Altering Activation Patterns in the Distal Upper Extremity After Stroke
Phase: NA
Conditions: Stroke, Muscle Spasticity, Hemiparesis
Sponsor: Shirley Ryan AbilityLab

STU#: 00078099
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HRP-593 / v110115
PROTOCOL TITLE:  Altering activations patterns in the distal upper extremity after stroke
PRINCIPAL INVESTIGATOR: Dr. Elliot Roth
Shirley Ryan AbilityLab
355 E Erie, Suite 14, Room 2118
Chicago, IL 60611
(312) 238-1657
VERSION NUMBER: 7
VERSION DATE: January 8, 2019
OBJECTIVES:
Aim 1: Determine the capability of an anti-serotonergic agent to reduce hyperexcitability 
poststroke without compromising voluntary strength.
Aim 2: Assess the efficacy of using a multimodal intervention combining an anti-
monoaminergicagent with upper extremity training.
Hypothesis: We investigators hypothesize that the group receiving the combined 
cyproheptadine and active movement therapy will have better outcomes than the groups 
receiving passive therapy or placebo.
BACKGROUD:  
Chronic sensorimotor impairment of the upper extremity is prevalent in more than 6 million 
stroke survivors in the U.S. (Go, et al., 2013), especially in the distal upper extremity (Trombly, 
1989).  In our studies of the impairment mechanisms of hand motor control after stroke, e.g., 
(Cruz, et al., 2005; Kamper, et al., 2006; Triandafilou, et al., 2011), we have been struck by two 
phenomena which arise following the original brain lesion: i) involuntary hyperexcitability of the 
motor units in certain muscles and ii) the difficulty in producing and controlling voluntary muscle 
activation. We propose to directly treat both of these phenomena simultaneously in order to 
improve motor control of the hand and arm. We will reduce motoneuronal hyperexcitability through 
administration of an anti-serotonergic drug which does not increase weakness, and we will guide 
the generation of proper muscle activation with a custom device and computer program. We 
believe that our multimodality treatment approach is innovative in that we combine the use of 
pharmacological agents with individualized movement therapy in a manner that can be used with 
patients with poor initial motor control. In separate preliminary studies, we were able to show that 
a single dose of the agent cyproheptadine could reduce unwanted muscle excitation without 
decreasing voluntary strength (Seo, et al., 2011) and that active motor training, assisted by an 
electromyographically (EMG) controlled actuated glove, could lead to statistically significant 
improvement both in measures of impairment and task performance. In this study, we will combine 
these approaches to create a novel treatment paradigm for improving motor control of the distal 
upper extremity after stroke. These techniques are amenable to rapid and widespread integration 
into the clinic for the arm and hand, and could be applied to the lower extremity as well.  
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INCLUSION AND EXCLUSION CRITERIA:
The following groups of individuals will be excluded from this study:
­
Adults unable to consent 
­
Individuals who are not yet adults (infants, children, teenagers) 
­
Pregnant women
­
Prisoners
In this study, we will recruit stroke survivors who:
•
are between the ages of 18 to 80;
•
have sustained a single, unilateral stroke at least 6 months prior to enrollment;
•
have substantial hand impairment as rated at Stage 2 or Stage 3 on the Stage of Hand 
section of the Chedoke-McMaster Stroke Assessment (Gowland, et al., 1993).
Subjects are excluded if they have:
•
excessive pain in the paretic upper limb;
•
cerebellar involvement;
•
contracture in the paretic upper limb;
•
hemispatial neglect (as assessed by the Behavioural Inattention Test (Wilson, et al., 
1987));
•
apraxia of the paretic upper limb (as assessed by the FABERS battery (Power, et al., 
2010));
•
rheumatoid arthritis or other orthopaedic impairments restricting finger or wrist 
movement;
•
conditions which necessitate the use of medication that may interfere with 
neuromuscular function.
