Moderate-Intensity Exercise Versus High-Intensity Interval Training to Recover Walking Post-Stroke
Phase: NA
Conditions: Stroke
Sponsor: University of Cincinnati

 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
 
NCT03760016 
 
Moderate-Intensity Exercise Versus High-Intensity Interval Training to 
Recover Walking Post-Stroke 
 
 
 
 
 
 
 
 
Last updated March 16, 2021 

v.5, 16Mar2021
1
UC IRB RESEARCH PROTOCOL 2017-5325
Moderate-Intensity Exercise Versus High-Intensity Interval Training to Recover Walking Post-Stroke
PI, Pierce Boyne PT, DPT, NCS; UD-site PI, Darcy Reisman PT, PhD; KUMC site-PI, Sandra Billinger PT, PhD
A. SPECIFIC AIMS
Fewer than 10% of stroke survivors regain adequate walking speed and endurance for normal daily functioning 
(e.g. grocery shopping).1-5 This limitation in walking capacity is caused by both neurologic gait impairments 
from the stroke and aerobic deconditioning due to inactivity.6,7 Current stroke rehabilitation guidelines 
recommend moderate-intensity aerobic training (MAT) to address both of these issues.6,8 However, recent 
evidence from our team suggests that a clinically feasible MAT duration (4 weeks) may have only negligible 
effects among chronic stroke survivors (>6 months post stroke).9 There is growing belief that a more vigorous 
training intensity (>60% vs. 40-60% heart rate reserve) may be a ‘critical ingredient’ for greater gait and 
aerobic fitness improvements, with less training time.10 Yet, the optimal training intensity has been difficult to 
determine among stroke survivors because neurologic impairments make it challenging to reach vigorous 
intensity, and previous attempts using conventional exercise have fallen short of 60% heart rate reserve, even 
with 6 months of training.7,11 What is needed is a new post-stroke therapy protocol capable of reliably eliciting 
vigorous intensity, so that the optimal training intensity for improving walking capacity can be established.
Our transdisciplinary team, consisting of national experts in post-stroke aerobic exercise & gait rehabilitation, 
neurologists focused on stroke recovery, an exercise physiologist, a cardiologist and a biostatistician, has 
developed a novel training protocol that safely enables persons with chronic stroke to achieve vigorous 
intensity in the first session (a mean 76% heart rate reserve).12 Based on the well-tested exercise science and 
cardiac rehabilitation strategy of high-intensity interval training (HIT), this protocol uses bursts of maximum 
speed walking with alternating recovery periods, to sustain higher aerobic intensities than physiologically 
possible with continuous exercise,13 and with lower perceived exertion.14 Our preliminary data demonstrate that 
this innovative locomotor HIT protocol can elicit >40% increases in walking capacity, gait speed and aerobic 
fitness in just 4 weeks. However, no previous studies have compared HIT with the current best-practice model 
post-stroke (MAT). Further, it is possible that the longer 12 week HIT durations tested in some heart disease 
studies might yield even better outcomes, approaching normal walking capacity, but this has not been tested. 
The objective of this proposal is to determine the optimal training intensity and the minimum training duration 
needed to maximize immediate improvements in walking capacity in chronic stroke. We propose a single-blind 
3-site RCT. Fifty persons >6 months post stroke will randomize to either 12 weeks of HIT or 12 weeks of MAT; 
each for 45 minutes, 3x/week. Clinical measures of walking function, aerobic fitness, daily walking activity and 
quality of life will be assessed at baseline (PRE) and after 4, 8 and 12 weeks of training (4WK, 8WK, 12WK).
Aim 1: Determine the optimal locomotor training intensity for eliciting immediate improvements in 
walking capacity among chronic stroke survivors. Primary study hypothesis: Compared with 4 weeks of 
MAT, 4 weeks of HIT will elicit significantly greater improvement in walking capacity, as measured by change 
in the 6-minute walk test from PRE to 4WK. This aim is powered for proof of concept that vigorous training 
intensity is a ‘critical ingredient’ for post-stroke locomotor recovery. 
Aim 2: Determine the minimum locomotor training duration needed to maximize immediate 
improvements in walking capacity. Hypothesis (based on our preliminary data15): Compared with 4 & 8 
weeks of HIT, 12 weeks of HIT will elicit significantly greater improvements in walking capacity and increased 
benefit over MAT. However, if effects peak earlier than 12WK, it would provide scientific justification to keep 
testing a shorter, lower-cost protocol to determine its sustained effects relative to longer training durations. 
4-weeks HIT
4-weeks MAT
4WK Testing
Consent & 
Screening
Randomize
PRE Testing
4-weeks HIT
4-weeks MAT
4-weeks HIT
4-weeks MAT
8WK Testing
12WK Testing
Aim 1
Aim 2

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These aims will provide foundational information to guide dosing of locomotor training intensity and duration in 
future studies and clinical practice. Further, the expected outcomes offer the potential to transform current 
stroke rehabilitation and make a positive impact on the disability burden of stroke. 
B. BACKGROUND AND SIGNIFICANCE
Stroke is a leading cause of chronic disability1 and limited walking capacity is a major barrier to stroke 
recovery.8 Despite declining mortality rates from stroke, 795,000 people continue to experience a stroke in the 
United States each year, resulting in 6.6 million Americans (2.6% of adults) currently living with the chronic 
sequelae of stroke.1 In addition, the chronic disability and financial burden associated with stroke are expected 
to continue to increase, due in part to the aging population.1,16 While the majority of persons in the chronic 
phase of stroke are able to walk without continuous physical assistance from another person,2,3 less than 10% 
have adequate walking capacity (speed and endurance) to allow normal daily functioning (e.g. work, grocery 
shopping).4,5 On average, community dwelling stroke survivors are able to walk about 0.5 m/s over short 
distances and 250 meters in 6 minutes,4,17-19 representing only ~40% of age-predicted normal gait speed and 
capacity (1.3 m/s and over 500 meters, respectively).20-22 This inadequate recovery of walking is devastating 
because it leads to a loss of life roles, social isolation, dependency, sedentary lifestyle and increased risk for 
secondary cardiovascular events.2,4-6,8,20,23-25 Therefore, improved walking capacity is a primary goal of stroke 
rehabilitation.8,26 Relevance: This project targets walking capacity limitations for persons with chronic stroke. 
Neurologic gait impairments and aerobic conditioning each contribute to limited walking capacity post-
stroke (Figure 1).6,8 Approximately 50% of stroke survivors have persistent motor impairment,1 leading to 
inefficient gait patterns that can double the metabolic cost of mobility.27-29 At the same time, mean aerobic 
capacity is reduced to about half of normal.30 This deconditioning alone is enough to render walking either 
impossible or unsustainable,31,32 and to put independent living out of reach.30 Thus, it is not surprising that even 
ambulatory, community dwelling stroke survivors 
average up to 75% fewer steps/day than even the most 
sedentary non-disabled older adults (1400 vs. 
5500).27,33-36 Such physical inactivity stymies motor 
recovery,33 perpetuates further deconditioning31,33 and 
contributes to a very high long-term risk for cardiac 
events23,24 and recurrent stroke,25,37 the leading causes 
of death among stroke survivors.38 Relevance: The 
interventions in this proposal are designed to address 
both gait impairment and aerobic deconditioning, thus 
simultaneously targeting both of the primary 
contributing factors to walking capacity.
Current guidelines recommend moderate-intensity aerobic training (MAT) to improve walking capacity 
and other outcomes post-stroke, but this approach has known limitations.6,8 Compared to conventional 
stroke rehabilitation therapies and lower intensity training, significant benefits of MAT have been observed for 
aerobic fitness,39-41 walking capacity,40-44 overall disability,44 fatigue,45 cardiovascular risk factors,46-49 blood flow 
(peripheral50 and cerebral51), brain activation,52 depressive symptoms,53 cognition,54 participation55 and quality 
of life.56 However, this approach has not been adopted in most clinical stroke rehabilitation settings,8 because: 
1) it has shown modest and inconsistent effects on gait speed,40,41,43 a primary stroke rehabilitation outcome,57-
59 and 2) protocols involve extended training durations (typically 45 min, 3x/wk for 6 months),33,46,50-52,60-62 which 
are impossible in clinical practice due to patient adherence issues63-65 and reimbursement constraints.66,67 
There is a clear need for a more efficacious intervention to improve walking capacity post-stroke. 
The proposed research seeks to address this need by advancing an innovative locomotor training intervention 
that has the unique potential to elicit clinically meaningful improvements with a clinically feasible and resource-
efficient training duration that could increase rates of exercise engagement among stroke survivors.
Locomotor high-intensity interval training (HIT) is a promising strategy for stroke rehabilitation, which 
uses bursts of maximum speed walking alternated with recovery periods to safely maximize training intensity.10 
The scientific rationale for using locomotor HIT to target post-stroke walking capacity includes converging basic 
and clinical data from the fields of exercise physiology, neuroscience, cardiac rehab and stroke rehabilitation:  
Stroke
Aerobic
Deconditioning
Walking Capacity
(Speed & Endurance)
Gait
Impairments
Sedentary
Behavior
Figure 1

