Cost-effectiveness and Efficacy of a Combined Intervention to Facilitate Motor Recovery Following Stroke
Phase: NA
Conditions: Stroke, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Vascular Diseases, Cardiovascular Diseases
Sponsor: The Cleveland Clinic

Cost-e'ectiveness and E'icacy of a Combined Intervention to Facilitate Motor Recovery 
Following Stroke  
NCT Number: NCT03819764 
Study Protocol and Statistical Analysis Plan 
Date: July 6, 2022 

Research Strategy 
Significance: For the first time, an innovative application of aerobic exercise (AE) in facilitating upper 
extremity motor recovery for patients with stroke will be studied considering both the clinical effectiveness and 
economic impact. We will use tested concepts and methods and apply them to the field of stroke rehabilitation 
while building a framework that could be used in future stroke and rehabilitation studies.  
Stroke, an endpoint of cardiovascular disease, is a leading cause of severe, long-term disability among 
older adults in the United States12. The total economic burden of stroke in the US is significant, with direct 
costs estimated at $38 billion and indirect costs approaching $30 billion annually13-15. Given the economic 
burden of stroke on individuals, families, and society, increased emphasis needs to be placed on innovative 
rehabilitation approaches that optimize motor recovery and reduce disability, thus lowering both direct and 
indirect costs. A fundamental gap exists in the rehabilitation of patients with stroke: lack of a rehabilitation 
model that is efficacious and cost-effective. The proposed project will, for the first time, simultaneously 
determine the effectiveness of a rehabilitation model from a motor recovery and cost perspective.   
An abundance of randomized clinical trials focused on improving upper and lower extremity function 
have been conducted over the past decade16-18. Despite the demonstration of efficacy, cost and therapist time 
are reported as primary barriers to the clinical adoption of intensive, motor learning-based rehabilitation 
approaches such as constraint-induced movement therapy3, 19, 20. To overcome this barrier, cost-effectiveness 
analyses can be conducted in parallel with clinical research21. Cost-effectiveness analyses inform decisions 
about the application of new and existing interventions to guide the judicious use of clinical and financial 
resources22, 23. While reimbursement decisions cannot ethically or legally be based on economic analyses22, 
resources in rehabilitation are finite. In the recently published Guideline for Adult Stroke Rehabilitation and 
Recovery, Winstein and colleagues acknowledged this disconnect, stating that “Of central interest is the 
need for a better understanding of the impact of rehabilitation care on patient outcomes, especially 
relative to resource use and cost.”24 Therefore, it is critical to consider, in parallel, the clinical efficacy and 
cost-effectiveness of approaches that maximize recovery while not exhausting clinical resources25.  
A novel application of aerobic exercise (AE) training 
in stroke rehabilitation may be more efficacious and cost-
effective in improving motor recovery and reducing 
disability than traditional motor learning approaches. It has 
been shown that AE training administered immediately 
prior to motor task practice enhances motor skill 
acquisition4. The direct neurophysiological effects of AE 
training which may be responsible for this behavioral 
outcome include increased levels of neurotransmitters and 
neurotrophic growth factors26, 27. The schematic diagram in 
Figure 1 depicts the hypothesized mechanism by which 
these neurophysiological effects may prime the central 
nervous system, creating a global response and a neural environment supportive of plasticity5, 26-28. While AE 
alone is not likely to induce neuroplasticity, performing purposeful motor task practice in close temporal 
proximity to AE training may harness the neurophysiological effects of AE, and facilitate motor recovery5.  
The role of AE in facilitating motor recovery following stroke has not been tested empirically. Previous 
studies related to AE post-stroke have focused on feasibility, safety, cardiovascular endpoints, and its potential 
to improve fitness and reduce disability29-37. While these studies assess safety and efficacy of an AE regime 
post-stroke, it remains unknown if AE, which clearly alters central nervous system (CNS) function5, can be 
used to facilitate motor recovery. We have conducted preliminary studies investigating whether AE training can 
enhance the motor learning benefits associated with task practice following stroke. Results from our R03 pilot 
study demonstrated safety, feasibility, and initial efficacy for individuals with stroke to complete an intensive AE 
intervention paired with upper extremity (UE) repetitive task practice (RTP)6, 7. Our outcomes indicated that 
those completing AE paired with an abbreviated session of UE RTP had greater improvements in motor 
recovery than time-matched UE RTP alone without an AE component (see preliminary data)7. Although we did 
not conduct a cost analysis, intuition indicates that our combined approach was more cost-effective in 
facilitating motor recovery. We anticipate that an economic analysis from both the health care and societal 
perspectives would demonstrate superiority of the combined AE and RTP approach compared to RTP alone22. 
While our intent is not to diminish the cardiovascular benefits of AE training post-stroke, it is critical to 
note that this project is not just another study investigating the role of AE in improving aerobic fitness. Rather, 
this project will for the first time simultaneously determine the clinical effectiveness and economic impact of an 
Figure 1: Diagram depicting 
proposed neurophysiologic 
effects of AE on motor recovery 