•
history of seizure disorder
•
altered dose of anti-spasticity medication (within 1 month of study start)
•
botulinum toxin injection(s) to the upper extremity (within prior 6 months of study start)
•
contraindicated conditions of the study drug, cyproheptadine (including hypersensitivity 
to cyproheptadine and other drugs of similar chemical stucture; monoamine oxidase 
inhbitor (MAOI) therapy, angle-closure glaucoma, stenosing peptic ulcer, symptomatic 
prostatic hypertropy, bladder, stomach or bowel obstruction, eldery debilitated patients
STUDY-WIDE NUMBER OF PARTICIPANTS: N/A
STUDY-WIDE RECRUITMENT METHODS: N/A
MULTI-SITE RESEARCH: N/A
STUDY TIMELINES:
After completing a preliminary screening and enrolling in the study by signing the informed 
consent, each subject will undergo a medical examination with the study doctor to verify 
suitability for participation.  A clinical assessment will be conducted to allow for a stratified group 
randomization based upon the Fugl-Myer Assessment (FMA) upper extremity score.   The 
subject will then be added to the queue to begin participation.  
A subject in the study will be asked to participate for a total of 13 weeks. Training sessions will 
occur within a 6-week span, starting Week 4. These training sessions will be divided into 3 1-
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hour visits a week, for a total of 18 sessions. Additionally, participants will be asked to come to 
the Arms and Hands Lab for 7 evaluation sessions, each lasting approximately 2 hours. These 
will take place during the titration phase (baseline and end of weeks 1, 2, and 3), at the midpoint 
of training (end of week 6), at the end of training (end of week 9), and one month following (end 
of week 13) (see Fig 1). 
3 1-hr
visits
3 1-hr
visits
3 1-hr
visits
3 1-hr
visits
3 1-hr
visits
3 1-hr
visits
1
2
3
Week
9
11
4
5
6
7
8
10
12
13
2-hr
Eval
2-hr
Eval
2-hr
Eval
2-hr
Eval
2-hr
Eval
2-hr
Eval
2-hr
Eval
Figure 1: Timeline for evaluation visits (baseline and end of weeks 1-3, 6, 9 and 13) and treatment therapy sessions (3 
visits per week for weeks 4-9).  Note that you will also be escorted to the outpatient lab area at the baseline visit and the 
end of week 3 (during chronic drug dose) to have your blood drawn.
­
Anticipated enrollment of participant’s completion date: October 2020.
­
The estimated date for the investigators to complete this study: October 2022
STUDY ENDPOINTS:
Primary Outcome Measure:
Change in mean completion time for Graded Wolf Motor Function Test (GWMFT)
Secondary Outcome Measure:
Change in grip relaxation time (following a maximum voluntary contraction (MVC)) Time 
required for muscle electromyographic (EMG) signals to reduce to within 3 SD of pre-MVC EMG 
activity.
PROCEDURES INVOLVED:
Study Design: 
Treatment, Parallel Assignment, Double Blind (Subject, Caregiver, Investigator, Outcomes 
Assessor), Randomized, Efficacy Study.
Over the course of the study, subjects will participate in a therapy regimen involving either active 
practice of hand and arm movements or passive stretching of the digits, while concurrently 
receiving either cyproheptadine or placebo. Thus, the study has two experimental factors: Drug 
(cyproheptadine hydrochloride/placebo) and rehabilitative movement training (active/passive). 
Subjects will be randomly divided into four groups, stratified by initial FMA score, consisting of the 
four combinations of Drug and Training: 
• cyproheptadine with active movement training
• placebo with active movement training
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• cyproheptadine with passive stretching
• placebo with passive stretching.
Twenty-five subjects in each group will complete the study for a total of 100 participants. The 
therapists, other research personnel (including the PI), and the subjects will all be blinded as to 
which agent each subject is taking.  
As cyproheptadine can have side effects, the dosage is generally titrated over time to the 
desired chronic daily dose in order to permit accommodation to the drug. This dosing schedule 
can alleviate the severity of some of the side effects. For this study, both cyproheptadine and the 
placebo will be titrated in the same manner, beginning at up to 8 mg (up to 4 mg taken 2 times 
daily) and increasing the next week to up to 16 mg (up to 8 mg taken 2 times daily) and reaching 
the desired dose level of up to 24 mg per day (up to 8 mg taken 3 times daily) the following week 
(Fig. 2). If side effects occur at higher doses, but not at lower doses, the subject will be maintained 
at the highest dose tolerated for the remainder of the treatment phase.  Participants will maintain 
this daily dosage for 6 weeks, during which time training will be performed. After completion of 
the training period, dosage levels will be reduced back to zero over a two-week period.  The drug 
dosage may be reduced from the target level as recommended by the study doctor.  
