Group Title: BMC Neurology
Title: Protocol for the Locomotor Experience Applied Post-stroke (LEAPS) trial: a randomized controlled trial
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 Material Information
Title: Protocol for the Locomotor Experience Applied Post-stroke (LEAPS) trial: a randomized controlled trial
Physical Description: Book
Language: English
Creator: Duncan, Pamela
Sullivan, Katherine
Behrman, Andrea
Azen, Stanley
Wu, Samuel
Nadeau, Stephen
Dobkin, Bruce
Rose, Dorian
Tilson, Julie
The LEAPS Investigative Team
Publisher: BMC Neurology
Publication Date: 2007
 Notes
Abstract: BACKGROUND:Locomotor training using body weight support and a treadmill as a therapeutic modality for rehabilitation of walking post-stroke is being rapidly adopted into clinical practice. There is an urgent need for a well-designed trial to determine the effectiveness of this intervention.The objective of the Locomotor Experience Applied Post-Stroke (LEAPS) trial is to determine if there is a difference in the proportion of participants who recover walking ability at one year post-stroke when randomized to a specialized locomotor training program (LTP), conducted at 2- or 6-months post-stroke, or those randomized to a home based non-specific, low intensity exercise intervention (HEP) provided 2 months post-stroke. We will determine if the timing of LTP delivery affects gait speed at 1 year and whether initial impairment severity interacts with the timing of LTP. The effect of number of treatment sessions will be determined by changes in gait speed taken pre-treatment and post-12, -24, and -36 sessions.METHODS/DESIGN:We will recruit 400 adults with moderate or severe walking limitations within 30 days of stroke onset. At two months post stroke, participants are stratified by locomotor impairment severity as determined by overground walking speed and randomly assigned to one of three groups: (a) LTP-Early; (b) LTP-Late or (c) Home Exercise Program -Early. The LTP program includes body weight support on a treadmill and overground training. The LTP and HEP interventions are delivered for 36 sessions over 12 weeks.Primary outcome measure include successful walking recovery defined as the achievement of a 0.4 m/s gait speed or greater by persons with initial severe gait impairment or the achievement of a 0.8 m/s gait speed or greater by persons with initial moderate gait impairment.LEAPS is powered to detect a 20% difference in the proportion of participants achieving successful locomotor recovery between the LTP groups and the HEP group, and a 0.1 m/s mean difference in gait speed change between the two LTP groups.DISCUSSION:The goal of this single-blinded, phase III randomized clinical trial is to provide evidence to guide post-stroke walking recovery programs.TRIAL REGISTRATION:NCT00243919.
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Study protocol


Protocol for the Locomotor Experience Applied Post-stroke
(LEAPS) trial: a randomized controlled trial
Pamela W Duncan*1,2,3, Katherine J Sullivan4, Andrea L Behrman5,6,
Stanley P Azen7, Samuel S Wu8, Stephen E Nadeau6,9, Bruce H Dobkin'0,
Dorian K Rose", Julie K Tilson4 for The LEAPS Investigative Team


Address: 'Division of Doctor of Physical Therapy, Department of Community and Family Medicine, Duke University, Durham, North Carolina,
USA, 2Center for Clinical Health Policy Research, Duke University, Durham, North Carolina, USA, 3Center for Aging, Duke University, Durham,
North Carolina, USA, 4Department of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, California, USA,
5Department of Physical Therapy, Brooks Center for Rehabilitation Studies, University of Florida, Gainesville, Florida, USA, 6Department of
Veteran Affairs Brain Rehabilitation Research Center, Gainesville, Florida, USA, 7Biostatistics Division, Department of Preventive Medicine,
University of Southern California, Los Angeles, California, USA, 8Department of Epidemiology and Health Policy Research, University of Florida,
Florida, USA, 9Geriatric Research, Education and Clinical Center, Malcom Randall VA Medical Center, Gainesville, Florida, USA, lODepartment of
Neurology, University of California, Los Angeles, California, USA and 11Department of Aging and Geriatric Research, University of Florida,
Gainesville, Florida, USA
Email: PamelaW Duncan* Pamela.Duncan@Duke.edu; Katherine J Sullivan kasulliv@usc.edu;
Andrea L Behrman abehrman@phhp.ufl.edu; Stanley P Azen sazen@usc.edu; Samuel S Wu samwu@biostat.ufl.edu;
Stephen E Nadeau snadeau@ufl.edu; Bruce H Dobkin bdobkin@mednet.ucla.edu; Dorian K Rose drose@aging.ufl.edu;
Julie K Tilson tilson@usc.edu
* Corresponding author