innovative application of AE in facilitating UE motor recovery. Demonstrating efficacy and cost-effectiveness 
may foster the clinical adoption of AE into stroke rehabilitation programs, as typical 45-minute therapy sessions 
have been shown to occur with heart rate values in the aerobic zone for less than three minutes38. While our 
primary outcomes are related to the recovery of UE function, the concomitant improvements in aerobic fitness 
and cardiovascular health are likely to have an even greater societal impact than traditional approaches. 
Aerobic exercise coupled with a motor learning approach reflects an innovative model of rehabilitation that is 
scalable, fits within current clinical models and is complimentary to the focus on value in healthcare25. 
 
Scientific Premise 
Several hypotheses have been proposed explaining the relationship between AE and the global behavioral 
responses observed related to brain function39-45. Aerobic exercise has been shown to increase cerebral blood 
flow, promote angiogenesis, and is associated with increased levels of dopamine, brain-derived neurotrophic 
factor (BDNF) and Insulin-like growth factor-1, all of which have been implicated in neuroplasticity and 
enhanced learning5, 39, 46-48. Increased concentrations of endogenous neurotrophins have been implicated as 
the mechanism for improved cognition, learning, and memory in healthy older adults40, 41, 44. Animal studies 
have shown enhanced motor training and recovery with high-intensity AE, resulting in lasting neuronal changes 
within the brain47, 49. In stroke rehabilitation, it has been posited that increased levels of neurotrophic factors 
and neurotransmitters are critical in facilitating the neural reorganization that likely underlies motor recovery5, 42, 
47, 50, 51. Therefore, there is substantial scientific rationale to hypothesize that AE, which results in increased 
levels of neurotrophic factors and neurotransmitters, could be used to “prime” the CNS to further enhance 
motor recovery post-stroke. We fully acknowledge that while identifying the mechanism underlying 
improvements in motor recovery is important, it is beyond the scope of the proposed project. 
 
Innovation 
Given that medical expenditures represent 15% of the US Gross Domestic Product13 and account for 60% of 
personal bankruptcies52, there is an imminent need to investigate the efficiency of healthcare by applying 
analytical techniques to determine the clinical and economic impact of novel interventions22. The two research 
aims of this project demonstrate different, yet equally innovative goals in neurorehabilitation research and the 
impact of social determinants on health. The multi-faceted health economics aim demonstrates a commitment 
to investigating value-based care in addition to population health. The Cleveland Clinic has been recognized 
for pioneering efforts to transcend cost-cutting strategies and to focus instead, on improving the efficiency of 
medical care25. My team of mentors and collaborators have the background and resources in health economics 
to help me achieve this aim. Investigating the cost-effectiveness of AE as it impacts neuroplasticity post-stroke 
demonstrates a keen, yet unique perspective in rehabilitation research that emphasizes a necessary shift of 
focus from volume to value. The clinical aim will determine if AE training can be utilized to facilitate 
neuroplasticity associated with motor task practice. Although the cardiovascular benefits of AE have been well 
documented, the global effects of AE, particularly as they relate to improving brain function and health, have 
only recently been investigated28, 45, 53, 54. I am uniquely positioned to lead the field of stroke rehabilitation in 
investigating the systemic effects of AE in improving motor function. Our lab has a long history of studying the 
effects of AE in individuals with PD, having shown improvements in motor and non-motor function following 
intensive AE and enhanced functional connectivity and activation patterns on neuroimaging55-58. Our 
preliminary study in individuals with stroke has been completed which supported the safety and efficacy of 
AE.6, 59 and a second study is in the final weeks of data collection. While field experts have theorized that AE 
training may facilitate neuroplasticity associated with task practice5, 60, to our knowledge, no large-scale trial 
has paired AE with RTP in individuals with stroke to systematically investigate its potential to enhance motor 
recovery. My career plan is to investigate the clinical efficacy of this combined rehabilitation approach along 
with decision analytic methodologies including cost-effectiveness analysis. This will allow me to analyze health 
care interventions from clinical and economic standpoints. Addressing the economic impact is unique in 
rehabilitation studies is timely considering the aging population and shift from volume to value in health care. 
The proposed plan will serve as a blueprint for testing clinical efficacy and economic impact of various 
rehabilitation approaches to facilitate the clinical translation of effective and efficient models of care. 
 