The hospital pharmacy will dispense the allotment of the study drug to research staff at each 
change in dosage over the course of the study (5 dispenses).  All pills will be encapsulated by the 
Research Pharmacist so that both cyproheptadine and placebo will be identical in appearance 
and weight. Only the Research Pharmacist and study Statistician will have the key identifying 
which drug each subject was given.  In this manner all other study personnel, including the PI, 
and the subjects will remain blinded as to group membership until the study is complete, or the 
revealing of this information is deemed medically necessary. Each week during the titration 
period, the subject will come to the Arms and Hands lab to receive his/her weekly allotment of 
pills from study staff.  Examination by the study doctor will occur at baseline, midpoint, and at the 
end of the study.  To monitor type and severity of potential adverse side effects of the medications, 
the study doctor or a study team member will complete a checklist for each subject weekly. All 
subjects, even those in the placebo group, will be given this checklist. Adverse side effects will be 
rated as “none”, “moderate”, or “severe” based on subject report. If a subject feels unable to 
Fig. 2.  Dosage and evaluation scheduling for the subjects. During 
the titration period, dosage is increased each week from 8 mg/day 
toward the target chronic dose of 24 mg/day. The 6 weeks of training 
will occur once the chronic dose has been established. Arrows 
indicate evaluation sessions.
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continue the study due to any side effects, she may end her study participation at that time. 
Transportation can be arranged to convey subjects to and from the Shirley Ryan AbilityLab during 
this period in order to preclude the need for subjects to drive when they may be experiencing 
dizziness or somnolence from the medication. Weekly pill counts will be performed to gauge 
subject compliance with taking the medication. Participants will receive the subsequent allotment 
of pills at each dosage change.
Once the chronic dosage is attained, therapeutic training will begin for all subjects. The 
sensorimotor therapy, consisting of 18 one-hour sessions held over 6 weeks, will focus on the 
impaired upper extremity, particularly the hand.
Active Movement Therapy (AMT), VAEDA:
A Voice and EMG-driven Actuated hand orthosis, the VAEDA glove, will be worn by all 
subjects during these therapy sessions. The VAEDA glove contains cables (Spectra kite wire) 
which run across the back of the digits in order to provide extension and resist flexion (Fig 3). 
Forces are transmitted through the cables from a DC micromotor (1724, Faulhaber, Inc), located 
remotely, to the digits. The single actuator controls torque or displacement in the cable. Tension 
in the cable is measured directly with a custom tension sensor; cable displacement is estimated 
from the motor encoder (IE2-16, Faulhaber, Inc.). The cable travels from the actuator through a 
Bowden cable to a forearm splint, at which point it is attached to the 5 cables running to the digits. 
Along the digits, the cables traverse through custom plastic blocks, which serve both to guide the 
cable and to prevent joint hyperextension. The weight of the glove with the cables and cable 
guides is 2.2 N and the forearm splint is an additional 1.5 N, thereby making the total weight on 
the arm less than 4 N.
Fig. 3.  Picture of the VAEDA glove system.  Cables run through cable guides on the dorsal side 
of the glove to facilitate extension and resist unwanted flexion (Left).  The cable is driven by a 
single actuator located remotely on the electronics box which can be worn on the back (Center).  
EMG signals, which control the glove, are processed by custom amplifiers before being 
transmitted to the microcontroller (Right).  
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The VAEDA glove can be controlled with up to 3 channels of EMG. Custom pre-amplifiers 
process the EMG signals before transmitting the data to the microcontroller (RabbitCore® RCM 
4510, Digi International, Inc., Davis, CA).  For this study, electrodes will be placed above flexor 
digitorum superficialis (FDS) and extensor digitorum communis (EDC). Assistance of hand 
opening can be provided by the VAEDA glove, but only if appropriate EMG activity is detected. 