Published: 8 November 2007 Received: 25 June 2007
BMC Neurology 2007, 7:39 doi: 10.1186/1471-2377-7-39 Accepted: 8 November 2007
This article is available from: http://www.biomedcentral.com/1471-2377/7/39
2007 Duncan et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Background: Locomotor training using body weight support and a treadmill as a therapeutic
modality for rehabilitation of walking post-stroke is being rapidly adopted into clinical practice.
There is an urgent need for a well-designed trial to determine the effectiveness of this intervention.
The objective of the Locomotor Experience Applied Post-Stroke (LEAPS) trial is to determine if
there is a difference in the proportion of participants who recover walking ability at one year post-
stroke when randomized to a specialized locomotor training program (LTP), conducted at 2- or 6-
months post-stroke, or those randomized to a home based non-specific, low intensity exercise
intervention (HEP) provided 2 months post-stroke. We will determine if the timing of LTP delivery
affects gait speed at I year and whether initial impairment severity interacts with the timing of LTP.
The effect of number of treatment sessions will be determined by changes in gait speed taken pre-
treatment and post-I 12, -24, and -36 sessions.
Methods/Design: We will recruit 400 adults with moderate or severe walking limitations within
30 days of stroke onset. At two months post stroke, participants are stratified by locomotor
impairment severity as determined by overground walking speed and randomly assigned to one of
three groups: (a) LTP-Early; (b) LTP-Late or (c) Home Exercise Program -Early. The LTP program
includes body weight support on a treadmill and overground training. The LTP and HEP
interventions are delivered for 36 sessions over 12 weeks.




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Primary outcome measure include successful walking recovery defined as the achievement of a 0.4
m/s gait speed or greater by persons with initial severe gait impairment or the achievement of a 0.8
m/s gait speed or greater by persons with initial moderate gait impairment.
LEAPS is powered to detect a 20% difference in the proportion of participants achieving successful
locomotor recovery between the LTP groups and the HEP group, and a 0.1 m/s mean difference in
gait speed change between the two LTP groups.
Discussion: The goal of this single-blinded, phase III randomized clinical trial is to provide evidence
to guide post-stroke walking recovery programs.
Trial registration: NCT00243919.


Background
Of the 730,000 individuals who will survive a stroke each
year, 73% will have residual disability [1]. Locomotor
ability is an important factor in determining the degree of
physical disability after stroke [2]. The impact of stroke on
walking is significant, with only 37% of stroke survivors
able to walk after the first week post-stroke [3-5]. Sixty to
eighty percent of individuals who achieve independent
ambulation, walk at speeds less than 0.8 m/s, which is
insufficient to function effectively in the community [6].
Significant residual deficits in balance persist with a 73%
incidence of falls among individuals with mild to moder-
ate impairment 6 months post-stroke [7,8]. Walking and
balance deficits contribute substantially to long-term dis-
ability post-stroke. In the Northern Manhattan Stroke
Study, over 40% of individuals with stroke living at home
required assistance with walking at 6 months. Among the
60% of individuals considered independent walkers by
ADL indices, significant disability due to limitations in
community ambulation skills persisted [9]. Ambulatory
stroke patients experience a 4-fold increase in falls risk,
and among those who fall, a 10-fold increase in hip
fracture [10].

A body weight support system and treadmill (BWST) is
one therapeutic modality for locomotor training that is
rapidly being adopted into physical rehabilitation to
improve walking after stroke. There are 20 clinical studies
that have examined the efficacy of this treatment
approach [11,12]. The most recently published trials of
walking programs that included treadmill training in
acute [13] and chronic [13-15] stroke patients reported
improved gait speed compared to individuals who partic-
ipated in non-specific low intensity exercise programs.
However, the conclusions of the Cochrane systematic
review and meta-analyses report that there is "not enough
evidence from trials to determine the effect of treadmill
training with or without body weight support for walking
after stroke [16]."

