Predicting Ipsilesional Motor Deficits in Stroke With Dynamic Dominance Model
Phase: NA
Conditions: Stroke
Sponsor: Robert L. Sainburg

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Predicting Ipsilesional Motor Deficits in Stroke With Dynamic Dominance 
Model 
 
Protocol and Statistical Analysis Plan 
 
 
NCT03634397 
 
Version 3/20/2020 
 
 

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HRP-591 - Protocol for  
Human Subject Research 
 
Protocol Title: 
Predicting Ipsilesional Motor Deficits in Stroke with Dynamic Dominance Model 
 
Principal Investigator: 
Name: Robert L. Sainburg, Ph.D. 
Department: Kinesiology and Neurology 
Telephone: 814-865-7938 
E-mail Address: rls45@psu.edu 
 
Version Date: 
3/30/20 
 
Clinicaltrials.gov Registration #: 
NCT03634397  
 
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Table of Contents 

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1.0 
Objectives 
2.0 
Background 
3.0 
Inclusion and Exclusion Criteria 
4.0 
Recruitment Methods 
5.0 
Consent Process and Documentation 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
7.0 
Study Design and Procedures 
8.0 
Subject Numbers and Statistical Plan 
9.0 
Confidentiality, Privacy and Data Management 
10.0 
Data and Safety Monitoring Plan 
11.0 
Risks 
12.0 
Potential Benefits to Subjects and Others 
13.0 
Sharing Results with Subjects 
14.0 
Subject Stipend (Compensation) and/or Travel Reimbursements 
15.0 
Economic Burden to Subjects 
16.0 
Resources Available 
17.0 
Other Approvals 
18.0 
Multi-Site Research 
19.0 
Adverse Event Reporting 
20.0 
Study Monitoring, Auditing and Inspecting 
21.0 
Future Undetermined Research: Data and Specimen Banking 
22.0 
References 
 
 

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1.0 
Objectives 
 
1.1 
Study Objectives 
 
In the previous cycle of this grant, we characterized hemisphere specific motor control deficits in 
the non-paretic arm of unilaterally lesioned stroke survivors. Our preliminary data indicate that 
functional performance in the non-paretic arm, measured by the Jebsen-Taylor Hand Function Test 
(JTHFT), is diminished in patients with severe paresis by on average, 66% following right-hemisphere 
damage and 115% following left hemisphere damage. We hypothesize that such large deficits in the 
non-paretic arm interfere with the performance of functional activities in patients with severe paresis, 
who also cannot use the paretic arm for prehension and manipulation.  
We have specifically designed an intervention to remediate the hemisphere-specific deficits in 
the non-paretic arm, using a virtual-reality platform. We then facilitate generalization and transfer to 
functional behaviors encountered in the natural environment by training speed and accuracy of 
manipulation using a variety of real objects. This intervention protocol is grounded in the premise that 
targeted remediation of fundamental control deficits exhibited by the non-paretic arm will generalize 
beyond practiced tasks to functional activities and functional independence. This intervention contrasts 
with the more typical approaches focused on paretic arm improvements, and the more pragmatic task-
specific training therapies of essential ADL’s which we argue is limited in scope, more cumbersome and 
ignores known fundamental motor control deficits. The impact of the proposed research is that we 
address persistent functional performance deficits in chronic stroke patients with severe paresis, who’s 
non-paretic arm impairments are generally ignored in most current rehabilitation protocols. We propose 
a 2-site, two-group randomized intervention with a treatment group, which will receive unilateral 
training of the non-paretic arm, through our Virtual Reality and Manipulation Training (VRMT) protocol. 
The control group will receive a comparison intervention, designed to match the experimental 
intervention in duration and frequency, but employs conventional therapies according to recently 
released practice guidelines for upper limb intervention in adult stroke. This proposal combines the 
research and recruiting strengths of two active laboratories, each with a history of studying hemisphere 
specific motor deficits in stroke survivors (Sainburg and Winstein), and stroke clinical trial intervention 
research (Winstein). We have already integrated our laboratories to conduct the pilot research that 
provides support for the predictions of the first two aims, detailed below. 
 
Aim 1: To determine whether non-paretic arm VRMT in chronic stroke survivors with severe paresis 
will produce durable improvements in non-paretic arm motor performance that will generalize to 
improve functional activities and functional independence to a greater extent than conventional 
therapy focused on the paretic arm. We predict that: 1a) Unilateral VRMT training of the non-paretic 
arm will produce functional improvements in non-paretic arm motor performance (JTHFT), 1b) 
Conventional therapy focused on the paretic arm should decrease paretic arm impairment (Fugl-Meyer) 
to a greater or equal extent than non-paretic arm VRMT. We will assess paretic arm impairment level 
using the upper extremity component of the Fugl-Meyer Assessment (UEFM) as our primary measure, 
and “work area” using kinematic analysis, as detailed by Dewald and Co-workers [5] as our secondary 
measure. 1c) The effects of non-paretic arm VRMT will generalize to functional activities (Abilhand) and 
functional independence (FIM-motor/Barthel) to a greater extent than conventional paretic arm 
therapy. This aim provides a strong test of our hypothesis that non-paretic arm motor training will have 
a greater impact on functional independence than conventional paretic arm training in patients who lack 
paretic hand function, a prediction supported by our pilot data (see Figure 8). 
 
Aim 2: To determine whether intervention-induced improvements in non-paretic arm performance 
are associated with improvements in hemisphere-specific reaching kinematics. We predict that VRMT 
-induced improvements in performance will be correlated with reductions in hemisphere-specific motor 
deficits [6-9], which are targeted by the VR component of our intervention. We will test this using a 
planar reaching paradigm that we developed and employed in the previous cycle of this grant for 

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quantifying hemisphere-specific non-paretic arm kinematics [6]. We predict that improvements in 
functional performance (JTHFT) will correlate better with early trajectory variance in LHD patients, but 
with late trajectory variance in RHD patients. These variables have previously been associated with left 
and right hemisphere processes, respectively.  
 
Aim 3: To determine whether our experimental intervention (non-paretic arm VRMT) might have 
detrimental effects on paretic arm impairment (Fugl-Meyer, Kinematics).  We predict that VRMT 
dependent improvements in non-paretic arm motor performance will not decrement paretic arm 
impairment level, a prediction supported by our pilot data (Figure 7) and the findings of Urbin et al [10]. 
This aim is important to ensure that VRMT of the non-paretic arm does not have a negative effect on 
paretic arm function. Our pilot data from 15 severely paretic patients supports this hypothesis, indicating 
that VRMT remediation of the non-paretic arm leads to modest reductions in paretic arm impairment. 
 