Approach  
The proposed project determining the clinical effectiveness of AE in facilitating motor recovery and 
determining the cost-effective strategy could fundamentally alter current rehabilitation approaches and 
drive the adoption of AE into stroke rehabilitation.  
Experimental Overview: A prospective, single-center, parallel group, rater-blind clinical trial is proposed. A 
schematic depicting workflow and outcomes is provided in Figure 2. A total of 60 individuals with chronic 

stroke (>6 months) will be randomized to one of two time-matched groups: 1) 
AE and RTP or 2) RTP only. All groups receive an identical dose of contact 
time (36 hours) over a course of 8 weeks (3X per week). Upper extremity 
motor outcomes (Aim 1) will be collected at baseline, mid-treatment, end of 
treatment (EOT), and EOT+4 weeks. Data concerning participant 
demographics, social determinants, and intervention resource utilization 
(including personnel) will be collected during the clinical trial and at 6-months 
(primary outcome on full data set, Aim 2) and 12-months follow-up 
(secondary outcome on subset of sample, Aim 2). 
The following elements of our experimental design ensure scientific 
rigor: 1) Randomization stratified according to baseline function and age; 2) 
Blinding of the rater; 3) Utilization of a time-matched control group; 4) 
Sample size justified to demonstrate group differences based on preliminary 
studies; and 5) Sound statistical analysis plan. An intent-to-treat approach 
will be used to address any missing data; to date <1% of data in our 
preliminary studies are missing.  
Recruitment and Sample: Sixty individuals from the Cleveland Clinic Health 
System (CCHS) and adjacent medical community with chronic stroke and 
the following criteria for inclusion will be recruited: 1) ≥ 6 months following 
single ischemic or hemorrhagic stroke confirmed with neuroimaging, 2) Fugl-
Meyer motor score 24-50 in the involved UE, 3) Ambulatory ≥ 20 meters with 
no more than contact guard assistance, and 4) 18-85 years of age. Exclusion 
criteria include: 1) hospitalization for myocardial infarction, heart failure or 
heart surgery within 3 months, 2) cardiac arrhythmia, 3) hypertrophic 
cardiomyopathy, 4) severe aortic stenosis, 5) pulmonary embolus, 6) significant contractures, 7), anti-spasticity 
injection within 3 months of enrollment and 8) other contraindication to exercise. The targeted population 
represents a collective cohort in whom spontaneous recovery is typically no longer occurring, potential exists 
for significant motor recovery, and risk associated with intensive AE training is minimized. Since our pilot R03 
study, we established numerous collaborative relationships in the Cleveland stroke research community and 
achieved our targeted enrollment of 30 participants over a 21-month period for the current 2-year AHA study. 
Drs. Frederick Frost, Chairman of Physical Medicine and Rehabilitation, and Irene Katzan, neurologist in the 
cerebrovascular center, have endorsed our work and actively support our recruitment efforts. Based on the 
proposed criteria outlined above and in detail in Human Subjects section, during the past 12 months ~1200 
CCHS patients would be eligible for the trial. To address transportation as a potential barrier to participation 
and adherence, the Cleveland Clinic offers free transportation to those who live within a 15-mile radius of the 
campus and free parking in an accessible, attached parking garage for those with their own vehicular 
transportation. Given our history and approach, recruiting 60 participants is feasible and will be accomplished.  
 