Of 20 trials of treadmill training, only 14 are RCTs and 8
of the 14 trials had 30 or fewer participants and the


maximum number of participants was 100. These trials
vary substantially in training intensity (i.e., walking time,
treadmill speed, and percent of weight support), fre-
quency of training sessions per week, total number of ses-
sions, timing of training (acute, subacute or chronic), and
locomotor impairment severity (non-ambulators to com-
munity ambulators). Due to the differences between exist-
ing studies, there is lack of evidence concerning (1) when
this intervention is most effective post-stroke (e.g. acute,
subacute, chronic), (2) the effect of locomotor impair-
ment severity on achieving clinically significant outcomes
and, (3) the optimal duration for the locomotor training
intervention. The studies have also failed to consistently
evaluate parameters of training, such as speed. Yet, recent
studies have consistently shown that treadmill training
(with or without BWS) at higher speeds (i.e., higher inten-
sity) is more effective at improving walking after stroke
than training at slower speeds [17-19]. Given the current
heterogeneity in study protocols and the inconclusive
results of systematic analysis of the trials, the Cochrane
review states that there is an "urgent need for well-
designed large-scale studies to evaluate the effects of tread-
mill training and body weight support on walking after
stroke [ 11]."

The Locomotor Experience Applied Post-Stroke (LEAPS)
trial is a 5-year, phase-III, single-blind, 5-site, randomized
controlled trial (RCT) to determine if there is a difference
between treatment groups in the proportion of partici-
pants who at one year post-stoke successfully recover
walking ability, as defined by gait speed. The intervention
groups under study are: (1) a specialized locomotor
training program (LTP) that includes use of body weight
support and a treadmill as a rehabilitation modality pro-
vided 2 months post-stroke (LTP-early), or (2) 6 months
post-stroke (LTP-late), and (3) a non-specific, low inten-
sity home-based exercise (HEP) intervention provided
2 months post-stroke.

The study is designed as a definitive RCT with the primary
outcome being successful recovery of walking. Successful
recovery of walking is defined as having achieved a


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0.4 m/s gait speed or greater for persons with initial
severe gait impairment (< 0.4 m/s), or as having achieved
a 0.8 m/s gait speed or greater for persons with initial
moderate gait impairment (> 0.4 m/s < 0.8 m/s). Aclin-
ically significant difference will be defined as a greater
than 20% difference in the proportion of participants
who achieve successful recovery.

We hypothesize that both the LTP-early and LTP-late
groups will have more success than the home exercise
group. We will also determine if the timing of LTP delivery
(early vs. late) affects the improvement in gait speed at 1
year and whether initial locomotor impairment severity
interacts with the timing of LTP delivery. We anticipate
that earlier intervention will be more efficacious because
it is conducted at a time when the endogenous neuroplas-
tic processes that follow stroke are more active [20]. How-
ever, we also suspect that there will be a timing by severity
interaction effect: participants with modest deficits may
be able to take full advantage of the neuroplastic effect
and thereby benefit more from early LTP, whereas partici-
pants with more severe deficits may have to experience
more extended spontaneous recovery to be able to take
full advantage of the LTP, thereby benefiting more from
late LTP. The LTP and HEP interventions are delivered for
36 sessions over 12 weeks to 16 weeks. The effect of
number of treatment sessions will be determined by
changes in gait speed measured pre-treatment, post-12,
post-24, and post-36 sessions. We anticipate that more
treatments will yield greater benefit, but that there may be
a severity interaction effect here also: participants with
milder deficits may be more likely to asymptotically
approach maximum therapeutic benefit in less than 36
sessions, whereas participants with more severe deficits,
by virtue of a slower rate of improvement, may continue
to improve throughout the entire 36-session course.

Methods/Design
All procedures conducted during this trial with human
participants were carried out in compliance with federal
and institutional ethical standards and in compliance
with the Helsinki Declaration. All research procedures
were approved by an Institutional Review Board at each
participating site: Duke University Health System Institu-
tional Review Board (protocol #9500-07-3RO), Univer-
sity of Florida Health Science Center Institutional Review
Board (protocol #262-2005), University of Southern Cal-
ifornia Health Sciences Campus Institutional Review
Board (protocol # HS-05-00365), Brooks Center for Reha-
bilitation Studies approved by the University of Florida
Health Science Center Institutional Review Board (proto-
col #262-2005), Centinela Freeman Regional Medical
Center approved by Western Institutional Review Board
(study # 1077658), Florida Hospital Institutional Review
Board (protocol # 2005.09.11), Long Beach Memorial


Hospital Memorial Health Service Research Council (pro-
tocol #286-05) and Sharp Rehabilitation Center Sharp
HealthCare Institutional Review Board (protocol
#050896).