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Accumulating evidence in stroke and non-stroke populations suggests that vigorous training intensity is a 
powerful stimulus for improving aerobic fitness10,68-74 and decreasing the risk of future cardiovascular 
events.10,70-72,75 For example, in our recent meta-regression analysis of post-stroke aerobic exercise studies 
(n=598 participants; 15 studies), aerobic fitness improvement (vs. control) was significantly greater in studies 
that attempted vigorous aerobic intensity (>60% heart rate reserve [HRR]) versus moderate intensity (40-
60% HRR) (VO2-peak Δ mean difference, +2.2 mL/kg/min [95% CI: +0.6, +3.9]).74 
Without HIT, vigorous intensity has been difficult to achieve post-stroke. In our recent survey of 568 
physical therapists involved in stroke rehabilitation, only 0-2% of respondents across settings reported 
prescribing vigorous intensity exercise. The most common perceived barrier was the limited ability of stroke 
survivors to exercise at a training level.11 Further, most previous stroke studies that have attempted to 
progress into vigorous aerobic intensity have either not reported the actual intensity achieved, or have fallen 
short of 60% HRR, even with 6 months of training.7 Conversely, HIT enables non-disabled adults to sustain 
very high aerobic intensities longer than physiologically possible with continuous exercise,13 and with less 
perceived exertion14 and better adherence.76,77 Therefore, the interval training strategy of HIT likely increases 
the feasibility and sustainability of vigorous intensity for persons with stroke.
Stroke rehabilitation studies and principles of motor learning & neuroplasticity also suggest that higher 
motor intensity results in better motor outcomes.10,68,74,78-87 For example, studies by our team and others 
have shown that faster gait speed challenges during training (i.e. higher intensities) result in greater 
immediate improvements in hemiparetic gait kinematics,88,89 kinetics,90 muscle activation patterns88 and 
efficiency,61,62,84,91  while conferring greater longitudinal improvements in gait speed.9,81-84 HIT enables healthy 
adults to train at higher gait speeds than are physiologically possible with continuous exercise.13 Therefore, 
the interval training strategy of HIT likely increases the feasibility and sustainability of maximal motor intensity 
for persons with stroke.
Among healthy adults, HIT delivers significant benefits remarkably fast (within 6 sessions over 2 
weeks),92-94 achieving similar performance & physiologic adaptation to MAT with up to 76% less training 
time.93,95-97 If HIT is able to elicit comparable changes among stroke survivors in 4 weeks of training (twice as 
much), it would provide a highly clinically feasible and resource-efficient alternative to the current best-
practice model (MAT), which could result in increased rates of exercise engagement among stroke survivors.
For persons with heart disease (coronary artery disease,77,98 myocardial infarction77,99,100 and heart 
failure76,99,101), HIT has shown superior clinical,76,99 aerobic fitness76,77,98-101 and adherence76,77 
outcomes compared to MAT with up to 53% less training time76,77,99 and no serious adverse events in 
well over 30,000 research training hours.65,72,76,77,98-101 Based on these impressive safety & efficacy data, HIT 
is now being considered as a new standard of care for cardiac rehabilitation.72,102 For stroke survivors, HIT 
may be even more efficacious, because of its potential to maximize motor outcomes in addition to aerobic 
fitness.9,81-84 Thus, HIT efficiently targets both of the main contributing factors to walking capacity. 
Scientific Premise. Our primary hypothesis that vigorous training intensity (>60% vs 40-60% heart rate 
reserve) is a critical ingredient for improving gait and aerobic fitness post-stroke is based on converging 
physiologic and clinical data, mostly from small to moderate sized, single-site, single-blind, randomized 
controlled studies, in stroke and non-stroke populations.10 Aside from our preliminary data below, the one 
previous stroke study in the literature attempting to directly test this hypothesis did not use HIT or report the 
actual training intensity achieved, and was further limited by the use of a single-site design, low power (n=34), 
lack of assessor blinding, a 6-month intervention lacking clinical feasibility and a 33% attrition rate without 
intent-to-treat analysis.73 Other stroke studies have shown promising results for “higher” intensity locomotor 
training, but were not designed to directly test this hypothesis because they did not include a moderate-
intensity aerobic control group (MAT).81-84,103-109 These studies have also been limited by failing to achieve 
vigorous intensity (mean >60% heart rate reserve) or to describe the actual mean aerobic intensity, single-site 
design and, in some cases, confounding from additional co-interventions in one group (e.g. body weight 
support, physical assistance) or from carryover effects in longitudinal crossover designs. 
We have overcome previous barriers to achieving vigorous intensity in stroke research, by 
systematically110 progressing a novel locomotor HIT protocol from conceptualization10 to initial protocol 
development,12 to protocol refinement (adding over ground HIT), while also establishing preliminary 
safety9,12,111 & promising outcomes and confirming the feasibility of recruitment & blinded testing procedures.9 
However, before we can justify and design a large efficacy trial, we still need an initial proof of concept that 

v.5, 16Mar2021
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vigorous intensity is a ‘critical ingredient’ for locomotor training and we need to optimize the training duration 
dose. HIT studies in non-stroke populations have successfully used training durations ranging from 2-12 
weeks,10 and our team’s previous chronic stroke study with a different locomotor training intervention found 
continuous changes in gait function across the 12 week intervention.15 However, no previous studies in any 
population have compared different HIT durations or examined the time course of outcome changes. 
The proposed study builds on our previous work and overcomes the limited scientific rigor of previous 
studies with a high-quality, moderately-sized, 3-site RCT, using our novel HIT protocol to ensure vigorous 
training intensity and a best-practice MAT control group. This study will determine the optimal training intensity 
and minimum training duration needed to maximize immediate improvements in walking capacity and other 
measures (gait speed, aerobic fitness, metabolic cost of gait, daily walking activity and quality of life) among 
chronic stroke survivors. This will be the first study designed to compare HIT and MAT in chronic stroke and 
the first study in any population to compare different HIT durations. Aim 1 is expected to provide proof of 
concept that vigorous training intensity is a ‘critical ingredient’ for locomotor recovery, by showing that HIT 
elicits significantly greater immediate improvement in walking capacity compared with MAT, using a clinically 
feasible 4-week training dose. Aim 2 is expected to show that longer durations of HIT elicit continued 
significant improvements, approaching normal walking capacity, with increasing benefit over MAT across 12 
weeks of training. However, if effects peak earlier than 12 weeks, it would provide scientific justification to keep 
testing a shorter protocol that is more aligned with patient preferences and current reimbursement models. 
Regardless of the outcomes, our aims will provide fundamental new knowledge to inform selection of 
intensity and duration dosing parameters for aerobic training and gait recovery interventions post-stroke. At the 
same time, this study will provide all remaining needed data to justify and design a subsequent definitive trial to 
determine the relative efficacy of HIT and MAT for eliciting clinically meaningful and sustained improvements in 
walking function. Therefore, the proposed study is significant because it is expected to constitute a critical step 
in a continuum of research that will lead to the clinical implementation of novel training strategies to 
synergistically and potently address both gait impairment and aerobic deconditioning post-stroke. This 
research will likely have a major impact on the massive112 disability and financial burden of stroke, because, 
unlike the currently recommended protocol for addressing these outcomes (MAT),33,46,50-52,60-62 HIT appears to 
provide meaningful benefits with a training duration that fits well within current clinical practice models and 
patient preferences.66,67,113 By elucidating the relative time course of changes in different outcomes, the data 
from this study will also inform future mechanistic and biomarker investigations in our team member’s areas of 
expertise, including brain connectivity, neurophysiology, molecular genetics and vascular function. In addition, 
the data will be made publicly available after study completion to support further exploration and meta-analysis.