For example, the EDC EMG signal must reach a specified threshold before extension assistance 
will be provided. Similarly, the FDS EMG signal has to surpass a threshold level during hand 
closing before the user is allowed to flex the digits. Additionally, maximum allowable FDS activity 
during hand opening and EDC activity during hand closing can be specified to address 
coactivation issues. Feedback of muscle activity and of opening force provided by the VAEDA 
glove is available to the user through a custom graphical user interface (Fig. 4). As detection of 
movement intent from EMG for 
even simple tasks, such as hand 
opening and closing, can be 
challenging in stroke survivors 
with significant impairment, the 
system also contains a voice 
recognition system, (VRS), (SR-
07 Electronic Express, NY), which 
can be trained specifically for 
each user within minutes.  The 
entire device can be worn, with 
the 
actuator, 
VRS, 
microcontroller, 
and 
batteries 
(Tenergy 7.4V Heavy Duty LIPO, 
Tenergy Corp Freemont, CA) on 
the 
lower 
back 
(Fig. 
3). 
Alternatively, they can be placed 
on a tabletop for a seated user.
Active Movement Therapy (AMT), EMG Video Game:
The alternate session will consist of directly training muscle activation patterns by playing a 
computer game.  A cursor, or “game piece” will be controlled by the patterns recorded from 
surface EMG electrodes (Bagnoli, Delsys, Inc.) positioned over a subset of the following muscles: 
FDS, EDC, thenar eminence, hypothenar eminence, first dorsal interosseous, flexor carpi radialis 
(FCR), and extensor carpi ulnaris (ECU). We will use principal component analysis (PCA) to 
determine basis vectors which can be used to explore the activation workspace defined by these 
muscle groups for each subject. Actions on the computer screen are associated with activation of 
specific principle components (PCs) (Fig. 5). For example, activation levels of the first and second 
PCs can correspond to the x- and y-coordinates for the user’s game piece. Movement of the game 
piece can then be used to spell specific words (Fig. 5b), reveal a hidden picture (Fig. 5c), navigate 
a maze, or play a version of Asteroids. As the user progresses, the PCs controlling the game 
piece will be periodically cycled, such that the third and fourth PCs control the x- and y-
coordinates, for example. Desired PCs can also be explicitly created from the graphical user 
interface, such as to have the user focus on activating individual muscles. If simultaneous control 
of 2 PCs proves too difficult, one-dimensional versions of the letter and hidden picture games can 
be used. Again, half of the subjects in this active training group will be concurrently taking 
cyproheptadine while the other half will be taking a placebo.
Fig. 4.  Graphical user interface for the VAEDA glove. Either the 
magnitude of EMG signals or the force in the cable can be displayed 
to provide feedback to the user and/or therapist. Green and yellow 
bars show the magnitudes of EDC and FDS muscles, respectively. 
The force graph displays the actual readings from the sensor in real-
time.  Data recorded during hand opening.
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Passive Stretching, VAEDA glove:
We recognize that exposure to a novel device such as the VAEDA glove and regular visits to 
the Coleman Hand Rehabilitation Laboratory could have a placebo effect by focusing attention on 
the impaired upper extremity. Thus, the comparison group, comprised of the other half of the 
subjects, will have similar exposure to the laboratory and device, but will not undergo active 
movement therapy. Instead, they will wear the VAEDA glove while it moves their digits from a 
flexed posture to full extension and then allows them to return to the flexed resting posture at a 
rate of roughly 15 cycles per minute. We have found this passive, cyclical stretching to have a 
transient impact on motor control, although the effects did not seem to carry over from one day to 
the next in individuals with chronic impairment (Triandafilou, et al., 2014). For each session, 
subjects will receive two 20-minute stretching sessions, with 10 minutes of rest in between. Half 
of this group will concurrently be taking cyproheptadine while the other half will be taking a 
placebo.
Outcome Measures:
Subjects will be tested at the Arms and Hands Lab at baseline and the end of each week 
during the titration phase. Thus, data will be collected prior to administration of any agent, after 
one week at the lowest dosage of up to 8 mg per day, after one week at the next dosage of up to 
16 mg per day, and after one week at the highest dosage of up to 24 mg per day. Data from the 
4 testing sessions will be used to assess the impact of cyproheptadine on stroke. All outcome 
measures will be collected during each testing session. Pill counts will be performed each week 
as well to gauge subject compliance.