1.2 
Primary Study Endpoints 
 
Non-Paretic Arm Evaluation: Jebsen-Taylor Hand Function Test  
Paretic Arm Evaluation: Upper-Extremity Fugl-Meyer Assessment  
Upper Extremity Functional Activity: Abilhand Assessment  
Functional Independence: Barthel Index 
 
1.3 
Secondary Study Endpoints 
 
Functional Independence Measure (FIM)-motor component 
 
Kinematic Outcomes:  
Positional Variance (Early and Late):  
• 
Peak Velocity, 
• 
End point of movement (tangential velocity minimum, after peak velocity that has an amplitude 
of less than 15% of maximum velocity) 
Work Area (Paretic Arm) 
 
2.0 
Background  
 
2.1 
Scientific Background and Gaps 
Stroke is a major health problem in the United States that leaves many survivors with chronic 
motor impairment, including hemiparesis in the limbs that are on the opposite side of the body to the 
damaged brain hemisphere. A substantial body of research has now established that the non-paretic 
arm often has motor deficits that limit performance of activities of daily living and thus functional 
independence [6, 8, 11-22]. The significance of the proposed research is that we developed a targeted 
remediation protocol to ameliorate persistent functional performance deficits in chronic stroke patients 
with severe paresis, who’s non-paretic arm impairments are generally ignored in most current 
rehabilitation protocols. Our intervention protocol is grounded in the premise that targeted remediation 
of fundamental control deficits exhibited by the non-paretic arm will generalize and transfer beyond 
practiced tasks to functional activities and functional independence. The previous cycle of this grant 
detailed the mechanistic underpinnings of non-paretic arm motor deficits. The scientific premise of this 
proposal is based on the finding that non-paretic arm motor deficits become functionally limiting in 
patients with severe paresis, who are unable to use the paretic arm for manipulation [23]. This group of 
patients is identified by an upper extremity Fugl-Meyer (FM) score between 0-28 and a score of 0 
(inability to perform) in the mass extension and prehension components of the Fugl-Meyer Assessment.  
Woytowicz et al [1] recently reported a cluster analysis of 247 stroke patients, and identified a 
severely paretic group in the FM score range of 0-28. With the exception of mass finger flexion, 95-100% 

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of the patients scored 0 (unable to perform) for each item of the wrist movement, mass finger 
extension, and each prehension item of the FM. Thus, this severely paretic group of stroke patients is 
unable to use the paretic arm for manipulation purposes in activities of daily living. Deficits in 
coordination of the non-paretic arm can thus produce substantial limitations in the speed and efficacy of 
functional activities in this population. In fact, our preliminary findings (see Figure 2) indicate that 
unilateral tasks with the non-paretic arm take, on average, twice as long to complete as the comparable 
arm of age-matched control participants, indicating labored and inefficient movement that can interfere 
with patient’s participation in activities. Unfortunately, clinical rehabilitation has yet to recognize the 
need to address non-paretic arm motor deficits, largely because scientific evidence has not yet been 
translated into clinical practice, nor has the best practice for this translation been specified through 
innovative intervention studies. This proposal will directly address these shortcomings, in order to 
provide a model for understanding how to incorporate non-paretic arm motor training into clinical 
rehabilitation practice for patients with severe paresis. It should be noted, however, that in animal 
models, training of the non-paretic arm in the acute phase of stroke recovery has been shown to 
interfere with subsequent paretic arm recovery [24, 25]. In addition, constraining the use of the non-
paretic arm can facilitate functional recovery in those stroke survivors with mild to moderate paresis 
who are capable of distal manipulation in the contralesional hand, but who avoid using that arm due to 
learned non-use [26, 27].  
Importantly, our proposed intervention focuses on patients with severe paresis who are in the 
chronic phase of stroke, and who do not have the sensorimotor requisites for paretic hand dexterity or 
manipulation. In this group of patients, recent findings indicate that intense resistance training of the 
non-paretic arm can reduce impairment measured in the paretic arm [10]. Consistent with this finding, 
our pilot data shows that intense non-paretic arm dexterity training also leads to a modest reduction in 
paretic arm impairment. Thus, we expect that the unilateral non-paretic arm VRMT training proposed 
here will improve functional independence without jeopardizing paretic arm function in patients with 
severe paresis (Aim 3). Our ultimate goal is to determine whether non-paretic arm remediation should 
be part of a package of rehabilitation that assesses and remediates fundamental control deficits in each 
arm of severely paretic stroke patients [4]. 
 
2.2 
Previous Data 
 
Preliminary Studies: Our findings from the previous grant cycle showed that the nature of non-
paretic arm motor deficits can be explained by a model of hemispheric lateralization for motor control 
[64]. Thus, damage to each hemisphere produces specific and unique motor deficits in the non-paretic 
arm [7, 9]. Figure 1A shows reaching movements in the non-paretic arm of patients with left and right 
hemisphere damage. While patients with left hemisphere damage (LHD) made highly curved 
movements with accurate final positions, patients with right hemisphere damage (RHD) made straight 
movements with poor final position accuracies. Figure 1B shows the variance in hand positions during 
the initial trajectory phase (bottom ellipses) and in the final position (top ellipses) of the movement. This 
demonstrates the double dissociation between hemisphere of damage and motor control process 
effected by the lesion: RHD patients had deficits in stabilizing accurate final positions across trials, while 
LHD patients had deficits in stabilizing accurate initial trajectories across trials. We characterized these 
hemisphere-dependent movement deficits in studies that restricted motion to the horizontal plane; this 
was necessary to better control experimental variables, such as the joint displacements associated with 
a particular target. To achieve Aim 2, we will use this well-established horizontal reaching paradigm that 
yields initial positional variance (at peak velocity) and final position variance (at movement end) to 
assess potential training-related changes in hemisphere-specific motor deficits. 
 
As an important foundation for the proposed research, we tested whether non-paretic arm 
motor function depends on the severity of paresis in the contralesional arm, and on the side of the brain 
that is damaged [23]. All patients were right-handed, prior to stroke. Figure 2 shows data from 54 right-
handed, age and gender matched control participants, 48 right-handed LHD survivors, and 62 right-
handed RHD survivors. The y-axis represents the time to complete the Jebsen-Taylor Hand Function Test 
(raw score). The JTHFT is a clinical assessment of unilateral arm function [65] that includes a range of 

Page 7 of 26 (V.04/27/2017)  
tasks that simulate the coordination requirements of functional daily activities [66, 67]. The left column 
in Figure 2 (control) shows the difference between healthy participants performing with the non-
dominant left arm (Black) and the dominant right arm (Grey). The data are stratified on the x-axis by 
hand, and severity of contralesional paresis, as measured by the upper extremity component of the 
Fugl-Meyer Assessment of motor impairment [68] (mild [43-66], moderate [29-42], Severe [0-28]). In 
stroke survivors, JTHFT scores are only for the non-paretic arm (ie. Gray = non-paretic right arm of RHD 
participants; Black = non-paretic left arm of LHD participants). Note that the ‘severe’ classification in this 
plot reflects the level of impairment we target in this proposal.  
 