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C. PRELIMINARY STUDIES
Our team developed a novel treadmill HIT protocol that enables persons with chronic stroke to achieve 
vigorous aerobic intensity (a mean 76% HRR) and fast treadmill speeds (a mean 178% of fastest floor 
speed) in the first session.12 This initial HIT protocol was 
developed by examining the influence of recovery period 
duration on treadmill speed and aerobic intensity (Figure 2).12 
The shortest recovery duration used in previous studies (120 
seconds)81,82 was suboptimal. R60 (60 second recovery) elicited 
the greatest immediate changes in treadmill speed while 30 
second recovery elicited the highest aerobic intensity and 
enabled all 18 participants to achieve vigorous intensity (≥60% 
HRR/VO2-peak). 
Our treadmill 
HIT protocol 
now uses R60 
for 5 min to 
maximize speed 
then transitions 
to R30 for 15 
min to ensure 
vigorous aerobic 
stimulation, thus targeting both gait function and aerobic fitness 
to synergistically improve walking capacity (Fig 3). 
Our preliminary clinical data suggest that locomotor HIT achieves remarkable improvements in just 4 
weeks. In our initial pilot randomized controlled trial with blinded outcome assessment (n=16),9 HIT elicited 
significant improvements in aerobic capacity, walking speed and the metabolic cost of walking, and some 
outcome changes were significantly better than MAT even with this small sample size (Table 1).
Further, our outcomes after 4 weeks of HIT were similar to those previously reported after 6 months of MAT.60 
However, only 28% of walking speed improvements on the treadmill translated into floor (overground) walking 
improvements, suggesting that outcomes could be further improved with the addition of task-specific 
overground training. Therefore, we added over-ground HIT to our treadmill HIT protocol and performed a 
single-group pre-posttest study (n=4) of this revised locomotor HIT protocol (45 minutes, 3x/week for 4 weeks). 
Outcomes showed better translation to floor walking with dramatic, clinically meaningful improvements, 
including: fastest walking speed, +0.43 m/s [95% CI: 0.10, 0.76] (+43%); comfortable walking speed, +0.19 m/s 
[0.00, 0.38] (+24%); walking capacity (6-min walk test), +115 m [11, 219] (+41%). While the limited sample 
Table 1. 4-Week Outcomes in Pilot RCT of Treadmill HIT and MAT                data presented as mean [95% CI]
Clinical Measure
HIT Group Change 
(n=11)
MAT Group Change 
(n=5)
HIT – MAT Change 
(n=16)
Aerobic capacity (ventilatory threshold), mLO2/kg/min
+4.4 [3.1, 5.7] 
(+43%)
+0.6 [-1.3, 2.5] 
(+4%)
+3.8 [1.5, 6.1]
Fastest treadmill walking speed, m/s
+0.36 [0.25, 0.47] 
(+41%)
+0.07 [-0.10, 0.24] 
(+7%)
+0.29 [0.09, 0.49]
Fastest (floor) walking speed (10m walk test), m/s
+0.10 [0.06, 0.13] 
(+13%)
+0.01 [-0.04, 0.06] 
(+1%)
+0.08 [0.02, 0.14]
Comfortable walking speed (10m walk test), m/s
+0.10 [0.06, 0.14] 
(+16%)
+0.02 [-0.03, 0.08] 
(+3%)
+0.08 [0.01, 0.14]
Metabolic cost of walking, mLO2/kg/m (lower is better)
-0.10 [-0.17, -0.03] 
(-25%)
-0.01 [-0.10, 0.09] 
(-4%)
-0.09 [-0.21, 0.03]
Method: Participants with chronic stroke were randomized 2:1 to treadmill HIT or MAT (25 min, 3x/wk, 4 weeks). A blinded rater assessed outcomes.
Gait
Function
Aerobic
Fitness
Walking
Capacity
Fig 3
Locomotor HIT
Speed
time
Max-speed
walking
practice
Vigorous
aerobic
stimulation
Method: Each 20 minute HIT protocol involved 30 
second bursts at maximum safe treadmill speed 
alternated with recovery periods of either 30, 60 or 120 
seconds (R30, R60 and R120). Eighteen participants 
with chronic stroke performed one session of each 
protocol in randomized order with one week in-between 

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sizes justify further study, these data support the potential for locomotor HIT to elicit greater increases in 
walking function and aerobic fitness than the current best-practice model (MAT), with less training time.
D. INVESTIGATOR EXPERIENCE
Pierce Boyne PT, DPT, NCS, Principal Investigator, is an Assistant Professor in the Department of 
Rehabilitation Sciences at the University of Cincinnati (UC) and Co-Director of the UC Neurorecovery 
Laboratory. He is a licensed physical therapist and a board-certified neurologic clinical specialist (American 
Board of Physical Therapy Specialties). He has a BS in Health Sciences with a concentration in exercise 
physiology and a Doctorate in Physical Therapy with a concentration in clinical research. He has also 
completed post-doctoral training in epidemiology and clinical/translational stroke recovery research at UC, 
Cincinnati Children’s Hospital Medical Center and the UC Health Daniel Drake Center for Post-Acute Care, 
including the KL2 Research Scholar’s program in the Cincinnati Center for Clinical and Translational Science 
and Training, funded by the NIH. In total, he has been involved with stroke recovery and rehabilitation research 
for 10 years, serving a variety of roles on numerous studies, including being the primary outcome testing 
therapist at the lead site in a national multi-site trial of post-stroke gait rehabilitation. Most relevant to this 
proposal, Dr. Boyne has also been the project manager and primary in-field investigator for all preliminary 
studies leading to this application and has led multiple previous successful collaborations with each of the 
external site PIs (Dr. Billinger and Dr. Reisman). 
Sandra A Billinger, PT, PhD, University of Kansas Medical Center (KUMC) Site Principal Investigator, is 
an Associate Professor in the Department of Physical Therapy and Rehabilitation Science, University of 
Kansas Medical Center (KUMC). Dr. Billinger is a licensed physical therapist and holds additional certifications 
from the American College of Sports Medicine (Certified Exercise Specialist) and the American Physical 
Therapy Association (Certified Exercise Expert for the Aging Adult). Dr. Billinger started her career in cardiac 
rehabilitation over 15 years ago, completed a research intensive joint PT/PhD program at KUMC in 2008 and 
received formal clinical research training related to exercise and vascular health in stroke through a career 
development award (K01HD067318; 2011-2016). She has developed several exercise testing protocols for 
people with chronic conditions such as stroke. Dr. Billinger also has extensive experience leading and 
collaborating on aerobic exercise studies, especially post-stroke, including studies funded by the American 
Heart Association, National Institutes of Health and industrial sponsors. Dr. Billinger was also the writing group 
chair and lead author of the American Heart Association’s Scientific Statement on physical activity and 
exercise for stroke survivors in 2014. In addition, she has previous experience with multi-site clinical trials, 
including being a site-PI for the Milestone trial, testing a pharmaceutical intervention for post-stroke gait 
recovery. 
Darcy Reisman, PT, PhD, University of Delaware (UD) Site Principal Investigator, is an Associate 
Professor in the Department of Physical Therapy at the University of Delaware (UD) and is Academic Director 
of the Neurologic and Older Adult Clinic. With the support of NIH and Foundation funding, she has been 
studying movement control and recovery following stroke for over a decade. Dr. Reisman has a strong track 
record investigating the interaction between biomechanics and neurophysiology after stroke (K01HD050582, 
P20GM103446-12, R01NS055383-05, R01HD078330-01A1) in order to design targeted interventions that 
impact the primary impairments underlying reduced activity and participation. Dr. Reisman has also lead or 
been a co-investigator on numerous locomotor rehabilitation studies of chronic stroke survivors 
(R01NR010786-05, R21HD07142-01A1, 1R01 HD086362-01). Dr. Reisman is currently PI on R01HD078330, 
investigating processes of locomotor learning after stroke, and PI on R01HD086362, a multi-center clinical trial 
investigating the independent and combined effects of fast treadmill walking and activity monitor biofeedback 
among stroke survivors. 
Kari Dunning PT, PhD, Co-Investigator, is a tenured Associate Professor in the Department of Rehabilitation 
Sciences with a secondary appointment in the Division of Epidemiology in the Department of Environmental 
Health at UC. She has a MS in Neuroscience, a PhD in Epidemiology and has been a physical therapist 
specializing in the evaluation and treatment of neurological patients for over 25 years. Dr. Dunning is Co-
Founder of the UC Neurorecovery Laboratory in which the preliminary studies leading to this grant were 
performed. She has been conducting stroke rehabilitation research for over a decade and has been 
responsible for the research design, data collection, data analysis and manuscript writing for numerous 
studies, including being coordinating PI of a national 11-site stroke rehabilitation trial and site PI on additional 

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multi-site studies. Dr. Dunning is the recipient of previous research grants from the American Heart 
Association, the Foundation for Physical Therapy and industrial sponsors. 
Daniel Carl PhD, Co-Investigator, is Assistant Professor in the Department of Rehabilitation Sciences at UC. 
He has a PhD in Exercise Physiology and has been conducting human subject research for over 10 years, 
including HIT and exercise testing as in the proposed study. Dr. Carl was also a Co-Investigator on the pilot 
studies leading to this proposal. 
Brett Kissela MD, MS, Co-Investigator, is Albert Barnes Voorheis Professor and Chair in the Department of 
Neurology and Rehabilitation Medicine at UC and Co-Founder of the UC Neurorecovery Laboratory in which 
the preliminary studies leading to this grant were performed. Dr. Kissela is a vascular neurologist with expertise 
on stroke trials, stroke recovery, rehabilitation and neuroplasticity. He has been involved with HIT research 
from conceptualization through the pilot studies that led to this proposal. 
Oluwole Awosika MD, Co-Investigator, is Assistant Professor in the Department of Neurology and 
Rehabilitation Medicine at UC and Co-Director of the UC Neurorecovery Laboratory. He is a board-certified 
adult neurologist with over eight years’ experience with analyzing and correlating clinical radiographs involving 
stroke patients. He also has a strong background in basic neuroscience, neurophysiology and neuroplasticity 
research, neurorehabilitation training, and a post-doctoral fellowship in motor learning, neurophysiology, and 
neuromodulation with Dr. Leonardo Cohen at NINDS. 
Myron Gerson MD, Co-Investigator, is Professor Emeritus of Cardiology and Internal Medicine at UC and 
Director of the Cardiovascular Stress Laboratory at UC Medical Center. Dr. Gerson is a cardiologist with 
expertise in exercise testing, cardiovascular safety and cardiometabolic health. He was also a Co-Investigator 
on the pilot studies leading to this proposal. 

