxation at home after lab 
sessions until they know the effect the increased concentration will have on them. 
 
In addition to the risk management for the study described above, subjects in the CCFES and cNMES 
groups will be given a group-specific user’s manual that describes how to use the stimulator safely. 
This will be reviewed with each subject before they are sent home with the stimulator. The manual will 
list the following safety precautions:  
 
Safety Information 
• IMPORTANT: Avoid handling the electrodes while the stimulator is on! Always remember to turn off 
the stimulator before you remove the electrodes. 
• Always wash and dry the skin before applying the electrodes. Any mild soap is fine; avoid deodorant 
or perfumed soaps or lotions, as these affect skin adherence. 
• Use new electrodes if the reused ones no longer stick well to the skin. 
• Place electrodes on the skin only where instructed. 
• Never position electrodes on the chest, across the heart, or on the neck. 
• Do not place electrodes over broken skin as this may cause pain and skin irritation. 
• Do not submerge the stimulator in water, or use around water (spills, bathtub/shower or sink). 
• Do not operate dangerous machinery or drive while using the stimulator. 
• Do not sleep while using the stimulator. Remain attentive during use to avoid skin burns. 
• A slight reddening of the skin under the electrode is normal. This should fade after 1hour once the 
electrodes are removed. If you note redness or blistering beyond this, discontinue use and inform your 
therapist. 
• The safety of electrical stimulation in pregnancy has not been determined; therefore, do not use the 
device if pregnant. 
• Electrical stimulation should not be used by patients with implanted electronic devices(cardiac 
demand pacemakers etc.) unless under specialized medical supervision. 
• Do not use the device if you have a history of potentially fatal cardiac arrhythmias. 

• Electrical stimulation should not be used by people who have poorly controlled epilepsy. 
• The stimulator has been programmed specifically for the intended user only. Do not allow anyone 
else to use the stimulator. 
 
 

Statistical Analysis Plan 
The primary analysis was based on a modified intention-to-treat (ITT) sample, which included 
participants in the group to which they were assigned who completed the treatment phase of the 
study. For all measures, changes from baseline were modeled using a linear mixed effects modeling 
approach, which accounts for missing values using maximum likelihood estimation. The linear mixed 
effects model using the restricted maximum likelihood (REML) estimator was employed, along with the 
Satterthwaite approximation to estimate the denominator degrees of freedom. While REML assumes 
normality of the random effects and residuals, it is generally more robust to violations of this 
assumption than traditional maximum likelihood, particularly in the estimation of fixed effects. The 
model included a random intercept to account for individual variability, and we specified a compound 
symmetry covariance structure to model the within-subject correlations. Least squares mean 
estimates were calculated after fitting each model for each group at each timepoint and were used to 
quantify within-group changes from baseline and between-group differences in change from baseline 
to 6 mos post-treatment. Statistical significance was set at p<0.05. No adjustments were made for 
multiple comparisons in order to maintain a balance between Type I and Type II error rates. This 
balanced approach to error control was prioritized rather than strictly minimizing Type I error at the 
expense of statistical power and increasing the risk of overlooking meaningful effects. Pair-wise Chi-
square tests were used to compare responder rates between groups.  
 
Exploratory subgroup analyses were performed using mixed effects models to test whether covariates 
(e.g., site, months since stroke, dose received, sex) moderated the change in BBT, UEFM, and ARAT 
scores across groups. A pre-planned analysis of only those participants with moderate hand weakness 
at baseline was conducted based on the prior study showing participants with moderate weakness 
achieved greater gains on the BBT than participants with severe hand weakness. Two pre-planned 
sensitivity analyses of the motor recovery outcomes were done. The first included all participants who 
were randomized to a treatment group regardless of the amount of treatment received. The second 
included only participants who received no other upper limb physical therapies during the treatment 
period and completed at least 80% of the planned treatment, i.e., at least 18 out of 22 FTP visits and 
at least 8 out of 10 home exercise sessions per week on average.