C)
Fig. 5.  Computer games to guide exploration of the activation workspace.  A) EMG signals are converted into PCs 
in real-time to drive a computer video game. B) Control of two PCs moves the game piece (here, a red dot) along 
the horizontal and vertical axes to reach the indicated letter (which turns color from green to yellow when the red 
dot is properly positioned). C) User moves the red dot to the correct tile (highlighted in green) to remove the tile and 
B)
A)
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Three 
potential 
manifestations 
of 
motoneuronal hyperexcitability will be quantified: 
spasticity, 
excessive 
coactivation 
during 
voluntary contraction, and prolonged muscle 
relaxation time.  Spasticity will be precisely 
measured 
using 
techniques 
we 
have 
successfully employed in the past in which all 
four fingers are coupled to a servomotor through 
a custom jig (Fig. 6). Rotation of the servomotor 
shaft produces equivalent rotation of the MCP 
joints. The servomotor will impose constant-
velocity rotation of the MCP joints in order to 
stretch the long finger flexors. Fast MCP rotation 
(300°/s) will be applied to evoke a stretch reflex. 
Slow MCP rotation (10°/s) will be imposed to 
measure nominally passive resistance. Wrist 
orientation and position will be fixed with a 
fiberglass cast which is subsequently clamped to 
a table (Fig. 6). MCP angle, angular velocity, and 
torque are recorded for analysis of spasticity. 
EMG recordings will be obtained with surface 
electrodes (Bagnoli) from EDC and FDS. Subject strength will also be assessed, by having 
subjects perform maximum voluntary MCP flexion and extension in the same testing jig while the 
servomotor provides resistance. The EMG data recorded during these isometric contractions will 
be used to quantify coactivation. Finally, FDS relaxation time will be determined by having the 
subject create maximal grip force in the jig and then relax upon hearing the termination of an 
auditory tone, as we have done previously. Both upper extremities may be tested in a subset of 
participants in order to determine the impact of cyproheptadine on the non-paretic (ipsilesional) 
side.
Clinical assessments will be performed at the baseline, pretreatment (week 3), mid, post and 
follow up evaluation sessions by the study research therapist and study team.  This battery of 
assessments includes the GWMFT, FMA, Chedoke McMaster Stroke Assessment – Stage of 
Hand (CMSA-H), grip and pinch strengths, the Modified Modified Ashworth Scale (MMAS), the 
Jebsen Hand Function Test, the Nine-Hole Peg Test, the Box and Blocks Test (BBT), and the 
Semmes Weinstein Monofilament Touch test.
In addition to these neuromechanical measurements, subjects will be evaluated in terms of 
sleepiness, depression, and weight gain. These are side effects that could dissuade use of the 
medication. The Epworth Sleepiness Scale (ESS) will be given to subjects at each testing session 
(Johns, 1991). This instrument consists of a self-assessment of the propensity to doze (ordinal 
scale, 0-3) during each of 8 activities of daily living (e.g., sitting and talking to someone). We will 
use the Beck Depression Inventory-II (BDI-II) for assessing depression in our subjects. The BDI-
II is a self-report of 21 items rated on an ordinal scale from 0-3 (Beck, et al., 1996). The BDI-II, a 
revised version of the Beck Depression Inventory (Beck, et al., 1961), was developed to remove 
possible bias for older adults from the original instrument. Additionally, subjects will be weighed 
each week to track fluctuations in weight. 
DATA AND SPECIMEN BANKING: N/A
DATA AND SPECIMEN MANAGEMENT: N/A
Motor Shaft
Air Bladder
Channel
Vacuum
Pump Tube
Fig. 6.   Depiction of the interface between the fingers 
and the device.  The motor shaft rotates the U-piece 
coupled to the proximal phalanges of the fingers.  For 
the spasticity experiments, the proximal and distal 
interphalangeal joints will be fixed in neutral with finger 
splints.
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PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS: 
A medical monitor will periodically evaluate the data collected regarding harms to determine 
whether participants remain safe.  Findings from the medical monitor will be reported to the IRB 
during scheduled continuing reviews.