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Stratified Blocked Randomization
Screening & Baseline Assessment:
(1) Record review; history & physical; motor/gait/balance/cognitive testing 
(2) Treadmill ECG graded exercise test
Figure 4. Study design
Informed consent
PRE: Blinded outcome testing
• Walking capacity (primary outcome) • Gait speed • Aerobic fitness
• Metabolic cost of gait • Daily walking activity • Quality of life
4 weeks of locomotor MAT
• 20 min treadmill MAT + 20 min 
overground MAT + 5 min warm up 
/ cool down • 3x/week
4 weeks of locomotor HIT
• 20 min treadmill HIT + 20 min 
overground HIT + 5 min warm up 
/ cool down • 3x/week
4WK (primary endpoint): Blinded outcome testing
4 weeks of locomotor HIT
4 weeks of locomotor MAT
4 weeks of locomotor HIT
4 weeks of locomotor MAT
12WK: Blinded outcome testing
8WK: Blinded outcome testing
E. EXPERIMENTAL DESIGN AND METHODS
E.1. Methods and Procedures
Study design
We propose a 3-site, 2-arm randomized 
controlled trial with blinded outcome 
assessment, stratified blocked randomization 
and an active control group (MAT) based on 
current best practice recommendations (Fig 4). 
Fifty persons with residual gait impairment >6 
months post stroke will be recruited, 
consented, screened and randomized to either 
locomotor HIT or locomotor MAT. Treatment 
sessions will be time-matched between groups 
at 45 minutes, 3x/week for 12 weeks. Walking 
function, aerobic fitness and quality of life will 
be assessed by blinded raters at baseline 
(PRE) and after 4, 8 and 12 weeks of training 
(4WK [primary endpoint], 8WK, 12WK). 
Outcome measures will include: walking 
capacity (6-Minute Walk Test, primary outcome 
measure), gait speed (10-Meter Walk Test), 
aerobic fitness (ventilatory threshold & VO2-
peak), metabolic cost of gait, daily walking 
activity and quality of life (Stroke Impact 
Scale).
Recruitment
As in previous studies, recruitment will utilize a 
multimodal approach, including: 1) Continuous 
outreach to regional therapists and physicians; 
2) Outreach to stroke support groups; 3) 
Advertisements in newspapers, magazines, social media, physician offices and therapy clinics; 4) Existing 
databases of local stroke survivors interested in participating in research; 5) Screening medical records for 
potentially eligible participants. This initial identification of potential participants via medical records will only be 
used by study staff at UC or KUMC. UD study staff will not recruit using medical records. 
Clinician referrals can be done in two ways: 1) the clinicians may provide the study team contact information to 
the potential participant; 2) if the potential participant verbally approves, the clinician can give the study team 
their name and contact information. Screening medical records for potentially eligible participants (by UC or 
KUMC study staff) will involve searching for cases of stroke and assessing other eligibility criteria in the 
electronic medical records system and databases of local hospitals and clinics, as in our previous UC IRB 
approved studies (e.g. 2013-7676, 2016-1916). We are requesting a HIPAA waiver for this purpose, as in our 
previous studies. For any potential participants who are identified solely by medical record review, we will only 
initiate a call to the participant if they have had a clinical encounter with one of the study investigators. 
Otherwise, we will initiate contact by mailing the participant an IRB approved flier (with the envelope addressed 
to “Current Resident”) or by emailing an IRB approved flier to the email address(es) listed in their medical 
records (with the email address blind carbon copied). 
For persons interested in participating, we will further explain the study, confirm initial eligibility and perform 
informed consent. After a research staff member explains the purpose of study and the consent, potential 
participants will be given the option to wait at least 24 hours to decide if they want to participate. During this 
consenting process, the potential participant will be provided a copy of the consent form. Standardized 
questions will be asked to ensure that the potential participant understands the study before consenting. 
HIPAA authorization will also be obtained as part of the consent process.  

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9
Spanish-speaking participants may be enrolled in the trial, if a site reports that Spanish-speaking individuals 
have expressed interest in participating. In this case, an approved Spanish-language version of the site’s 
informed consent document will be used during the informed consent process. The consent process will be 
conducted as described in the previous paragraph. However, an official medical interpreter will be present 
during the consent process to interpret from English to Spanish and Spanish to English. A Spanish-speaking 
team member or medical interpreter will also be available during the study visits. 
Eligibility criteria (Table 3) are based on our research experience, previous studies,33,50,51,54,69,76,77,81,82,98-101,141 
and exercise guidelines6,142 and will maximize safety while balancing internal & external validity.143 
Screening and Baseline Assessment
After informed consent, participants will undergo screening and baseline assessment to confirm eligibility and 
to obtain baseline characteristics and potential cofactors. This testing may include: a medical record review 
(possibly including clinical radiography159), a history & physical assessment (including pre-stroke functional 
status, stroke severity,145 motor impairment,155,156 gait57,144 and balance154,157,158 testing), cognitive testing,154 
depression screening,147 a treadmill screening test144 and a stroke-specific treadmill ECG graded exercise 
stress test.148 Female participants will also be asked about the possibility of pregnancy and will agree (as part 
of the informed consent process) to notify research staff if they have any reason to think they might be 
pregnant during the study. In this case, study activities would continue only after a urine pregnancy test is done 
and found to be negative.
Stress testing will be performed according to published guidelines127,137-139 by trained, experienced exercise 
testing laboratory staff at each of the sites. Assistance will be provided as needed from a licensed physical 
therapist or physical therapist assistant on the study team. Participants will wear a harness secured to an 
overhead support system for safety in case of loss of balance. ECG and vitals will be monitored. Participants 
will perform a maximal effort, graded treadmill exercise test to volitional fatigue. Treadmill speed will begin 
below the participant’s fastest safe speed from the treadmill screening test. Increases in speed and/or grade 
will be used to gradually increase the workload until peak exercise capacity is reached. Test termination criteria 
will include participant request to stop at volitional fatigue, severe gait instability, or according to published 
guidelines.127,137-139 
Table 3. Eligibility Criteria
Inclusion Criteria
Exclusion Criteria
1) Age 40-80 years
2) Single stroke for which participant 
sought treatment, experienced 6 
months to 5 years prior to study entry
3) Walking speed <1.0 m/s on the 10 
meter walk test21,57 
4) Able to walk 10m over ground with 
assistive devices as needed and no 
continuous physical assistance from 
another person (guarding and 
intermittent assistance for loss of 
balance allowed)33 
5) Able to walk 3 minutes on the 
treadmill at ≥0.13m/s (0.3 mph) 
(treadmill screening test)142,144
6) Stable cardiovascular condition (AHA 
class B,142 allowing for aerobic 
capacity <6 METs)
7) Able to communicate with 
investigators, follow a 2-step 
command and correctly answer 
consent comprehension questions
1) Exercise testing uninterpretable for ischemia or arrhythmia (e.g. resting ECG 
abnormality that makes an exercise ECG uninterpretable for ischemia,142 and no other 
recent (within the past year) clinical testing to rule out these conditions).
2) Evidence of significant arrhythmia or myocardial ischemia on treadmill ECG graded 
exercise test142 in the absence of recent (within the past year) more definitive clinical 
testing (e.g. stress nuclear imaging) with a negative result.
3) Hospitalization for cardiac or pulmonary disease within past 3 months
4) Implanted pacemaker or defibrillator
5) Significant ataxia or neglect (score of 2 on NIH stroke scale item 7 or 11)145 
6) Severe lower limb spasticity (Ashworth >2)146 
7) Recent history (<3 months) of illicit drug or alcohol abuse or significant mental illness
8) Major post-stroke depression (Patient Health Questionnaire [PHQ-9] ≥ 10147)  in the 
absence of depression management by a health care provider
9) Currently participating in physical therapy or another interventional study
10) Recent botulinum toxin injection to the paretic lower limb (<3 months) or planning to 
have botulinum toxin injections
11) Foot drop or lower limb joint instability without adequate stabilizing device, as 
assessed by a study staff physical therapist 
12) Clinically significant neurologic disorder other than stroke or unable to walk outside 
the home prior to stroke
13) Other significant medical condition likely to limit improvement or jeopardize safety, 
(e.g. joint contracture, gait limited by pain), as assessed by a study staff physical 
therapist
14) Pregnancy
15) Previous exposure to fast treadmill walking (>3 cumulative hours) during clinical or 
research therapy in the past year