Aim 1: To determine the effects of aerobic exercise paired with UE repetitive task practice compared to 
time-matched UE task practice on the recovery of UE motor function in individuals with stroke. 
Rationale: Declines in UE function are common in the majority of patients with stroke. Aerobic exercise has 
been theorized to facilitate motor recovery following stroke5, 51; however, the proposed study will be the first to 
test this to theory empirically. Our preliminary data indicate that our AE approach combined with a reduced 
dosage of RTP resulted in significantly greater gains in motor function than time-matched RTP without an AE 
component, supporting the scientific hypothesis that AE facilitated motor recovery associated with RTP.  
Outcomes: The primary clinical outcomes to evaluate changes in motor function and impairment are the Action 
Research Arm Test (ARAT)8 and Fugl-Meyer Assessment (FMA)9, respectively. To determine the impact on 
motor control processes, participants will complete a bimanual dexterity task in which grasping forces and 
torques will be quantified. Finally, the Wolf Motor Function Test61 (WMFT) will serve as a secondary outcome.  
Expected results and interpretation: It is hypothesized that the AE+RTP group will demonstrate greater 
improvements in UE motor function and impairment compared to RTP only. Animal and human studies 
suggest that intensive AE facilitates neurophysiologic changes in the brain, several of which have been 
implicated neuroplasticity47, 48. Preliminary data from our R03 study demonstrated improved motor outcomes in 
those completing AE+RTP compared to RTP only, implying that AE may exploit the motor learning benefits 
associated with RTP and could be used to decrease the dosage of RTP required for UE motor recovery7.  
Aim 2: To determine the cost-effectiveness of pairing aerobic exercise with UE repetitive task practice 
compared to UE repetitive task practice only to facilitate motor recovery following stroke. 
Figure 2: Study Workflow and Outcomes 

Rationale: Stroke-related disability has a significant economic impact on patients, their families, and society as 
a whole. Novel approaches that improve recovery, overall health, and optimize resources including indirect 
costs borne by patients, are necessary to maximize the value of stroke rehabilitation31. The proposed 
intervention is hypothesized to increase value by providing an 
approach that improves outcomes and is delivered in a manner 
that is less resource intensive. As preliminary data suggest that 
outcomes were superior with the combined approach of AE+RTP, 
a cost-effectiveness analysis using a decision analytic model is 
proposed to address the clinical and economic differences 
between the two proposed interventions. The model will address: 
cost-effectiveness in the short and long term; cost-effectiveness 
from the healthcare provider and patient perspective, and 
identifying specific social determinants of health that impact the 
cost-effectiveness of the interventions. A tornado diagram from a 
study investigating the cost-effectiveness of primary stroke 
centers is presented in Figure 3. This diagram is included as a 
sample output, as it depicts one-way sensitivity analyses for 
variables which influence the ICER, and the magnitude and range 
of their contributions. The modeling techniques I learn as part of 
my training will produce comparable visualizations, demonstrating 
the impact of variables contributing to the ICER (such as absolute change in motor function, level of disability, 
change in cardiovascular function, employment, mortality, etc) in a quantitative manner.  
Outcomes: The primary outcome will be the ICER (change in dollars and QALY’s62 between interventions) at 
six months, while the secondary outcome will analyze the ICER on a subset of participants at 12 months.22, 23. 
The ICER is an analytic tool in which costs and effects of two or more interventions are calculated and 
presented in a ratio of incremental cost versus effect22. Quality metrics will be derived from the Stroke Impact 
Scale (SIS)63, 64 and PROMIS 2965. Additional analyses will be conducted for the stroke recurrence, 
readmission, mortality, change in depression, return to work, and participation/compliance. All analyses will be 
conducted from the perspective of the healthcare sector and society, per recommendations by the second 
panel on cost-effectiveness in health and medicine22. Based on 6- and 12-month ICER outcomes, forecasting 
will be used to predict the optimal intervention at 2 and 5 years. Dr. Udeh has used these analytical 
approaches extensively and will oversee all aspects of the cost-effectiveness analyses66-69.  
Expected results and interpretation: Reimbursement for medical and rehabilitation services in the US is shifting 
from a model of volume-based to value-based25. A result is the advent of Accountable Care Organizations 
(ACO), in which insurers partner with healthcare organizations to manage population health, and reward them 
for optimization of cost and quality70. Based on preliminary data, it is hypothesized that AE+RTP will be optimal 
in terms of the ICER at six and 12 months. Demonstrating value, by improving outcomes and reducing cost, is 
novel and would serve to engage ACO’s in terms of potential adoption of the proposed rehabilitation approach.   
It is also hypothesized that the ICER will improve for the optimal strategy as the time frame is increased. Given 
the significant potential for AE to impact overall cardiovascular health, disability, morbidity, and mortality, it is 
hypothesized that the ICER will be most improved from the societal perspective, favoring AE+RTP.    
 