In stroke survivors, JTHFT performance with the non-paretic arm was impacted substantially by 
both the severity of paresis and the side of brain damage. Participants with the most severe paresis in 
the contralesional arm had the greatest motor deficit in the non-paretic arm. Furthermore, the 
magnitude of the deficit depended on the side of the lesion, such that left hemisphere damage was 
associated with a 115% increase in JTFT score, while right hemisphere damage increased the time to 
complete the JTFT by 66%. These comparisons are relative to performance of the same arm (right or 
left) of age-matched control participants. However, it should be stressed that in LHD patients, the non-
dominant arm must now function as a dominant controller, indicating an even larger deficit relative to 
age-matched dominant arm performance. Thus, stroke survivors who are forced to rely most extensively 
on the non-paretic arm for performance of ADL have the greatest deficits in coordination in the non-
paretic arm. These stroke survivors were tested, on average, 1.8 years (±0.3 SE) after stroke, which 
suggests that these deficits do not spontaneously improve over time. To provide a reference, imagine 
using only your non-dominant arm to carry out all your activities of daily living, such as preparing food, 
dressing including buttoning, putting on socks, and shoes, etc. This would be somewhat frustrating. Now 
imagine that your non-dominant arm has become 115% slower and less coordinated than it was-the 
case for our severely impaired LHD patients. RHD patients get to use the previously dominant arm, but 
with a 66% decrement in function. Overall, these impairments are substantially functionally limiting. 
 
2.3 
Study Rationale 
 
While motor deficits in the non-paretic arm of patients with unilateral stroke have been 
documented as early as 1967 [42], more recent research has shown that these deficits are functionally 
limiting and that they persist throughout the chronic phase of stroke [6-9, 11, 17, 19-22, 29, 31, 33, 43-
51]. In fact, studies of non-paretic arm function in chronic stroke patients have reported performance 
deficiencies on a number of clinical tests, including the Purdue Pegboard Test [52], the Jebsen-Taylor 
Hand Function Test [8], and a variety of tests that directly assess or simulate activities of daily living [11, 
53, 54]. Furthermore, significant deficits in movement coordination and accuracy have been shown 
through studies that use motion analysis [7-9, 17, 28-30, 33, 43, 46, 48, 55-62]. Winstein’s laboratory 
published some of the earliest research characterizing the hemisphere specificity of ipsilesional 
movement deficits in stroke [50, 59] while in the previous grant cycle, Sainburg systematically detailed 
the hemisphere specificity, neural foundations, and functional implications of non-paretic arm motor 
deficits [9, 17, 28-30, 32, 33, 43, 60]. Together, our findings have demonstrated that stroke-related non-
paretic arm motor deficits result from a loss of the contributions of the ipsilateral hemisphere to motor 
control, and that right- and left-hemisphere damage lead to deficits in different aspects of motor control 
[9, 29, 36, 59, 63]. Most relevant to the current proposal is the finding that hemisphere specific motor 
deficits in the non-paretic arm produce deficits in functional performance [8]. Our findings have 
demonstrated that stroke-related non-paretic arm motor deficits result from a loss of the contributions 
of the ipsilateral hemisphere to motor control, and that right- and left-hemisphere damage lead to 
deficits in different aspects of motor control [9, 29, 36, 59, 63]. Most relevant to the current proposal is 
the finding that hemisphere specific motor deficits in the non-paretic arm produce deficits in functional 
performance. 
 
3.0 
Inclusion and Exclusion Criteria 
 

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3.1 
Inclusion Criteria 
 
1. Right handed (pre-stroke) 
2. Neurological confirmation of unilateral stroke 
3. Ipsilesional deficits (JTHFT > 70 seconds or 40 (RHD)/45 seconds (LHD) seconds without writing 
time), contralesional deficits (upper extremity) (UEFM mass extension and prehension 
components score of 0) 
4. Over the age of 18 
5. Chronic stage of stroke 
 
3.2 
Exclusion Criteria 
 
1. Neuroradiological confirmation of extensive periventricular white matter changes (based on 
consultation with neuroradiology) 
 
A history of:  
1) neurological disease other than stroke (e.g., head trauma),  
2) a major psychiatric diagnosis (e.g., schizophrenia, major affective disorder),  
3) hospital admission for substance abuse 
4) peripheral disorders affecting sensation or movement of the arms, including pain or arthritis 
5) currently taking prescription drugs with known sedative properties that might interfere with 
sensory-motor function 
6) significant joint pain that is activity limiting. 
 
3.3 
Early Withdrawal of Subjects 
 
3.3.1 Criteria for removal from study 
 
• 
failure of subject to adhere to protocol requirements (attending sessions) 
• 
subject consent withdrawal 
• 
new stroke or disabling disorder 
 
3.3.2 
Follow-up for withdrawn subjects 
 
Following withdraw from the study investigators will call participants 1 week later to follow up. 
Data will be used if enough has been collected for analysis. If not, subject will be replaced by 
additional recruitment. 
 
4.0 
Recruitment Methods 
 
4.1 
Identification of subjects 
Participants will be recruited from Penn State Hershey Medical Center (PSHMC) and University of 
Southern California (USC) local stroke network. At Penn State, recruitment will include the Sainburg 
Laboratory’s current database consisting of a large number of current and previous stroke participants, 
and by Penn State Hershey Medical Center’s neurologists including Dr. David Good, and local stroke 
support groups/hospitals. At USC, recruitment will include the Winstein Laboratory’s current database, a 
database of current and previous stroke survivors at USC, USC’s Neurology Department, and local stroke 
support groups/hospitals. We will also use StudyFinder for recruitment. Participants may also contact 
researchers directly. Flyers may also be placed in local locations. 
 

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4.2 
Recruitment process 
After identifying potential subject, they will be sent a letter to notify them of the study, unless the 
participant contacts the lab first. They will be contacted be a study team member by telephone within 2 
weeks of sending the letter.  
 
4.3 
Recruitment materials 
Letter to patient, Flyers 
(See StudyFinder page) 
 
4.4 
Eligibility/screening of subjects 
See StudyFinder page for telephone script. 
 
5.0 
Consent Process and Documentation  
 
5.1 
Consent Process  
  
5.1.1 Obtaining Informed Consent 
 
5.1.1.1 Timing and Location of Consent 
Informed consent will be obtained from all participants at the beginning of the 
first session at either Hershey Medical Center (Room C2852) or USC, Biophysical 
Therapy Dept. 
 