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10
Participants will be verbally notified about the results of their stress test. If they are disqualified from further 
participation in the study based on the results, they will also be given the option to have the results sent to their 
physician.
Blinded Outcome Testing
Outcome testing will be administered by licensed physical therapists or physical therapist assistants who are 
blinded to group randomization. Testing will occur before intervention (PRE) and after approximately 4, 8 and 
12 weeks of training (4WK [primary endpoint], 8WK, 12WK). Each testing session will last approximately 2 
hours and may include the following measures:

Walking capacity testing (6-minute walk test, primary outcome measure) involves walking back and forth 
around two cones, using assistive devices, orthotics, guarding and rest breaks as needed.148 The distance 
that the participant is able to walk in six minutes is recorded. 

Walking speed testing (10-meter walk test) will be performed with a stopwatch and/or a commercially 
available electronic walkway.146,147 Participants will walk down a hallway and/or electronic walkway, using 
assistive devices, orthotics and guarding as needed. Each test may be performed twice at comfortable 
speed and twice as fast as possible. 

Aerobic capacity testing involves respiratory gas measurement (VO2 and VCO2) by having the participant 
breathe through a facemask during an exercise test. This testing will use the same exercise protocol as the 
stress test above and may be performed simultaneously with the stress test. Peak aerobic capacity is 
defined as the highest VO2 measurement achieved during the test. After finishing this test and a rest 
period, participants may complete a verification phase to help determine whether maximum physiologic 
capacity (a true VO2-max) was reached.151 During this verification phase, the participant would be asked to 
walk as fast as possible for approximately 3 minutes. The treadmill screening test may be repeated at each 
testing time point to inform speed selection for aerobic capacity testing.

The metabolic cost of gait is measured by the oxygen consumption rate (VO2) during gait, with adjustment 
for walking speed and resting VO2.79 The metabolic cost of gait will be assessed with treadmill walking at 
approximately the average speed recorded during the 6-minute walk test. 

Daily walking activity assessment involves wearing an activity monitor continuously during waking hours for 
≥3 days and possibly recording sleep/wake times.152-155 The monitor will be worn on the non-paretic leg. 

The Stroke and Aphasia Quality of Life Scale,157,158 Stroke Impact Scale,138 EQ-5D and Patient Health 
Questionnaire147 are reliable and valid self-report quantitative surveys that include questions about quality 
of life. One or more of these questionnaires will be used. 

The Global Rating of Change (GROC)159 is a questionnaire that assesses overall impressions of change in 
health status from the perspective of the participant. The GROC is a 15 point ordinal scale with −7 
indicating “a very great deal worse,” 0 indicating “no change,” and +7 indicating “a very great deal better”. 
The GROC is not applicable at baseline testing because it measures change only.
Heart rate data may also be recorded during the above testing. If there are any issues with data capture (e.g. 
equipment malfunction), it is possible that participants could be asked to repeat individual tests as long as it 
would still be possible to obtain quality data without increasing risk to the participant.
Randomization
Participants will be enrolled after PRE testing and randomized to either HIT or MAT. Randomization will be 
stratified by site and by baseline walking speed (<0.4, ≥0.4 m/s), to help ensure that groups are balanced 
within sites and on this critical prognostic factor.149,150 Within each stratum, we will randomize in block sizes of 
2 or 4. Block size will be randomly permuted to prevent personnel from being able to predict the last 
randomization within a block. 
Training Intervention Protocols
Common features between protocols. Participants in both groups will be asked to perform 36 training sessions 
over approximately 12 weeks, with repeated outcome testing after each [12 session / 4 week] block. Target 
training frequency will be 3 sessions per week. Both groups will train for approximately 45 minutes per session, 

v.5, 16Mar2021
11
using orthotic & assistive devices and handrail balance support on the treadmill as needed.144 Each session 
will include a 3 minute warm up, 10 min overground training with guarding from a physical therapist, 20 min 
treadmill training wearing a harness for fall protection, another 10 min overground training and a 2 min cool 
down. Target heart rates (HRs) will be based on the peak HR from exercise testing, to account for β-blocker 
medications.144 
Locomotor high-intensity interval training (HIT). This protocol was developed and refined in our preliminary 
studies. It involves repeated bursts of walking at speeds up to the participant’s fastest safe speed, alternated 
with recovery periods of slower walking or rest. During overground HIT, burst speed is increased using visual 
feedback about the distance covered during each burst and encouragement to increase distance. During 
treadmill HIT, speed is systematically progressed throughout each session based on participant performance 
criteria and heart rate response.9,81,82 Target average HR for each session is approximately 85% HRpeak (~70% 
HR reserve [HRR])
Locomotor moderate-intensity aerobic training (MAT). Similar to 
our pilot randomized controlled trial,9 this protocol will follow the 
widely reported training regimen of Macko et al,33,46,50,51,60-
62,144,215,216 used as the basis for current post-stroke exercise 
guidelines.6,8 The only adjustment for this study will be the addition 
of overground MAT109 to match the training modes and duration of 
locomotor HIT. During both treadmill and overground MAT, speed 
will be continuously adjusted to maintain an initial target HR of 40 
± 5% heart rate reserve (HRR), progressing by 5% HRR every 2 
weeks up to 60% HRR, as tolerated.144 
Intervention fidelity measures 
Integrity of the training protocol may be assessed by the following 
measures:
Adherence will be measured by the number of training sessions attended
Aerobic intensity will be measured by training heart rates. Heart rate data may be collected by a heart rate 
transmitter worn around the chest (e.g. Polar H7), an ECG, a pulse oximeter and/or manual palpation. Heart 
rate data may be processed using an iPod (or similar) application (e.g. FitDigits iCardio).  
Anaerobic intensity may be measured by blood lactate concentration after the treadmill training portion of 
one or more  sessions, using a finger stick and a point-of-care blood lactate analyzer. Blood lactate 
accumulation is a key feature of vigorous training intensity that provides a mechanistic basis for expected 
benefits over moderate intensity. Our preliminary data confirmed that among persons with chronic stroke, the 
anaerobic threshold still occurs almost exactly at the 60% HR reserve transition point between moderate and 
vigorous intensity.136 Further, we demonstrated that our treadmill HIT protocol elicits a consistent and robust 
lactate response in this population, which is significantly greater than the null effect elicited by MAT (p<0.001; 
Fig 5). In animal and healthy adult studies, increased blood lactate has been shown to drive skeletal muscle 
mitochondrial adaptations that increase aerobic capacity,166 to upregulate neurotrophins that facilitate brain 
plasticity167 and to predict greater motor learning when paired with skill practice.168     
Neuromotor intensity may be measured by treadmill and over ground training speeds each session. 
Repetition of practice may be measured by step counts during each session, using an activity monitor on the 
non-paretic leg.27,34,35,169,170 
Concurrent outside interventions
To test for other between-group differences during the intervention period that could explain differences in 
outcomes, we may also assess the following measures:
Method: Sixteen participants with chronic stroke 
performed one 20 minute session each of HIT and 
MAT in randomized order and had blood draws 
before, during and after each session.