Clinical Trial Methodology 
Cardiopulmonary Exercise Fitness Testing Protocol: As in our R03 and AHA projects with stroke and our 
R01 with PD patients, prior to randomization, all subjects satisfying initial screening criteria for participation will 
undergo cardiopulmonary exercise (CPX) testing on an electronically controlled Lode cycle ergometer and a 
MedGraphics CardiO2/CP system with Breeze software. Briefly, a 12 lead electrocardiogram will be assessed 
prior to exercise and monitored continuously throughout exercise and recovery. A continuous incremental 
protocol starting at 20 Watts (W) and increasing in 20W stages every two minutes will be employed. Subjects 
will be encouraged to continue exercise to the point of volitional fatigue or onset of test termination criteria as 
described in the ACSM Guidelines for Exercise Testing and Prescription71. Within 5 days of completing their 
final session, all subjects will repeat the CPX testing. Similar to our previous studies, Dr. Blackburn, Director of 
Cardiac Rehab, will conduct and interpret the results of the CPX testing to ensure participant safety. All 
participants in the R03 and AHA projects completed the protocol, as respiratory exchange ratio values ≥1.1.  
Aerobic Exercise Intervention: Individuals in the AE group will participate in a supervised exercise protocol 
on a stationary semi-recumbent cycle ergometer, comprised of three 45-minute sessions per week for eight 
weeks. Target heart rate (HRtarget) zone for each subject, based on ACSM recommendations, will be 
Figure 3: Sample tornado diagram depicting sensitivity  
analysis of variable impact on ICER 
 

determined using the Karvonen formula at the 60-80% range, based 
on the results of initial CPX testing72. Participants will be instructed to 
exercise within their HRtarget during the 35-minute main exercise set, 
occurring between a 5-minute warm-up and cool-down phase. The 
high-rate AE protocol will be used, based on methodology used in our 
previous studies6, 56, 59. This mode of AE is safe and has been found 
most efficacious in our pilot studies6, 59. Furthermore, it allows 
participants who may be deconditioned to tolerate the 45-minute AE 
session without compromising aerobic intensity. Figure 4 depicts 
continuous HR monitoring of a single, representative participant on 
visit 8 (left panel) and visit 18 (right panel). The participant was able to 
exercise within his HRtarget for ~ 90% of the main 35-minute set 
between the warm-up and cool-down phases. As in our previous 
studies, if any patient exhibits signs of cardiac distress or hemodynamic compromise, the session will be 
stopped immediately and the on-call physician will be paged to the laboratory. All training will be under the 
supervision of a physical therapist or exercise physiologist certified in Basic Cardiac Life Support.  
RTP Intervention: RTP is the current standard of care for UE stroke rehabilitation, with Class IA evidence 
supporting its use12, 24. Tasks performed with the more impaired UE are modeled after Birkenmeier and Lang73, 
and identical to the approach used in our preliminary studies6, 59. Tasks that require a combination of reaching, 
grasping, manipulating and/or moving, and releasing an object are included. Tasks are designed to challenge 
each individual’s abilities, practiced repeatedly, and graded to increase difficulty by requiring movement out of 
synergy, increasing range of motion requirements for task accomplishment, incorporating increasingly difficult 
grasp types, increasing force requirements, varying the sizes of the objects, and varying the use of adaptive 
equipment. An example of a task is grasping a mug with a handle versus a hard plastic tumbler, a Styrofoam 
cup, or a 3 ounce Dixie cup. A simple iteration may be to grasp the tumbler, push it to a target, release it, and 
repeat. A complex iteration would be to grasp a 3 ounce Dixie cup filled with water, pour the water into a bowl 
and place the empty cup onto a shelf, all while standing. Repetitions and time dedicated to RTP are recorded. 
All RTP is administered by a neurologic PT experienced in stroke rehabilitation and trained in RTP.  
 