5.1.1.2 Coercion or Undue Influence during Consent 
 
To minimize the possibility of coercion or undue influences, each participant will 
be thoroughly explained the purpose and expectations of the study. The 
participants will also be made aware that the study is completely voluntary and 
they can withdraw themselves at any time. In addition, consent will be 
explained to the patient by a member of the research team who doesn't have 
any prior relationship with the potential participants. 
 
 
5.1.2 Waiver or alteration of the informed consent requirement 
The study team is requesting a waiver of informed consent to allow for recruitment from clinical 
schedules and curated databases. 
5.2 
Consent Documentation 
 
5.2.1 
Written Documentation of Consent 
 
Consent will be documented in writing by having the participant sign the informed consent form 
at the beginning of the first research session, and documents will be kept in a locked filing 
cabinet (please see consent documents). Participants will receive a paper copy of the signed 
informed consent document at their first session. 
 
5.2.2 
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) 
The study team is requesting this waiver to allow for telephone screening and scheduling. 
 
5.3 
Consent – Other Considerations  
 
5.3.1 
Non-English Speaking Subjects 
not applicable 

Page 10 of 26 (V.04/27/2017)  
 
5.3.2 
Cognitively Impaired Adults 
not applicable 
5.3.2.1 Capability of Providing Consent 
not applicable 
5.3.2.2 Adults Unable To Consent 
not applicable 
5.3.2.3 Assent of Adults Unable to Consent 
not applicable 
 
5.3.3 
Subjects who are not yet adults (infants, children, teenagers)  
not applicable 
5.3.3.1 Parental Permission 
 
 
not applicable 
5.3.3.2 Assent of subjects who are not yet adults 
not applicable 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
 
6.1 
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
Check all that apply: 
  
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable] 
 
 
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable] 
 
 
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3] 
 
 
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3] 
 
 
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3] 
 
6.2 
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
6.2.1 
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual 
 
6.2.1.1 Plan to protect PHI from improper use or disclosure 
 
Information is included in the “Confidentiality, Privacy and Data Management” 
section of this protocol. 
 
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers  
The list linking subject numbers to their PHI will be deleted following publications 
of study within 2 years of study closing. Any paper copies will be shredded. 
 

Page 11 of 26 (V.04/27/2017)  
6.2.2 
Explanation for why the research could not practicably be conducted without access to and 
use of PHI 
In order to identify potential participants, stroke patients’ charts must be accessed to screen for 
inclusion criteria. Because we exclude hundreds of subjects from the stroke database due to 
exclusion criteria, it would not be practical to contact patients unless they are an appropriate fit 
for the study. In addition, contact information needs to be obtained. 
 
6.2.3 
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization 
 Given the number of subjects and the possibility that subjects may no longer be living this 
research would not be practical without waiver. No clinical information which would be 
pertinent to the care of individual subjects is expected to result from this study. 
 
6.3 
Waiver or alteration of authorization statements of agreement 
 
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations.  
 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations.  
 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented. 
 
7.0 
Study Design and Procedures 
 
7.1 
Study Design 
 
• 
Two 20-40-minute components comprise each session, one consists of virtual reality (VR) 
‘games’ that separately target right- and left-hemisphere specific motor deficits, and the next 
component consists of dexterity training. The order of these sessions will be counterbalanced 
between subjects.  
• 
The VR component is designed to focus on specific aspects of control that we have previously 
shown to be deficient in the non-paretic arm of right or left hemisphere damaged stroke 
patients. For the first 20-30 minutes of training, patients with LHD and RHD will practice tasks 
adapted to the motor control deficits associated with the damaged hemisphere. LHD patients 
will practice virtual shuffleboard, which focuses on predictive aspects of trajectory control, while 
RHD patients will play tracing games that focus on feedback mediated control.  
• 
We then follow this with 30-40 minutes of hemisphere-independent speed and accuracy 
training of manipulation using a variety of real objects, designed to facilitate generalization and 
transfer to functional behaviors encountered in the natural environment.  In this phase of the 
session, participants will first engage in mild resistive exercises, using theraputty and theraband, 
elastic substances designed for resistive exercises of the hand and arm, respectively. After 6 
minutes of preparation, all participants will engage in a series of 6 tasks. The order that the tasks 
are presented will be randomized between sessions for each participant. Each task will be 
practiced for 4 minutes. The number of items successfully completed in each task will be 
counted and recorded as a ‘target’ to beat in the next session, providing motivation for 
improvement within and between sessions. While most of these tasks are self-explanatory, the 

Page 12 of 26 (V.04/27/2017)  
cup-stacking task uses 100 16-ounce disposable plastic cups, which are stacked in rapid 
sequence. The nuts and bolts task uses 5 varied diameter inverted bolts attached to a wooden 
base. The participants must pick up and screw on as many nuts as possible in 4 minutes. These 
tasks were chosen to have no overlap with the components of the JTHFT.  
• 
While our pilot data indicates the effectiveness of this intervention package, it is beyond the 
scope of this proposal to assess the relative efficacy of its individual components. However, in 
aim 2, we will determine whether this package of training specifically ameliorated hemisphere-
specific movement deficits in RHD and LHD patients. If so, this would suggest that the 
hemisphere-specificity of the VR training may be important in reducing such deficits.  
Comparison Intervention:  
• 
Our comparison intervention is designed to match our experimental intervention in duration 
and frequency (3X/week for 1 hour over 5 weeks), but using conventional therapeutic activities, 
based on the best-practices framework for arm recovery post stroke that was developed by an 
international group of clinicians and researchers in post-stroke rehabilitation [3]. This group, 
which included occupational therapists, physical therapists, physiatrists, neurologists, and 
scientists, developed an algorithm for a clinical decision tree which was implemented through a 
smartphone app, ViaTherapy. In short, recommended therapies are stratified based on research 
evidence for efficacy, take into account chronicity, potential for reported shoulder pain, and are 
filtered by co-morbidities such as neglect, cognitive impairment, aphasia, and apraxia.  
• 
To avoid any confounds with the experimental intervention, we exclude any interventions 
requiring technology that might not be found in a typical community-based rehabilitation clinic, 
such as robotic rehabilitation, functional electric stimulation, or computer based interfaces. For 
a typical patient in our study (> 6  months chronicity, no activity limiting shoulder pain, able to 
partially abduct the shoulder against gravity and partially extend the elbow without gravity, but 
cannot initiate finger and thumb extension three times within a minute), recommendations 
include 1) Proximal strength training, 2) Motor imagery and mental practice, 3) Mirror Therapy, 
using a midsagittal mirror reflecting the non-paretic arm, while the patient attempts bilateral 
symmetrical forward reaching, and 4) Task specific training, involving reaching toward 
meaningful objects, with manual assistance as required. The first ten minutes of the 60-minute 
session will begin with passive range of motion, gentle stretching, and proximal weight bearing, 
which will help relax spasticity (if present) and prepare the proximal muscles for activity. This 
will be followed by two of the first 3 recommended therapies (10 minutes each), and then will 
be followed by 30 minutes of active assisted task-specific reach training. While the specific 
recommendations may vary slightly based on the decision algorithm, all therapies will begin 
with 10 minutes of proximal preparation, and all sessions will end with 30 minutes of assisted 
task-specific reaching of the paretic arm in various directions. 
• 
This study is after the standard care of treatment has been finished or in addition to standard 
care of treatment, not in place of standard care. 
 