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Concurrent walking practice may be measured by step counts outside of training sessions. Participants 
would be asked to take an activity monitor home to wear during waking hours throughout study 
participation.171 
Concurrent therapy may be measured by any changes in medications and the number of sessions of outside 
therapy (e.g. speech & occupational therapy).156   

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E.2. Data Analysis and Data Monitoring
General approach
The REDCap® web-based system217 will be used for data entry and data monitoring. All baseline variables and 
data on intervention fidelity and concurrent outside interventions will be compared between groups with t-tests 
and Χ2. The primary analysis will follow intent-to-treat methods and any missing data will be handled with the 
method of maximum likelihood, assuming that patterns of missingness do not violate the missing at random 
assumption.218 
The primary general linear model for both Aims will include fixed effects for intercept, group (HIT, MAT), time 
(PRE, 4WK, 8WK, 12WK), [group X time], site (UC, KUMC, UD), [site x time], baseline gait speed category 
(<0.4, ≥0.4 m/s) and [baseline gait speed category x time] (to account for the stratification factors)218,222 with an 
unstructured covariance matrix (to account for the repeated nature of the data without making assumptions 
about covariance patterns).218 Time will be modeled as a categorical factor (i.e. analysis of response 
profiles218), since there is no available information about the expected pattern in the HIT mean response over 
time. 
Sample Size
This study is powered to detect the minimal clinically important difference (MCID) of 20 meters in walking 
capacity (6-minute walk test) change220 between groups. 
GLIMMPSE221 was used to estimate the sample size needed to 
detect a significant [group x time] effect at each time point, 
using the model above with a two-sided α of 0.05. The 6-minute 
walk test change estimate for the MAT group (+15 m / 4 wks) 
was taken from our 4-week pilot study9 and resulted in a 12WK 
change estimate (+45 m) somewhat larger than previously 
observed (+25 m).60 In contrast, the HIT group estimate (MAT 
group change plus MCID = +35 m / 4 wks) was notably lower 
than observed in our most recent 4-week pilot study (+115 m in 
4 wks), indicating that the true effect size may be much larger 
and easier to detect than the MCID. Variance & covariance 
parameters for each time point were estimated by pooling data 
across our two previous 4-week studies (n=20), using the mean 
variance for each time point and the highest suggested 
exponential decay rate (0.5)221 for the repeated measures 
correlations involving 8WK and 12WK. These calculations 
indicated a target sample size of 40 (20/group) for ≥80% power 
(Fig 6). To conservatively account for attrition, we plan to enroll 
at least 50 and up to 75 participants. 
Hypothesis Testing
Aim 1: Determine the optimal locomotor training intensity for eliciting immediate improvements in walking 
capacity among chronic stroke survivors
Hypothesis 1a (H1a): Compared with MAT, HIT will elicit significantly greater improvement in walking capacity 
(6-minute walk distance) from PRE to 4WK (primary study hypothesis) 
Hypothesis 1b (H1b): Compared with MAT, HIT will elicit significantly greater improvement in secondary 
outcomes from PRE to 4WK 
H1a will be tested by the significance of the [group x time] contrast from Baseline to POST-4wk for the 6-minute 
walk test at α=0.05. For H1b, secondary outcomes will be tested separately using the same model as H1a to 
identify the most sensitive measures to carry forward into future studies.110 The Benjamini-Hochberg 
procedure223 will be used to control the false discovery rate (FDR) for the secondary outcomes.  
Aim 2. Determine the minimum locomotor training duration needed to maximize immediate effects
Red line shows estimated variance (Σ). Orange and 
yellow lines show 10 & 20% variation in Σ, respectively. 
Scale factor 1.0 for group x time effect size is the MCID 
(20m). Other scale factors show the effect of 10 & 20% 
variation in this effect size. Effect sizes smaller than the 
MCID (scale factor 1.0) are not meaningful to detect.

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Hypothesis 2a (H2a): Within the HIT group, walking capacity (6 minute walk test distance) and secondary 
outcomes will significantly increase from 4WK to 8WK and from 8WK to 12WK
Hypothesis 2b (H2b): Compared to MAT, HIT will elicit significantly greater improvements in walking capacity 
and secondary outcomes from PRE to 8WK and from PRE to 12WK
H2a will be tested by the significance of the respective time contrasts within the HIT group. H2b will be tested by 
the significance of the respective [group x time] contrasts. Secondary outcomes will have FDR control.223
Data and Safety Monitoring Plan
An adverse event (AE) is an undesired medical occurrence in a participant who is undergoing study 
procedures and does not necessarily have a causal relationship with the treatment or study procedures. This 
includes any adverse clinical change that occurs at any time following consent. A serious AE (SAE) is any 
adverse experience occurring during study participation that results in any of the following outcomes: death; a 
life threatening situation; inpatient hospitalization or prolongation of existing hospitalization; a persistent or 
significant disability/incapacity.209,210 The data and safety monitoring plan for this study will include participant 
monitoring for AEs and other problems, review of AEs and other problems by the study team and IRB, and an 
independent data safety monitoring board (DSMB). 
Participant safety monitoring
Based on safety data from our preliminary studies9,12 and the extensive previous HIT research among persons 
with heart disease,65,72,76,77,98-101 and MAT research among persons post-stroke,33 we expect a similar rate of 
non-serious adverse events (AEs) between HIT and MAT (e.g. temporary exercise-related soreness and 
fatigue), without any study-related serious AEs. As in our previous studies, we will systematically monitor for 
AEs. Each study visit, participant voluntary reporting of AEs will be encouraged and AEs of interest will be 
specifically queried, including: falls, injuries, faintness, pain and fatigue. During training, safety monitoring will 
include HR, blood pressure, and continuous observation for other signs or symptoms of cardiorespiratory 
insufficiency, worsening neurologic impairments or orthopedic injury, using accepted stopping criteria.142,208 
AEs will be followed until resolution and categorized according to type and severity (grade 1-5),209,210 causal 
relationship with the intervention (yes/possibly/no) and whether anticipated (listed in the protocol / informed 
consent form or expected in the target population).
Reporting and review of AEs and other problems involving risk
All observed or volunteered AEs and other problems involving risk to research participants or others that occur 
throughout the study will be recorded and reported to the IRB according to UC IRB protocol, as well as 
reported to the DSMB (see further information about the DSMB below).. As such, all unanticipated AEs and 
other problems involving risk will be reported to the IRB and DSMB within 10 days  of study staff knowledge of 
the event. AEs or other problems resulting in temporary or permanent interruption of the study activities by the 
PI to avoid potential harm to participants will be reported to the IRB and DSMB immediately (within 48 hours). 
Other AEs or study problems will be reported to the IRB at the time of continuing review and to the DSMB at 
least annually. AEs will be discussed between site PIs during regular conference calls. Withdrawal from the 
study and modifications to study procedures as a result of an AE or because of therapeutic measures taken to 
treat an AE will be at the discretion of the site PIs, in consultation with the study physicians as appropriate. 
Data safety monitoring board (DSMB)
The DSMB will consist of at least 3 members separate from the study team, including at least one physician 
and at least one biostatistician, with collective experience in the management of patients with stroke, exercise 
and clinical trials. A quorum will require at least 2 members, including the chair. Persons with a significant 
conflict of interest (financial, institutional or scientific) will not be permitted to be DSMB members. The DSMB 
will meet at least (approximately) annually. A summary report will be sent to the DSMB prior to each meeting, 
including safety and clinical outcome data. DSMB meetings will include open sessions where the DSMB may 
discuss any issues with the study team and closed sessions where the DSMB alone decides on its 
recommendations. The DSMB will assess the risks and benefits of study participation for all participants and 
will provide a written report of their analyses and recommendation as to whether the study should continue, 
whether modifications to the study are needed or if the study should be terminated. These reports will be sent 
to the investigators and the IRB. 

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Safety Data Analysis
In the unexpected event of one or more SAEs, the SAE rate will be compared between groups to confirm that 
there is no significant difference in major safety risk between HIT and MAT. This analysis will use a logistic 
regression model with SAE (yes/no) as the dependent variable and fixed effects for group, site and baseline 
gait speed category. If there are SAE(s) in one group only, a continuity correction (0.5 SAEs added to each 
group) will still allow the odds ratio to be calculated.9 Secondary safety outcomes (different grades/categories 
of AEs) will be tested using the same model, with [# AEs / # training sessions] as the dependent variable.9 
E.3. Data Storage and Confidentiality
Risk of any breach to participant privacy or confidentiality will be minimized by: 1) maintaining all physical 
participant files in locked filing cabinets; 2) minimizing use of participant identifiers on data collection forms, 
electronic files and the secure REDCap web-database; 3) not storing any participant identifiers on peripheral 
devices used for data processing (e.g. electronic walkway for gait testing, iPod application used for heart rate 
data); 4) only allowing de-identified data exports from REDCap and ensuring that the final dataset does not 
include any identifiers or other variables that could lead to deductive disclosure of individual participant 
identities before submitting it to a public research data archive (e.g. NIH/NICHD data and specimen hub 
[DASH]); 5) uploading files that need centralized review (e.g. clinical brain imaging data and metabolic cart 
data files from exercise testing) to a secure server designed for research data (REDCap or a UC research data 
server); 6) only allowing study personnel and laboratory staff (e.g. Cardiac Stress Laboratory) to access the 
data and giving only as much access as necessary to perform study roles and ensure participant safety; and 7) 
destroying the link between participant identifiers and participant ID number after the final data analysis is 
completed.
E.4. Setting
Most study activities will be performed in rehabilitation/exercise research laboratories at each site. Stress 
testing will be conducted in either clinical or appropriately equipped research exercise testing laboratories.
E.5. Laboratory Methods and Facilities
None
E.6. Estimated Period of Time to Complete the Study
We estimate that each participant will be involved in the study for approximately 5 months and that the overall 
study will take approximately 5 years to complete. 