Experimental Groups 
Aerobic Exercise and Repetitive Task Practice (AE+RTP): Participants in the AE+RTP group (N=30) will 
complete 24 intervention sessions, each ~90 minutes in length. The first 45 minutes will be spent performing 
AE as described in detail above under “aerobic exercise intervention”. Hemodynamic response will be 
monitored via continuous heart rate monitoring and blood pressure measurements obtained prior to initiating, 
every 10 minutes during, and immediately following the exercise protocol. A 45-minute session of UE RTP as 
described in detail above will occur within ~10 minutes of exercise session completion.  
Time-matched Upper Extremity Repetitive Task Practice (RTP only): Participants in the RTP only group 
(N=30) will complete two back-to-back 45-min sessions of RTP (90 min total) with a 5-10 min break between 
sessions. The RTP intervention will be administered in the same manner using the same approach by the 
same personnel as with the AE+RTP group. The planned dose of RTP has been found to be efficacious to 
elicit improvements in motor recovery73; and the protocol ensures similar contact time across both groups.  
 
Data Variables 
Exercise Training Variables: The customized software that controls the cycle records overall time, active 
exercise time, and monitors and stores heart rate, speed, cadence and power. The primary training variables 
of interest for each exercise session are: AE intensity measured as percent heart rate reserve (%HRR) during 
main 35-minute exercise set, average cadence and work (power) produced by the patient and motor.  
Clinical and Biomechanical Measures of UE Function (Aim 1): The 33-item UE motor portion of the Fugl-
Meyer Assessment (FMA) will be used to determine change in UE motor impairment9. The ARAT (primary 
outcome) and WMFT (secondary outcome), will be used as measures of motor function8, 74. To ensure rigorous 
experimental design, all measures of UE function will be obtained by an occupational therapist who has 
undergone training in the standardized administration of each test, has administered all testing for our previous 
studies, and is blinded to group assignment59, 75-77. The FMA, ARAT, and WMFT have been used in our 
previous studies, and have provided sufficient sensitivity in demonstrating change in motor function despite the 
heterogeneity of our sample. In addition to obtaining clinical measures of motor function, we have also used 
biomechanical measures of bimanual dexterity in our previous studies with stroke (see preliminary data) 11, 78-80 
and other neurological diseases10, 81-83. Grasping forces and torques produced by both limbs are recorded by 6-
DOF ATI force-torque transducers. Participants will complete 10 trials at each testing session: 5 trials in which 
Figure 4: Heart rate response for the same participant on 
two separate visits demonstrating increased time spent 
within HRtarget zone and sustained elevated HR response.  

each hand fulfills the role of the stabilizing limb and manipulating limb. These biomechanical data will provide 
greater insight into motor control mechanisms underlying functional recovery. Dr. Alberts developed this device 
and has published results extensively10, 80-82. He will provide the equipment and assist with data interpretation. 
Cost-Effectiveness Analysis Variables (Aim 2): Extensive participant demographics including age, gender, 
education, employment, support system, and social responsibilities will be collected at each time point in 
addition to the SIS63 and PROMIS 2965. These measures will ensure the accurate calculation of quality indices 
and indirect costs. Direct medical costs including personnel time, equipment, and additional resources and 
consumables associated with each intervention will be collected throughout the intervention period. Labor 
prices will be sourced from the Bureau of Labor and Statistics using US averages. All costs will be adjusted to 
the same base year using the Medical Component of the Consumer Price Index. Discounting will be applied in 
line with the Recommendations of the 2nd Panel on Cost-Effectiveness in Health and Medicine22.  
 