7.2 
Study Procedures 
 
7.2.1 
Visit 1 (pre-test 1): 
 
Visit 1 (pre-test/screening): subjects will be consented, and then tested using standardized tests 
including the primary and secondary measures. In addition, the Edinburgh handedness 
inventory, Confidence in Arm and Hand Movement (CAHM), Multidimensional Scale of 
Perceived Social Support, NIH stroke scale, tests for comorbidities including testing of grip 
strength, visual neglect, and apraxia. If they meet criteria for the study, they will be randomly 
assigned to either the intervention or comparison condition. Tests may be videotaped for 
scoring and standardization purposes. Participant’s names will not be associated with the 
videotapes. A data safety monitoring board will monitor the study for safety and to minimize 
risk. 

Page 13 of 26 (V.04/27/2017)  
 
7.2.2 
Visit 2 (pre-test 2): 
 
Visit 2 will include the same assessments as visit 1 to establish stability in baseline measures. 
Participants will also receive an MRI of the brain, which will take about one hour, as long as they 
are able to have one. The research grade MRI is used for data analysis regarding lesion location 
and volume. It is standard for studies of this nature to collect this information. 
 
7.2.3 
Visit 3-17:  
Intervention condition: Two 20-40-minute components comprise each session, one consists of virtual 
reality (VR) ‘games’ that separately target right- and left-hemisphere specific motor deficits, and the 
next component consists of dexterity training. The order of these sessions will be counterbalanced 
between subjects. The VR component is designed to focus on specific aspects of control that we have 
previously shown to be deficient in the non-paretic arm of right or left hemisphere damaged stroke 
patients. For the first 20-30 minutes of training, patients with LHD and RHD will practice tasks adapted 
to the motor control deficits associated with the damaged hemisphere. LHD patients will practice virtual 
shuffleboard, which focuses on predictive aspects of trajectory control, while RHD patients will play 
tracing games that focus on feedback mediated control. We then follow this with 30-40 minutes of 
hemisphere-independent speed and accuracy training of manipulation using a variety of real objects, 
designed to facilitate generalization and transfer to functional behaviors encountered in the natural 
environment.  In this phase of the session, participants will first engage in mild resistive exercises, using 
theraputty and theraband, elastic substances designed for resistive exercises of the hand and arm, 
respectively. After 6 minutes of preparation, all participants will engage in a series of 6 tasks. The order 
that the tasks are presented will be randomized between sessions for each participant. Each task will be 
practiced for 4 minutes. The number of items successfully completed in each task will be counted and 
recorded as a ‘target’ to beat in the next session, providing motivation for improvement within and 
between sessions. These tasks are shown in the flow chart in Figure 5. While most are self-explanatory, 
the cup-stacking task uses 100 16-ounce disposable plastic cups, which are stacked in rapid sequence. 
The nuts and bolts task uses 5 varied diameter inverted bolts attached to a wooden base. The 
participants must pick up and screw on as many nuts as possible in 4 minutes. These tasks were chosen 
to have no overlap with the components of the JTHFT. While our pilot data indicates the effectiveness of 
this intervention package, it is beyond the scope of this proposal to assess the relative efficacy of its 
individual components. However, in aim 2, we will determine whether this package of training 
specifically ameliorated hemisphere-specific movement deficits in RHD and LHD patients. If so, this 
would suggest that the hemisphere-specificity of the VR training may be important in reducing such 
deficits. 
 
Comparison (sham) Intervention: Our comparison intervention is designed to match our experimental 
intervention in duration and frequency (3X/week for 1 hour over 5 weeks), but using conventional 
therapeutic activities, based on the best-practices framework for arm recovery post stroke that was 
developed by an international group of clinicians and researchers in post-stroke rehabilitation [3]. This 
group, which included occupational therapists, physical therapists, physiatrists, neurologists, and 
scientists, developed an algorithm for a clinical decision tree which was implemented through a 
smartphone app, ViaTherapy. In short, recommended therapies are stratified based on research 
evidence for efficacy, take into account chronicity, potential for reported shoulder pain, and are filtered 
by co-morbidities such as neglect, cognitive impairment, aphasia, and apraxia. To avoid any confounds 
with the experimental intervention, we exclude any interventions requiring technology that might not 
be found in a typical community-based rehabilitation clinic, such as robotic rehabilitation, functional 
electric stimulation, or computer based interfaces. For a typical patient in our study (> 6  months 
chronicity, no activity limiting shoulder pain, able to partially abduct the shoulder against gravity and 
partially extend the elbow without gravity, but cannot initiate finger and thumb extension three times 
within a minute), recommendations include 1) Proximal strength training, 2) Motor imagery and mental 

Page 14 of 26 (V.04/27/2017)  
practice, 3) Mirror Therapy, using a midsagittal mirror reflecting the non-paretic arm, while the patient 
attempts bilateral symmetrical forward reaching, and 4) Task specific training, involving reaching toward 
meaningful objects, with manual assistance as required. The first ten minutes of the 60-minute session 
will begin with passive range of motion, gentle stretching, and proximal weight bearing, which will help 
relax spasticity (if present) and prepare the proximal muscles for activity. This will be followed by two of 
the first 3 recommended therapies (10 minutes each), and then will be followed by 30 minutes of active 
assisted task-specific reach training. While the specific recommendations may vary slightly based on the 
decision algorithm, all therapies will begin with 10 minutes of proximal preparation, and all sessions will 
end with 30 minutes of assisted task-specific reaching of the paretic arm in various directions. 
 
Note: sessions may be videotaped for standardization purposes. 
 