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F. HUMAN SUBJECTS
F.1. Sample Size
Approximately 17 participants (up to 30) will be enrolled in this study at each site (UC, UD, KUMC). 
Approximately 50 total participants (up to 75) will be enrolled in the study. 
F.2. Eligibility Criteria
F.3. Gender, Age Range, Racial/Ethnic Distribution and Vulnerability
The target age range is 40-80 years old. This age range is consistent with the majority of the post-stroke 
population and will provide sufficient homogeneity to maximize study internal validity. We will not recruit based 
on gender, race or ethnicity, nor will we exclude anyone on these bases. Based on our previous clinical and 
research experience and stroke incidence rates, we expect approximately 50% of participants to be 
Caucasian, approximately 30% to be African American and approximately 45% to be female.225-227 No 
vulnerable populations will be included in this study. Because some stroke survivors may be considered 
vulnerable due to cognitive impairments, we will ask a series of comprehension questions after reviewing the 
informed consent form that participants must answer correctly to be enrolled, as in our previous studies.
F.4. Recruitment Sources and Plans
As in previous studies, recruitment will utilize a multimodal approach, including: 1) Continuous outreach to 
regional therapists and physicians; 2) Outreach to stroke support groups; 3) Advertisements in newspapers, 
magazines, social media, physician offices and therapy clinics; 4) Existing databases of local stroke survivors 
interested in participating in research; 5) Screening medical records for potentially eligible participants. This 
initial identification of potential participants via medical records will only be used by UC or KUMC study staff. 
UD study staff will not recruit using medical records. 
Clinician referrals can be done in two ways: 1) the clinicians may provide the study team contact information to 
the potential participant; 2) if the potential participant verbally approves, the clinician can give the study team 
their name and contact information. Screening medical records for potentially eligible participants (by UC or 
KUMC study staff) will involve searching for cases of stroke and assessing other eligibility criteria in the 
Table 3. Eligibility Criteria
Inclusion Criteria
Exclusion Criteria
1) Age 40-80 years
2) Single stroke for which participant 
sought treatment experienced 6 
months to 5 years prior to study entry
3) Walking speed <1.0 m/s on the 10 
meter walk test21,57 
4) Able to walk 10m over ground with 
assistive devices as needed and no 
continuous physical assistance from 
another person (guarding and 
intermittent assistance for loss of 
balance allowed)33 
5) Able to walk 3 minutes on the 
treadmill at ≥0.13m/s (0.3 mph) 
(treadmill screening test)142,144
6) Stable cardiovascular condition (AHA 
class B,142 allowing for aerobic 
capacity <6 METs)
7) Able to communicate with 
investigators, follow a 2-step 
command and correctly answer 
consent comprehension questions
1) Exercise testing uninterpretable for ischemia or arrhythmia (e.g. resting ECG 
abnormality that makes an exercise ECG uninterpretable for ischemia or arrythmia,142 
and no other recent (within the past year) clinical testing available to rule out these 
conditions) 
2) Evidence of significant arrhythmia or myocardial ischemia on treadmill ECG graded 
exercise test142 in the absence of recent (within the past year) more definitive clinical 
testing (e.g. stress nuclear imaging) with a negative result.
3) Hospitalization for cardiac or pulmonary disease within past 3 months
4) Implanted pacemaker or defibrillator
5) Significant ataxia or neglect (score of 2 on NIH stroke scale item 7 or 11)145 
6) Severe lower limb spasticity (Ashworth >2)146 
7) Recent history (<3 months) of illicit drug or alcohol abuse or significant mental illness
8) Major post-stroke depression (Patient Health Questionnaire [PHQ-9] ≥ 10147)  in the 
absence of depression management by a health care provider
9) Currently participating in physical therapy or another interventional study
10) Recent botulinum toxin injection to the paretic lower limb (<3 months) or planning to 
have botulinum toxin injections
11) Foot drop or lower limb joint instability without adequate stabilizing device, as 
assessed by a study staff physical therapist
12)  Clinically significant neurologic disorder other than stroke or unable to walk outside 
the home prior to stroke 
13) Other significant  medical condition that would limit improvement or jeopardize safety 
(e.g. joint contracture, gait limited by pain), as assessed by a study staff physical 
therapist
14) Pregnancy
15) Previous exposure to fast treadmill walking (>3 cumulative hours) during clinical or 
research therapy in the past year

v.5, 16Mar2021
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electronic medical records system and databases of local hospitals and clinics, as in our previous UC IRB 
approved studies (e.g. 2013-7676, 2016-1916). We are requesting a HIPAA waiver for this purpose, as in our 
previous studies. For any potential participants who are identified solely by medical record review, we will only 
initiate a call to the participant if they have had a clinical encounter with one of the study investigators. 
Otherwise, we will initiate contact by mailing the participant an IRB approved flier (with the envelope addressed 
to “Current Resident”) or by emailing an IRB approved flier to the email address(es) listed in their medical 
records (with the email address blind carbon copied). 
For persons interested in participating, we will further explain the study, confirm initial eligibility and perform 
informed consent. After a research staff member explains the purpose of study and the consent, potential 
participants will be given the option to wait at least 24 hours to decide if they want to participate. During this 
consenting process, the potential participant will be provided a copy of the consent form. Standardized 
questions will be asked to ensure that the potential participant understands the study before consenting. 
HIPAA authorization will also be obtained as part of the consent process.  Incorporated into the consent 
document is the option to agree to or refuse to participate in video recording or photographs of research 
activities that may be used for educational or training purposes apart from the collection of research data.
G. RISK/BENEFIT ASSESSMENT
G.1. Potential Risks
As with any exercise, there is risk of discomfort, soreness and fatigue associated with participation as well as a 
very low risk of musculoskeletal injury, skin abrasion and cardiovascular events.142 There is also very low 
potential risk of falling during clinical outcome testing and training. There may also be a risk of faintness, 
especially if the participant is dehydrated or does not eat on the day of exercise. Finger stick blood sampling 
for lactate measurement may cause a small amount of pain. Mild bruising or scarring is possible, but atypical. 
The risk of local infection is very low.
These risks will be minimized by: 1) recruiting a study sample with stable cardiovascular condition and normal 
cardiovascular responses to an exercise test (among other criteria);6 2) using a screening and exercise testing 
protocol with a strong safety track record across >500 recorded exercise tests and well over 15,000 recorded 
treadmill aerobic exercise sessions among persons with stroke;33,144 3) using HIT protocols that were 
developed and optimized by our research team in previous studies9,12 and in collaboration with a cardiologist. 
These protocols were also based on previous HIT studies among persons with heart disease that 
demonstrated no serious adverse events in well over 30,000 recorded exercise hours;10 4) securing 
participants during all treadmill walking using a harness connected to an overhead support system for safety in 
case of loss of balance; 5) using appropriate guarding during overground walking and balance testing, which 
will be performed by physical therapists and physical therapist assistants; 6) instructing participants to stay 
hydrated and to eat within 3 hours prior to arriving for each exercise testing or training session; 7) providing 
water or a snack if the participant reports insufficient intake; 8) asking participants with insulin-dependent 
diabetes to take a blood glucose reading prior to exercise using their own testing supplies, providing a snack if 
blood glucose is low, and postponing study activities if blood glucose remains out of range (generally <95 or 
>250 mg/dL); and 9) ensuring that personnel performing finger stick blood sampling for lactate testing are 
trained in antiseptic technique and only collect the minimal needed amount of blood (approximately one drop).
We have completed 4 IRB-approved studies to date involving similar or identical screening, testing and training 
procedures, involving a total of over 50 participants. These studies have included extensive monitoring for 
adverse events (AEs), including participant interviews before and after each session and continuous 
observation of participants and electrocardiograms throughout each session. No serious AEs related to 
locomotor HIT have occurred. Normal exercise-related soreness and fatigue are the most commonly reported 
AEs, especially after the initial training sessions. These symptoms do not typically interfere with normal 
functioning or last longer than a day. In our pilot RCT, AE rates were similar between HIT and MAT (Table 7).9 