The data monitor will have access to all data collected, including side effects checklists, surveys 
and untoward events.  This information is collected at the evaluation study visits beginning with 
the medical examination with the study doctor and Baseline evaluation.  The data monitor will 
perform monitoring every 6 months for the first 1-2 years of the study, then annual if no change 
to the unanticipated adverse effects of this study.
WITHDRAWAL OF PARTICIPANTS:
Non-compliance with study protocol, or if it is deemed appropriate for the subject’s safety by the 
study doctor or PI, will result in removal from the study.
If a subject chooses to stop involvement in the study prematurely, the study doctor will be notified, 
and will recommend beginning the titration process for weaning the subject from the study drug.  
This will be handled on a case-by-case basis which would involve at least one additional visit with 
the study doctor.
RISKS TO PARTICIPANTS:
The primary risks for involvement in this study are associated with the pharmacological agent to 
be tested. Although cyproheptadine hydrochloride itself is not being used or administered 
differently than the FDA approved method, it is being used for a potentially different outcome, 
namely reduced unwanted muscle tone following stroke.
Some of the potential side effects of taking cyproheptadine include: diminished mental 
alertness, drowsiness, dizziness, hallucinations, insomnia, muscle weakness, chest congestion, 
headache, hypertension, increased appetite, upset stomach, diarrhea, difficulty urinating, vision 
problems, skin rash and dry mouth, nose, and throat, and convulsions. Although reported 
clinical experience has not identified differences in responses between the elderly and younger 
patients, elderly patients should be more cautious of possible risks. These risks may include 
decreased hepatic, renal or cardiac function. 
To minimize these risks, we will begin with low levels of the drug and gradually titrate (increase) 
up to the optimal target dose for the study, which is still well within the safe level of this drug. 
Patients will be evaluated weekly and will be able to contact the study doctor at any time 
with questions or concerns. As a precautionary measure, liver profiles (requiring blood draws) 
will be run prior to initiation of drug administration and at the end of week 3 (chronic drug dose) to 
check drug impact on liver function although liver damage is not a known side effect.  Following 
the medical screening, additional labs may be ordered at the discretion of the study doctor. 
Adverse events, including falls, will be assessed weekly at minimum.
Additionally, the medication may have side effects when combined with other types of drugs 
and/or alcohol. Some side effects of taking combined drugs may lead to confusion, high blood 
pressure, high fevers, tremor or muscle rigidity, and increased activity. 
The effects of the study drug, cyproheptadine, on human sperm and eggs have not been 
studied and are therefore unknown. The effects of cyproheptadine in humans have not 
shown to cause negative conditions in either the mother or the fetus during pregnancy. 

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However, studies in animals have shown an increased risk of birth defects and fetal hormonal 
imbalances. The effects of this medication in women who are nursing have been shown to 
produce hormonal imbalances in the newborn.
Although not in the FPI for cyproheptadine, risks of falls, cognitive decline and increased mortality 
have been associated with use of other such drugs with antihistaminic and anticholinergic effects.
There are also risks with the use of the actuated hand orthosis, the VAEDA glove, to provide 
extension assistance or stretching. This device, as well as the motor used during the 
evaluations, has the potential to cause too much stretching, which may cause pain or damage 
to the joint. A number of safety features, however, have been implemented to attempt to reduce 
these risks, such as mechanical stops and limit switches. Additionally, the subject will be 
monitored continuously by research staff while using this equipment.
Skin irritation could result from the use of self-adhesive surface electrodes. This will be minimized 
by cleaning the skin with alcohol before and after their application. In case of any incident, 
emergency medical services are routinely available at the Rehabilitation Institute of Chicago and 
at the adjacent Northwestern Memorial Hospital emergency room.
Due to the repetitive motions of the arm and hand, subjects also risk experiencing fatigue, 
muscle pain, or soreness. 
The electrical stimulation used to measure muscle activation can cause pain; for some people it 
is sharp like a prick of a needle. We will use a series of stimulation pulses that we have found to 
be least painful. Additionally, we will carefully adjust the stimulation level to minimize discomfort. 
The cast saw used to remove the fiberglass cast placed around the wrist for the evaluations could 
produce burns if left for too long in one place. All study personnel will be trained in the proper use 
of this saw. 