Data analysis 
Consideration of Relevant Biological and Sociological Variables: Participants in both groups will be 
compared on potentially confounding baseline variables (age, gender, socio-economic status, education, 
fitness, co-morbidities, degree of hemiplegia, location/type of stroke, side of lesion) to assess the extent of any 
imbalances across groups. Baseline variables in which there is a clinically important difference between groups 
may be included as covariates. Participants will also be compared using participation and adherence metrics. 
While recent evidence has shown that genetic polymorphisms may influence motor recovery following stroke84-
87, it is beyond the scope of this project due to cost and lack of expertise to consider these as covariates.  
Analysis of Motor Outcomes (Aim 1): Motor outcomes for each group will be compared at baseline, mid-
treatment, EOT, and EOT+4. The group effect on ARAT, FMA, and WMFT will be estimated using separate 
linear mixed effects models with a random effect for subject, fixed effects for group, examination time, and 
baseline value of the outcome. An appropriate covariance structure (e.g.: unstructured, compound symmetric, 
autoregressive) will be used as determined using Akaike’s information criterion88. The effects of group, time, 
and the group-by-time interaction will be assessed for each outcome. To adjust for multiple comparisons, the 
family-wise error rate will be controlled via Bonferroni-type adjustment required for multiple comparisons89. 
Tukey’s and other post-hoc comparisons will be used to explore pairwise differences in main effects of group 
membership. To further investigate the effect of the intervention group assignment on the various sub-scales of 
the ARAT, a multivariate analysis of variance will be used along with a separate principle component analysis 
to study if further dimension reduction is possible in using these two tests in the study. Transformations of the 
data will be made to achieve normality or other model assumptions. The overall alpha level will be set at 0.05. 
Bimanual dexterity data: All force and torque data will be filtered with a phase-symmetric low-pass filter using 
Woltring's algorithm with existing Matlab programs11, 80. The primary kinetic and kinematic outcomes will be: 
coordination of grip-load coupling, time delay between grasping force initiation for each limb, overall time to 
task completion and rate of grip force production for each limb11, 80, 90.   
Cost-Effectiveness Analysis (Aim 2): A decision analytic model using a systematic, quantitative approach 
using Treeage Pro® will be developed comparing AE+RTP and UE RTP only. All possible outcomes will be 
incorporated into the model. A hospital/payer perspective will be adopted and include all relevant costs and 
outcomes. All outcome probabilities used in the model will be determined from the clinical trial’s data collection 
at the 6 time points. As part of my training, I will learn cost-effectiveness methodologies, including approaches 
to analyze variability and uncertainty in the model and the population, and methods to evaluate model 
generalizability (sensitivity analysis) in accordance with current recommendations22, 23, 62. For this analysis, a 
cost effectiveness summary will be produced, including the costs and effects of each intervention, the cost-
effectiveness ratio of the interventions, and the incremental cost-effectiveness ratio between the interventions 
from two perspectives: healthcare sector and society. Deterministic and probabilistic sensitivity analyses will be 
used to evaluate result uncertainty attributable to the model and population variability91. Sensitivity analyses 
will be summarized to show that the optimal strategy is the choice strategy in ‘what’ percentage of time and for 
‘what’ variable values and be reported as a cost-effectiveness acceptability curve91.  
 
Power and Sample Size Justification:  
The power and sample size calculation is based on FMA scores from our R03 study. A minimal clinically 
important difference (MCID) range of 4.25-7.25 points has been reported for the FMA92 with baseline subject 
standard deviation of 5.7 – 6.3 points. To be conservative, we have assumed the MCID to be 4.25 for the 
purposes of our power calculations. Based on results from our R03 which included 3 intervention groups, the 
forced AE+RTP group, voluntary AE+RTP group, and RTP only groups improved on the FMA by a mean of 
12.33(4.13), 4.83(4.91), and 4.4(4.87), respectively. In the sample size and power computation, it is assumed 
that there is an increase of 2*MCID for the AE+RTP group and 1*MCID for the RTP only group, along with 

statistically significant differences between the groups at EOT. Further, it is assumed that subject SD will 
remain ~10 points within the group. Based on these assumptions, with n=30 in each of the intervention groups, 
we will have a .87 power at the 0.05 significance level to detect pairwise group differences equivalent to an 
effect size of .4. All computations were completed using the PASS 13 program (East Kaysville, Utah). 
 