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Table 7. Adverse Events (AEs) in Pilot RCT
Data reported as no. of participants with AE (total no. of AEs) [AE incidence rate per 100 sessions]
HIT 
(n=13, sessions=141)
MAT 
(n=5, sessions=60)
HIT/MAT AE odds 
ratio (95% CI)
Any AE
9 (21) [14.9]
4 (8) [13.3]
1.14 (0.47-2.73)
Related to intervention
6 (13) [9.2]
1 (4) [6.7]
1.42 (0.44-4.55)
  -Grade 1 (mild)
5 (10) [7.1]
1 (3) [5.0]
1.45 (0.38-5.47)
  -Grade 2 (moderate)
2 (3) [2.1]
1 (1) [1.7]
1.28 (0.13-12.59)
  -Grade 3-5 (severe-death)
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Cardiac disorder
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Joint/muscle pain
5 (8) [5.7]
1 (4) [6.7]
0.84 (0.24-2.91)
  -Fatigue
3 (3) [2.1]
0 (0) [0.0]
3.03 (0.15-59.56)*
  -Nausea
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Lightheadedness
1 (2) [1.4]
0 (0) [0.0]
2.15 (0.10-45.43)*
  -Other nervous system
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Fall
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Other injury
0 (0) [0.0]
0 (0) [0.0]
N/A
Unrelated to intervention
6 (8) [5.7]
3 (4) [6.7]
0.84 (0.24-2.91)
  -Grade 1 (mild)
5 (7) [5.0]
2 (2) [3.3]
1.51 (0.31-7.51)
  -Grade 2 (moderate)
1 (1) [0.7]
2 (2) [3.3]
0.21 (0.02-2.33)
  -Grade 3-5 (severe-death)
0 (0) [0.0]
0 (0) [0.0]
N/A
-Atrial fibrillation
1 (2) [1.4]
0 (0) [0.0]
2.15 (0.10-45.43)*
  -Other cardiac disorder
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Joint/muscle pain
2 (2) [1.4]
1 (2) [3.3]
0.42 (0.06-3.03)
  -Fatigue
1 (1) [0.7]
0 (0) [0.0]
1.28 (0.05-31.86)*
  -Nausea
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Lightheadedness
1 (1) [0.7]
0 (0) [0.0]
1.28 (0.05-31.86)*
  -Other nervous system
0 (0) [0.0]
0 (0) [0.0]
N/A
  -Fall
1 (1) [0.7]
2 (2) [3.3]
0.21 (0.02-2.33)
  -Other injury
1 (1) [0.7]
0 (0) [0.0]
1.28 (0.05-31.86)*
AE odds ratios are from logistic regression modeling of no. of AEs / no. of sessions per participant. CI, 
confidence interval. *Continuity corrected by adding 0.5 AEs to each group so that AE odds ratios could be 
calculated. HIT, high-intensity interval training; MAT, moderate-intensity aerobic training 
Emergency Response Planning. Although we expect that the study will be safe, we are also well prepared for 
any unlikely events. AEs will be promptly reported to the IRB and DSMB (see Data and Safety Monitoring Plan 
above) and referrals for follow up care will be made according to the severity and type of event. Should an 
emergency medical situation occur during study activities, emergency medical care would be provided and the 
participant would be transported to the nearest emergency room.
G.2. Potential Benefits
All eligible participants will receive graded exercise testing, clinical testing and up to 36 locomotor training 
sessions at no cost. Both training protocols being used in this study have some evidence of efficacy for 
improving walking speed, walking capacity, the metabolic cost of walking and aerobic capacity. While these 
benefits are not guaranteed for individual participants, we believe that the potential benefits outweigh the 
potential risks, especially since these outcomes have been previously associated with increased quality of life 
in this population. Our qualitative experience also indicates that persons with stroke generally find the risks to 
be acceptable and the results to be beneficial. In the case of abnormal findings on graded exercise tests, it is 
also possible that these tests could result in early detection of cardiovascular conditions.
Importance of the Knowledge to be Gained

v.5, 16Mar2021
19
This study will provide fundamental new knowledge to inform selection of intensity and duration dosing 
parameters for aerobic training and gait recovery interventions post-stroke. At the same time, this study will 
provide all remaining needed data to justify and design a subsequent definitive trial to determine the relative 
efficacy of HIT and MAT for eliciting clinically meaningful and sustained improvements in walking function. 
Therefore, the proposed study is significant because it is expected to constitute a critical step in a continuum of 
research that will lead to the clinical implementation of novel training strategies to synergistically and potently 
address both gait impairment and aerobic deconditioning post-stroke. This would likely have a major impact on 
the massive112 disability and financial burden of stroke, because, unlike the currently recommended protocol 
for addressing these outcomes (MAT),33,46,50-52,60-62 HIT appears to provide significant benefits with a training 
duration that fits well within current clinical practice models.66,67,113 By elucidating the relative time course of 
changes in different outcomes, the data from this study will also inform future mechanistic and biomarker 
investigations in our team member’s areas of expertise, including brain connectivity, neurophysiology, 
molecular genetics and vascular function. In addition, the de-identified data will be made publicly available after 
study completion to support further exploration and meta-analysis. We believe that the minimized risks to 
participants are reasonable based on the potential positive implications of this project.
G.2. Alternatives to Participation
This study will recruit participants with chronic stroke discharged from all forms of therapy. Therefore, the 
alternative to study participation is not to participate.
H. PAYMENT
Participants will be paid $75 at each outcome testing visit (PRE, 4WK, 8WK, 12WK; up to $300 total). 
I. SUBJECT COSTS 
All study testing and treatment will be provided at no cost. Parking will also be provided at no cost. 
J. CONSENT FORM 
See separate documents

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K. MOCK STUDY PARTICIPANTS FOR PERSONNEL TRAINING
Each site has over 8 years of experience in successfully completing stroke rehabilitation research.135,139,140 As 
in previous studies, personnel will be trained for study roles using lecture, audiovisual supports, demonstration 
and/or experiential learning with hands-on practice. For demonstration, hands-on practice and creating 
audiovisual supports, persons with and without stroke will be recruited at each site and asked to play the role 
of mock study participant to assist with personnel training. These mock participants will be asked to perform 
one or more of the study activities described in this protocol on one or more visits. Prior to performing these 
activities, mock participants will also be asked to:

Provide written informed consent and HIPAA authorization following procedures outlined above, using 
a separate consent form specifically designed for mock participants

Provide demographic information for IRB continuing review

Undergo any study screening procedures described above that are needed for the safety of the activity 
being performed
o
Prior to any maximal effort exercise testing, mock participants will have the following screening:

Medical history

Gait observation

Treadmill acclimation
o
Prior to any exercise training, mock participants will have the following screening:

Medical history

Gait observation

Treadmill acclimation

Exercise stress test with electrocardiographic monitoring. This requirement will be 
waived if the mock participant: 

Has had a similar or more definitive test (e.g. pharmacologic stress, nuclear 
imaging) done within the past 3 years with negative results, OR

Is classified as “Low-Risk” for vigorous exercise according to American College 
of Sports Medicine (ACSM) criteria:142
o
Apparently healthy men <45 years old and women <55 years old, with no 
known cardiovascular, pulmonary or metabolic disease who are 
asymptomatic and have <2 cardiovascular risk factors
o
Persons with cerebrovascular disease are not considered low-risk 
o
Cardiovascular risk factors include:

Smoker, or quit smoking in past 6 months

Blood pressure >140/90 or take blood pressure medication

Blood cholesterol >200 mg/dL or LDL >130 mg/dL

Pre-diabetes or fasting blood glucose 
100 mg/dL 
≥

Family history of heart attack or heart surgery before age 55 
(father or brother) or age 65 (mother or sister)

Body mass index >30

Physically inactive (<30 minutes moderate-intensity exercise, 
3d/wk)
Other areas where the protocol differs for mock participants are described below.
Sample Size
Up to 10 mock participants will be enrolled in this study at each site (up to 30 total).
Eligibility Criteria
Mock participants will be screened with the same eligibility criteria as actual study participants, with the 
following exceptions: 1) mock participants may or may not have had a stroke; 2) mock participant age range 
will be 18-80 years; and 3) some eligibility criteria may not be assessed if they are not relevant to the safety of 
the activity to be performed.

v.5, 16Mar2021
21
Data Storage and Confidentiality
Mock participant data and confidentiality will be maintained using the same procedures used for actual study 
participants, except that mock participant data will be kept separate from actual study data (e.g. separate 
REDCap database for personnel training) and will not be used for any purpose other than personnel training 
and education.
Setting
Setting will be the same for mock and actual participants, except that exercise testing for mock participants at 
UC and KUMC may be done in a rehabilitation research laboratory rather than a cardiac stress laboratory if the 
mock participant meets the ACSM Low-Risk criteria or has had a negative cardiac stress test within the past 3 
years. 
Estimated Period of Time to Complete the Study
Mock participants will be involved in the study for just one visit or up to 5 months. If the same mock participant 
is willing to participate again after 5 months have passed, we would redo the consent process at that time.
Payment
Mock participants will not be paid for participation.

v.5, 16Mar2021
22
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