Some questions we ask from the BDI-II examination may be upsetting or make the subject feel 
uncomfortable. If they do not wish to answer a question, they may skip it and go to the next 
question.  A BDI-II total score above 13 will be reported to the study doctor immediately, and a 
private consultation with the study doctor arranged.  Likewise, any suicidal ideations revealed 
through the BDI, regardless of total score, will be reported to the study doctor.  In either case, the 
individual will be advised to seek counseling.
POTENTIAL BENEFITS TO PARTICIPANTS:
Although it has been shown that some benefit may be derived from taking cyproheptadine or from 
performing repetitive motion tasks or stretching, subjects are not guaranteed any direct benefit 
from participating in this research study. Participation in this study may aid in our understanding 
of the nature of movement impairment after stroke and may eventually improve rehabilitation of 
upper extremity function.
VULNERABLE POPULATIONS: N/A
COMMUNITY-BASED PARTICIPATORY RESEARCH: N/A
SHARING OF RESULTS WITH PARTICIPANTS:

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This study is registered on clinicaltrials.gov NCT02418949.  Therefore, study results for the 
outcome measures will be available at the completion of the study.  Individual laboratory test 
results will not be shared with participants unless deemed necessary by the study doctor nor will 
they be available on clincicaltrials.gov.
SETTING:
All training, hand evaluation sessions will be held in the Arms and Hands Lab (22 floor) of the 
Shirley Ryan AbilityLab, 355 E. Erie St. Chicago, IL 60611. This is also where subjects will be 
given their allotment of pills for each change in dosage and see the study doctor for 
examinations.  Research staff will escort subjects to the outpatient lab for blood draw at 
baseline and the end of week 3 (before beginning therapy treatment) to monitor the drugs effect 
on your liver function.
RESOURCES AVAILABLE:
The Shirley Ryan AbilityLab will provide all space and resources required for the completion of 
the proposed study, including areas to conduct subject assessments and experiments, offices for 
the Principal Investigator, Dr. Elliot Roth, and the other project personnel, and administrative and 
information system support. Specifically, the proposed study will be conducted in the Arms and 
Hands Lab of the Shirley Ryan AbilityLab, which contains 17 laboratories devoted to the study of 
human sensorimotor integration and control.
The RIC is a 182-bed specialty hospital in the downtown Chicago area with full accreditation by 
the Joint Commission on Accreditation of Healthcare Organizations and the Commission on 
Accreditation of Rehabilitation Facilities. The RIC brings together high quality comprehensive care 
for individuals with disability, research into the mechanisms and management of disabling 
conditions, and training of professionals and the public about disability and approaches to its 
management. It provides acute inpatient rehabilitation, day rehabilitation, outpatient clinics, and 
home health for stroke, spinal cord injury, traumatic brain injury, and orthopedic patients. The RIC 
is an academic affiliate of the Northwestern University Feinberg School of Medicine and is the 
home of its Department of Physical Medicine and Rehabilitation.
Stroke survivors who are willing to participate in the proposed study will be drawn from the 
outpatient facility of the Shriley Ryan AbilityLab. In addition, the Sensory Motor Performace 
Program (SMPP) maintains an Institutional Review Board (IRB) approved Clinical Neuroscience 
Research Registry of over 900 stroke survivors who wish to be contacted for possible participation 
in research studies.
Shirley Ryan AbilityLab has its own pharmacy. Cyproheptadine and placebo will be dispensed 
from this pharmacy. 
Shriely Ryan AbilityLab is highly supportive of research and is striving to further integrate research 
and clinical care. Therapists working in SMPP typically split their time between SMPP and the 
clinic. RIC currently hosts a number of federally funded centers, including the Rehabiltiation 
Research and Training Center for Stroke, sponsored by the National Institute on Disability and 
Rehabilitation Research. Dr. Roth is the PI and Director for this Center. Additionally, RIC is 
constructing a replacement facility to open in 2017, two blocks from its current site. The concept 
for the new facility is to infuse biomedical science and research into the clinical environment. 
Thus, research laboratories will sit adjacent to clinical therapy space and a culture of interaction 
and cooperation will be fostered. As a model, in the current facility RIC opened the Patient 
Recovery Unit in which patients receive intensive, customized therapy guided by the latest 
research findings.