Preliminary Studies 
Our preliminary study in patients with stroke7 and larger studies in Parkinson’s disease55-58 (NIH R01HD056316, 
R21 HD056316) have provided the majority of clinical efficacy data and technology that will be utilized for the 
proposed project. Cost-effectiveness analyses have not been conducted on prior studies. The primary goals of 
the stroke study were to determine feasibility and initial efficacy of utilizing two different modes of AE in 
patients with stroke as a means to promote functional motor recovery. In our R03, patients were randomized to 
forced-rate aerobic exercise (FE) along with RTP (FE+RTP), voluntary-rate aerobic exercise (VE) along with 
RTP (VE+RTP) or time-matched RTP only without an AE component. Preliminary data are presented from 17 
participants who completed all study-related interventions and testing. Using a more rigorous study design 
from our R03, we recently achieved our target enrollment of 30 participants 
for our ongoing AHA study within a 22 month time period. No data from the 
ongoing AHA study are reported, as the trial remains active. 
Cardiopulmonary Testing is Safe and Effective for Screening 
Individuals with Stroke: The pre-CPX medical screen and subsequent 
CPX testing protocol in this proposal was used successfully in all 
participants in our preliminary studies in determining the safety of 
individuals with history of stroke and cardiovascular co-morbidities to 
participate in the study intervention. Both AE groups demonstrated 
improvements in peak VO2 with the VE+RTP improving by a mean of 2.4 
mL/kg/min and the FE+RTP group improving by a mean of 1.3 mL/kg/min.  
Individuals with Stroke can safely exercise 
at moderate to high aerobic intensity: 
Continuous heart rate monitoring was used 
to ensure participant safety and to monitor 
compliance31, 32. On average, participants in 
the FE+RTP and VE+RTP groups exercised 
at mean intensities of 56.5 [±15.7%] and 
55.9 [±8.7%] HRR, well above minimum 
recommendations93.  
Aerobic exercise improves motor function 
following stroke, despite smaller RTP dose: All 
three groups demonstrated decreased motor 
impairment from baseline to EOT as measured by the 
FMA, exceeding MCID values92. The RTP group completed ~75% more reps of RTP per visit than the AE 
groups7. Despite this significant difference in RTP dosage, the forced AE group was the only of the three 
groups to exhibit and maintain significant improvements as evaluated by the FMA (p<0.01), with a mean 
improvement of 12.3 [±1.6] points from baseline to EOT. Fig 5 depicts the mean change (SD) in the FMA from 
baseline to EOT and EOT+4 for all groups47. Improvements were significantly greater for the FE group from 
baseline to EOT compared to the VE and RTP only groups41.  Biomechanical data were obtained during a 
bimanual task (Figure 6a), in which the participant attempts to disconnect the top and bottom portions of the 
device. Two force transducers measure the coordination of grasping forces from the stabilizing limb and 
manipulating limb. Data from a representative AE group participant in our AHA study shows a delay in the 
coupling of grasping forces and diminished force production from the involved UE (solid blue tracing) at 
baseline (Fig 6b), with improved coordination and quality of inter-limb grasping forces at EOT (Fig 6c).  
 
Limitations and Future Directions: While we have provided theoretical rationale regarding mechanisms 
associated with motor recovery as a result of the proposed interventions, we have opted to focus on objective 
clinical and biomechanical outcomes rather than attempting to identify the potential mechanism(s) responsible 
for enhanced neuroplasticity as a result of AE. Additionally, in order to obtain all data within the 5-year span of 
the study, the primary economic analysis is for a timeframe of 6 months with an interim analysis for a subset of 
the sample at 1 year. Nonetheless, the training I obtain from this K award will provide me with the foundational 
knowledge to conduct clinical research with scientific rigor, and will create a template for formal longitudinal 
cost effectiveness analyses on larger datasets, comparing the value of various rehabilitation approaches.  
 
Fig 5: Mean (SD) change in Fugl-Meyer 
Assessment impairment for each group. 
Delay in 
coupling of 
grasping
6a 
b 
Fig 6a: Bimanual dexterity assessment system.  At baseline (6b) the patient 
exhibited a sequential activation of grasping forces while following AE+RTP 
(6c), grasping forces were initiated nearly simultaneously.   
Reduction in 
delay in 
coupling of 
grasping
C