7.2.4 
Visit 18: Post test 
Visit will include the same assessments as visit 1 
 
7.2.5 
Visit 19: Post test 2 (short term retention) 
Visits will include the same assessments as visit 1, 2 weeks following completion of training sessions 
 
7.2.6 
Visit 20: Post test 3 (long term retention)  
Visits will include the same assessments as visit 1 six months following completion of training sessions 
 
7.3 
Duration of Participation 
 
This study will require each participant to attend three 60-minute sessions per week for 5 weeks, as well 
as 5 separate test (pre and post) sessions, for a total of 20 sessions. If participant misses a session, it will 
be made up the following week, or by adding it to the end of training sessions. The first two separate 
pretests take place at visit 1 and 2, one to two weeks apart. The other additional testing sessions take 
place the visit after the conclusion of therapy sessions, 2 weeks later, and a 6 months following 
conclusion of therapy sessions. 
8.0 
Subject Numbers and Statistical Plan 
 
8.1 
Number of Subjects 
We seek to recruit a total of 30 participants for the study per year between sites, and after screening 
and attrition rate, have 20 subjects a year complete the research procedures, for a total of 120 
participants. 
 
8.2 
Sample size determination 
Based on our primary outcome measures (Barthel, FIM-motor, Abilhand, UEFM, JTHFT) the proposed 
sample size of 60 participants per group provides adequate power (>=0.80) to assess each prediction 
when the effect size (Cohen's f) is 0.35 or greater. Cohen suggested that researchers consider f=0.1 as a 
small effect, f=0.25 as a medium effect, and f=0.4 as a large effect. To determine sample size, we used a 
power analysis program, SOLO [81], and computer simulation. SOLO permitted us to vary effect sizes 
and determine the test's power for a fixed group size. The simulation permitted us to use our pilot data 
to generate multivariate normal data; fit a model with fixed effects for group, test, and group by test 
interaction; conduct tests to include those for the linear contrasts; and record the p-value and 
associated effect size. The pilot data was particularly useful because the participants had been chosen so 
that they would span the expected impairment levels, and included right- and left-hemisphere-damaged 
participants. We will go through the major measures and analyses for each aim below. We have 
collected pilot data for 15 participants, using a cross-over design, for Aims 1 and 2, which provide 
preliminary support for our predictions. 
 

Page 15 of 26 (V.04/27/2017)  
8.3 
Statistical methods 
To assess our intervention, we will fit linear mixed models (LMMs) with single-degree-of-freedom linear 
contrasts [80] to determine if the data support our predictions (see next section). We will use a linear 
mixed model with main effects for group (experimental, control) and time (Test) and the group by time 
interaction simply provides a more flexible approach to the typical analysis of variance (ANOVA) model 
for a randomized pretest-posttest design. Specifically, LMMs will permit us to account for participant 
matching with a random cluster effect; and they permit each participant to have her or his initial value 
(random intercept) and different change patterns across the tests (random coefficients for an underlying 
piecewise regression). LMMs allow us to use covariates to adjust for any potential confounders. Finally, 
these models can tolerate missing data on the response, which is not true of the standard ANOVA-based 
model. 
 
Lesion Reconstruction Methods: Winstein’s laboratory personnel will reconstruct stroke lesions from the 
research grade MRI scans. They will superimpose lesions on each axial slice to identify common areas of 
lesion overlap associated with damage to the right or left hemisphere and to assess comparability of 
intrahemispheric lesion location in our two tracks. This grant will not specifically examine 
intrahemispheric lesion location, but these data will provide pilot data for future studies. To calculate 
the CST lesion load, we will use the tractography based atlas of human brain connections from the 
natbrain lab [72]. We will use the MRIcron descriptive tool for the calculation of the CST-lesion overlap 
volume. The binary lesion mask file will be overlaid onto either the left or right binary template CST 
atlas, and the percentage of CST which overlaps with the lesion is calculated. 
9.0 
Confidentiality, Privacy and Data Management  
9.1 
Confidentiality 
 
9.1.1 
Identifiers associated with data and/or specimens 
 
9.1.1.1 Use of Codes, Master List 
 
 
 
Each site will have a code linked to subject’s identifiable information in a locked  
document. The list will not be shared between sites or with members that are not part of the 
research group.  
 
9.1.2 
Storage of Data and/or Specimens 
Data will be kept electronically on password-protected computers and backed up on external 
hard-drives locked in filing cabinets in room C2852 at the COM or Carolee Winstein’s Laboratory 
at USC. Hardcopies of the data will be kept as well, also locked in room C2852 at the COM or 
locked in Carolee Winstein’s laboratory at USC. 
 
9.1.3 
Access to Data and/or Specimens 
Electronic key card access is required to enter room C2852. A list of approved personnel is kept 
by the neurology dept. USC also has locks on the door and a list of approved personnel. 
 
9.1.4 
Transferring Data and/or Specimens 
De-identified data will be collected at both sites (PSU, USC) and managed using REDCap (Research Electronic Data 
Capture) at Penn State. REDCap is a secure web application designed to support data capture for research studies, 
providing user-friendly web-based case report forms, real-time data entry validation (e.g. for data types and range 
checks), audit trails and a de-identified data export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-
Plus). The system was developed by a multi-institutional consortium which includes The Pennsylvania State University 
and was initiated at Vanderbilt University. The database is hosted at the Penn State Hershey Medical Center and College 
of Medicine data center, which will be used as a central location for data processing and management. REDCap data 
collection projects rely on a thorough study-specific data dictionary defined in an iterative self-documenting process by 
all members of the research team. This iterative development and testing process results in a well-planned data 

Page 16 of 26 (V.04/27/2017)  
collection strategy for individual studies. REDCap is flexible enough to be used for a variety of types of research and 
provides an intuitive user interface for database design and data entry. Deidentified data can be sent via password 
protected files. Videotapes will be shared for standardization and scoring purposes. They will be shared on a secure 
server, hosted by USC. https://uscbknpt.sharepoint.com/sites/IPSI/default.aspx 
There is a password protected account for PSU members and a separate account for USC members. A list is available 
documenting team members that have access to the site. Participants are coded with a label and names are not used, 
however their faces are visible in the videotapes. 
  
 
9.2 
Subject Privacy 
 
Research team can access medical records of stroke patients after completing HIPPA training. Participants 
can choose to not interact with specific team members if requested, and may decline to provide any 
personal information. The personal identifiable information will be previously collected from medical 
record. However, if the participant does not want to answer any questions on the questionnaires, they 
may choose not to. Researchers will be through in response to participant questions and assure 
participants that their answers are confidential. 
10.0 Data and Safety Monitoring Plan 
 
Not Applicable/minimal risk 
10.1 
Periodic evaluation of data 
 
10.2 
Data that are reviewed 
 
10.3 
Method of collection of safety information 
 
10.4 
Frequency of data collection 
 
10.5 
Individuals reviewing the data 
 
10.6 
Frequency of review of cumulative data 
 
10.7 
Statistical tests 
 
10.8 
Suspension of research 
 
11.0 Risks 
 
Loss of confidentiality is a risk for data analysis and/or chart review research. The techniques employed in this 
study are non-threatening, non-invasive, and pose no risk beyond that experienced during normal daily 
activities. In general, subjects may experience fatigue or discomfort due to the two 30 minute increments of 
sitting. 
 