IRB #: STU00078099 Approved by NU IRB for use on or after 6/23/2020 through 6/22/2021.

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PRIOR APPROVALS: N/A
RECRUITMENT METHODS:
Recruitment for potential participants will be done through the IRB approved research registry. 
Flyers will be placed in Shirley Ryan AbilityLab, clinics, and the Life Center and on the clinical 
trials webpage for the Shirley Ryan AbilityLab  Referrals from the study doctor or other 
colleagues will also be screened. 
Following the initial screening with the research staff, further participation will require passing a 
medical examination with the study doctor as well as completing a clinical assessment for 
randomization purposes prior to study enrollment.  The stipend is $20 for this visit.
During the study, the stipend for each treatment session is $20 and the stipend for each evaluation 
session is $40.  These funds are provided to help support time and travel associated with 
participation.  If a session needs to be repeated at the behest of the study doctor, PI, or due to 
researcher conflicts and/or equipment malfunction the stipend will be duplicated.
RIC is moving away from using petty cash.  During this transition period you may be paid in 
cash or by ClinCard. If a ClinCard is available when you enter into the study, you will be paid by 
card. If a ClinCard is not available, then you will receive cash payments on the day of your 
research visit.
NUMBER OF LOCAL PARTICIPANTS:
We are targeting 100 subjects to complete the study.
This would break down into four groups of 25:
-
Cyproheptadine and Active Hand Therapy
-
Placebo and Active Hand Therapy
-
Cyproheptadine and Passive Stretching
-
Placebo and Passive Stretching
We estimate needing to enroll 200 subjects in order to reach our target due to participants not 
meeting inclusionary/exclusionary criteria or to dropping out of the study.  
CONFIDENTIALITY: N/A
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS:
A private room may be provided to the subject during administration of the side effects checklist, 
medical examinations, or other surveys, such as BDI-II, where sensitive information is discussed.  
As always, the subjects have the right to refuse to answer any questions which may make them 
feel uncomfortable.
The study doctor may access medical records or sensitive information for recruiting purposes.
COMPENSATION FOR RESEARCH-RELATED INJURY:
If a subject becomes ill or gets an injury or illness as a result of study medications or 
procedures, you should seek medical treatment through your doctor or treatment center of 
choice. You should promptly tell the study doctor about any illness or injury.
IRB #: STU00078099 Approved by NU IRB for use on or after 6/23/2020 through 6/22/2021.

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The hospital will not pay for medical care required due to an injury or illness as a result of their 
participation in this research study. However, this does not keep them from seeking to be paid 
back for care required because of a bad outcome. Subjects are welcome to seek medical 
treatment through their doctor or treatment center of choice.
ECONOMIC BURDEN TO PARTICIPANTS:
There will be no costs to participants for being in this study. The cost of the drug, the therapies 
and the lab work tests will be covered by the study.
CONSENT PROCESS:
This study will obtain written informed consent from all study participants.  The consenting process 
will take place at Shirley Ryan AbilityLab, 355 E. Erie St., Chicago IL, 60611 with an approved 
member of the study team. A full discussion about the study will take place before the medical 
examination; research staff will be available to answer any questions.  Subjects will be given 
ample time to meet with family or friends to discuss details of the study prior to giving consent.  
For documentation of the consent process, a participant’s signature may be obtained 
electronically.
Adults Unable to Consent
The individuals from whom permission will be obtained in order of priority: durable power of 
attorney for health care, court appointed guardian for health care decisions, spouse, and adult 
child.
PROCESS TO DOCUMENT CONSENT IN WRITING:
Informed consent will be documented in writing through our Consent and HIPAA Authorization for 
Research form and uploaded to the Nitro Study Tracker.
DRUGS OR DEVICES:
The drugs used in this study will be administered by the Shirley Ryan AbilityLab pharmacy for 
each subject.  A study team member will deliver the prescription to the participant during a 
scheduled visit.  If there is any time the drug will be in the lab prior to this delivery, it will be 
temporarily locked in a designated cabinet approved by the pharmacy.
IRB #: STU00078099 Approved by NU IRB for use on or after 6/23/2020 through 6/22/2021.