Because the MRI scanner contains a very strong magnet, participants will not be able to have the MRI if they have 
certain kinds of metal in your body (for example, a heart pacemaker, a metal plate, certain types of heart valves 
or brain aneurysm clips).  Someone will ask them questions about this before they have the MRI. Having a MRI 
may mean some added discomfort to the participant. In particular, they may be uncomfortable inside the MRI 
scanner if they do not like to be in closed spaces (“claustrophobia”). They may also be bothered by the loud 
banging noise during the study. Temporary hearing loss has been reported from the loud noise. This is why they 

Page 17 of 26 (V.04/27/2017)  
will be asked to wear earplugs. During the procedure, they will be able to talk with the MRI staff through a speaker 
system. They can tell them to stop the scan at any time. 
 
It is possible that the study procedures (brain MRI scan) could detect a possible unknown medical problem that is 
unrelated to the purpose of this study.  If the research procedures uncover findings that may be important for the 
participant to know about, such as the possibility of a previously unknown medical condition, a member of the 
study team may contact them to find out if they would like to learn more. These findings may require additional 
testing or treatment.  The cost of any additional tests or related treatment will be their responsibility. 
12.0 Potential Benefits to Subjects and Others 
 
12.1 
Potential Benefits to Subjects 
There is no guaranteed direct benefit to the research subjects. However, they may increase non-paretic 
arm function. There is minimal risk to the study participants, so the risk/benefit ratio is quite favorable. 
 
12.2 
Potential Benefits to Others 
This study addresses important questions regarding motor training in stroke patients. If, as 
hypothesized, these techniques demonstrate potential as therapeutic agents, this research may lead to 
clinical intervention research, and ultimately to the development of more effective rehabilitation 
techniques. 
13.0 Sharing Results with Subjects 
Not applicable 
 
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements 
Subjects will be paid $50 per visit. Additional travel reimbursement will be given if traveling more than 25 miles 
from study site, up to $50 per visit. 
 
15.0 Economic Burden to Subjects 
 
15.1 
Costs  
not applicable 
 
15.2 
Compensation for research-related injury 
not applicable 
 
16.0 Resources Available 
 
16.1 
Facilities and locations 
Hershey Medical Center & University of Southern California 
 
16.2 
Feasibility of recruiting the required number of subjects 
Previous experience indicates that we can recruit a minimum of 20 eligible participants each year, from 
each site. This, in combination with the current databases at each site, makes the recruitment goal of 30 
participants per year (15 per site), over the four-year course of recruitment (120 total), realistic. The 
HMC database has every stroke patient that is a patient in the hospital, which is over 100 per month. 
However, we have selective criteria, therefore we aim to recruit less than 5% of them. 

Page 18 of 26 (V.04/27/2017)  
 
16.3 
PI Time devoted to conducting the research 
PI will reduce teaching load to less than one class per semester in order to devote more time to this 
study. 
 
16.4 
Availability of medical or psychological resources 
Both sites have qualified medical personnel available at each location 
 
16.5 
Process for informing Study Team 
 
Personnel will be trained prior to the start of the study. Twice a year researchers will fly between sites to 
provide refresher training. Meetings will be Skyped between the two sites. 
 
17.0 Other Approvals 
17.1 
Other Approvals from External Entities 
USC’s IRB has agreed to let COM IRB be the IRB of record for this study (letter uploaded) 
 
17.2 
Internal PSU Committee Approvals 
 
Check all that apply: 
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.   
 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals 
 
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy). 
 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that 
had been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of 
HRP-901 - Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. 
This form is available in the CATS IRB Library.  
 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way. 
 
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest. 
 
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a 
copy of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This 
form is available in the CATS IRB Library. 
 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE. 

Page 19 of 26 (V.04/27/2017)  
 
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The 
scientific review requirement may be fulfilled by one of the following: (1) external peer-review 
process; (2) department/institute scientific review committee; or (3) scientific review by the Clinical 
Research Center Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute 
Scientific Review Committee is required if the study involves cancer prevention studies or cancer 
patients, records and/or tissues. For more information about this requirement see the IRB website 
at: http://www.pennstatehershey.org/web/irb/home/resources/investigator  
 
18.0 Multi-Site Research 
 
18.1 
Communication Plans 
In order to facilitate communication and interaction, Drs. Winstein and Sainburg will communicate 
weekly and via conference call formally once a month that will include all members of the research 
teams at both sites. As mentioned, Drs. Sainburg and Winstein have an ongoing collaboration and have 
an established foundation of communication. Dr. Sainburg and Dr. Winstein, as well as one main 
representative from each research team, will travel to the other laboratory one time per year, to review 
methods and materials, prevent drift and to insure consistent procedures between laboratories. 
 
18.2 
Data Submission and Security Plan 
• 
De-identified data will be collected at both sites (PSU, USC) and managed using REDCap  
(Research Electronic Data Capture) at Penn State. REDCap is a secure web application designed 
to support data capture for research studies, providing user-friendly web-based case report 
forms, real-time data entry validation (e.g. for data types and range checks), audit trails and a 
de-identified data export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-
Plus).  
• 
The database is hosted at the Penn State Hershey Medical Center and College of Medicine data 
center, which will be used as a central location for data processing and management. REDCap 
data collection projects rely on a thorough study-specific data dictionary defined in an iterative 
self-documenting process by all members of the research team. This iterative development and 
testing process results in a well-planned data collection strategy for individual studies. REDCap is 
flexible enough to be used for a variety of types of research and provides an intuitive user 
interface for database design and data entry.  
• 
De-identified research data generated by the project will be shared through ScholarSphere 
(https://scholarsphere.psu.edu/), the repository service that both the University Libraries and 
Information Technology Services administer at Penn State. Researchers will be able to access 
the data via ScholarSphere, which ensures persistent access to deposited content. The data will 
be discoverable via Google and other major search engines, as well as by request to Dr. Sainburg 
or Dr. Winstein. 
• 
A master list for data will be kept at each site, locked in filing cabinets in a locked room 
(previously described). 
• 
Videotapes will be shared for standardization and scoring purposes. They will be shared on a 
secure server, hosted by USC. https://uscbknpt.sharepoint.com/sites/IPSI/default.aspx There is 
a password protected account for PSU members and a separate account for USC members. A list 
is available documenting team members that have access to the site. Participants are coded 
with a label and names are not used, however their faces are visible in the videotapes. 
 
18.3 
Subject Enrollment 
 

Page 20 of 26 (V.04/27/2017)  
One statistician will be responsible for randomizing all subjects across both sites and will have 
communication with researchers weekly. 
 
18.4 
Reporting of Adverse Events and New Information 
 
We appreciate the importance of accurately monitoring patient accrual and data collection as well as 
the possibility of the occurrence of any serious adverse event (expected and unexpected). To deal with 
these issues we have included a data and safety monitoring board (DSMB), which consists of a Chair and 
3 members all external to the study and including two medical monitors, one from each of the two sites. 
The DSMB will be established to monitor the well-being of the study participants, ensure scientific 
integrity of the study, and assure timely patient accrual. See the Table (section 3.3 of grant, uploaded). 
The site IRB will review and approve all study protocols, require annual updates of the study and 
monitor for adverse events. The DSMB will assist the IRB’s and the study personnel in the careful 
monitoring of the risk / benefit ratio of the implementation of this study. The DSMB will meet regularly 
(determined by the Chair) to ensure the safety of the participants during the course of the study and the 
validity and integrity of the data. They will monitor patient safety, recruitment, adherence to inclusion 
and exclusion criteria, retention, deviations from assigned treatments, quality control, and interim 
analyses of primary and main secondary outcomes as well as the occurrence of adverse events and 
other indicators of patient safety. All adverse events and participant drop outs will be reported to the 
PIs immediately so the case can be examined in detail with the on-site Medical Monitor to determine 
the reason for drop out and/or circumstances behind the adverse event. Should any adverse events 
deemed to increase risks to participants be identified, the study will stop immediately and an 
investigation will be conducted. The local Medical Monitor at each site (who is not part of the 
investigative team) will be responsible for reviewing the activities of the clinical trial including the 
incidence and type of adverse events. The Medical Monitor at each site will consult with the local Site PI 
(Sainburg, Hershey; Winstein, USC) relative to complications and any questions regarding inclusion, and 
progression through the protocol. All serious adverse events will be reported immediately to the 
Medical Monitor, as well as the IRB, and DSMB. 
 
The investigative team has established definitions for adverse events, criteria for causally related and an 
adverse event protocol. These definitions and protocols will be used for reporting all adverse events 
from each site for this study. Any adverse events from either of the two sites will be recorded and 
monitored as required by the respective Institutional Review Boards and the Study Data Safety and 
Monitoring Board (DSMB). A composite report will be generated by each site coordinator and submitted 
to the DSMB every 6 months. Each site PI will submit a signed report to their local IRB in compliance 
with their standard policies and procedures. The DSMB will provide on-going monitoring of adverse 
events for a pattern of events that would indicate increased risk or potential harm. This information 
could indicate a need to change the protocol or cease the trial. During the course of the study all severe 
adverse events will be immediately entered into a Redcap database, and at the same time, an adverse 
event report will be sent to the Chair of the Data Safety Monitoring Board, and each site PI. All serious 
events will be reported to each site IRB within five days. A cumulative adverse event-reporting table will 
be completed for annual continuing review. 
 
 
18.5 
Audit and Monitoring Plans 
 
The PIs and the site study coordinators will monitor ongoing data collection, perform quality checks on 
the actual participant files for recording accuracy, and monitor data entry into Redcap for accuracy, 
including random checks throughout the duration of the study. 
 

Page 21 of 26 (V.04/27/2017)  
19.0 Adverse Event Reporting 
 
19.1 
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB 
 
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures. 
 
20.0 Study Monitoring, Auditing and Inspecting 
 
20.1 
Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the Penn State quality 
assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory, etc.). 
 
21.0 Future Undetermined Research: Data and Specimen Banking 
 
21.1 
Data and/or specimens being stored 
 
Name, birthday, address, phone number 
 
21.2 
Location of storage 
 
Room C2852 (COM), Dr. Carolee Winstein’s laboratory, USC 
 
21.3 
Duration of storage 
 
Deidentified data will be made available through online data sharing resources for reproducibility. 
Identifiable data will be discarded within 2 years following final publications of study. 
 
21.4 
Access to data and/or specimens 
 
Only members of the research team will have access to data. 
 
21.5 
Procedures to release data or specimens 
 
De-identified data will be collected and managed using REDCap  (Research Electronic Data Capture) at 
Penn State with access granted to study team members at both locations (COM, USC). REDCap is a 
secure web application designed to support data capture for research studies, providing user-friendly 
web-based case report forms, real-time data entry validation (e.g. for data types and range checks), 
audit trails and a de-identified data export mechanism to common statistical packages (SPSS, SAS, Stata, 
R/S-Plus). The system was developed by a multi-institutional consortium which includes The 
Pennsylvania State University and was initiated at Vanderbilt University. The database is hosted at the 
Penn State Hershey Medical Center and College of Medicine data center, which will be used as a central 

Page 22 of 26 (V.04/27/2017)  
location for data processing and management. REDCap data collection projects rely on a thorough 
study-specific data dictionary defined in an iterative self-documenting process by all members of the 
research team. This iterative development and testing process results in a well-planned data collection 
strategy for individual studies. REDCap is flexible enough to be used for a variety of types of research 
and provides an intuitive user interface for database design and data entry. De-identified research data 
generated by the project will be shared through ScholarSphere (https://scholarsphere.psu.edu/), the 
repository service that both the University Libraries and Information Technology Services administer at 
Penn State. Researchers will be able to access the data via ScholarSphere, which ensures persistent 
access to deposited content. The data will be discoverable via Google and other major search engines, 
as well as by request to the PI. 
 
21.6 
Process for returning results 
 
Others may use data when it is uploaded through above procedures. 
 
22.0 References 
 
1.  Woytowicz, E.J., J.C. Rietschel, R.N. Goodman, S.S. Conroy, J.D. Sorkin, J. Whitall, and S. McCombe 
Waller, Determining Levels of Upper Extremity Movement Impairment by Applying a Cluster Analysis to 
the Fugl-Meyer Assessment of the Upper Extremity in Chronic Stroke. Arch Phys Med Rehabil, 2017. 
98(3): p. 456-462. 
2. Woodbury, M.L., C.A. Velozo, L.G. Richards, P.W. Duncan, S. Studenski, and S.M. Lai, Dimensionality 
and construct validity of the Fugl-Meyer Assessment of the upper extremity. Arch Phys Med Rehabil, 
2007. 88(6): p. 715-23. 
3. Wolf, S.L., G. Kwakkel, M. Bayley, M.N. McDonnell, and G. Upper Extremity Stroke Algorithm Working, 
Best practice for arm recovery post stroke: an international application. Physiotherapy, 2016. 102(1): p. 
1-4. 
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