Type of Design
This is a three arm, single blinded, phase III randomized
controlled trial of a locomotor training program provided
at 2 months post-stroke or 6 months post-stroke versus a
home exercise program provided at 2 months post-stroke.
Participants are randomized to the three intervention
groups at 2 months post-stroke. The primary outcome is
the proportion of participants who successfully recover
walking one year post-stroke. The sequence from screen-
ing, enrollment and to randomization is represented in
Figure 1.

Study Enrollment
Individuals post- stroke over the age of 18 are recruited 5-
30 days post-stroke from five clinical sites. The five clinical
intervention sites: Brooks Rehabilitation Hospital in Jack-
sonville, Florida; Centinela Freeman Regional Medical
Center in Inglewood, California; Florida Hospital in
Orlando, Florida; Long Beach Memorial Hospital in Long
Beach, California and Sharp Rehabilitation Center in San
Diego, California. Each site is expected to recruit approxi-
mately 80 participants.

Accessing and Collecting Personal Health Information
A two part process for accessing and collecting personal
health information ensures protection of potential partic-
ipants' rights under the Health Information Portability
and Accountability Act (HIPAA). First, each site obtains a
HIPAA Waiver from the site's Institutional Review Board
or the Health Information Safety Committee. The HIPAA
Wavier allows a cursory screening of patient's chart to
identify criteria that are exclusionary: diagnosis, age, med-
ical comorbidities, life expectancy and distance of dis-
charge residence from clinical site. No personal health
information is recorded at this stage. Second, if this cur-
sory chart screen is passed, potential participants are
approached by a site research team member to explain the
study and to request a HIPAA authorization. This HIPAA
authorization permits study staff to fully review the
patient's chart to determine study eligibility and to collect
and record personal health information. In the event that
a potential participant declines at this point, no identifia-
ble information is kept on that participant. However, we
do report the reasons for exclusion as either (1) did not
meet primary diagnosis of stroke; (2) did not meet age cri-
teria (3) had other major medical comorbidity, (4) life
expectancy less than one year, (5) plan to be discharged
greater than 50 miles from intervention site, or 6) declines
participation.



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5 LEAPS
SSites with
Approved
\ HIPAA
Waiver
Admission to Inpatient
Rehabilitation

Cursory ScreE
for Eligibility

IrHIPAA Authorization for
researchers to collect I-- /
medical information -


Figure I
Sequence of participant screening, enrollment and
randomization.


Informed Consent
Informed consent for study participation and enrollment
occurs in two phases: (1) a screening informed consent to


participate in a physical screen to determine study eligibil-
ity is obtained after the HIPAA authorized chart review
and (2) an intervention informed consent is obtained at 8
weeks post-stroke that provides consent for an exercise
tolerance test, baseline and follow-up assessments, and
intervention. Participants are informed that successful
completion of the exercise tolerance test is required prior
to randomization to an intervention group.

Screening Process
Table 1 summarizes the consent, screening processes, and
assessments that are conducted at 5-30 days, 6-8 weeks,
and at 2 months post-stroke, prior to randomization.

The purpose of the 5-30 day screening phase is to deter-
mine if the individual post-stroke is willing to participate in
the LEAPS trial and meets preliminary inclusion and exclu-
sion criteria for study participation. If the participant volun-
tarily provides informed consent and successfully
completes all 5-30 day physical and cognitive screens, the
participant's treating physician is asked to review the LEAPS
inclusion and exclusion criteria and provide a letter of sup-
port for inclusion in the study. At 6 weeks post-stroke, a
phone contact is made by a study team member to confirm
interest and to determine continued eligibility. The partici-
pant or a proxy family member is asked about the partici-
pant's current health status, recent hospitalizations,
changes in residential status (i.e., moved to a nursing
home) and whether or not they wish to continue in the
trial. Specific questions are asked regarding possible cardiac
conditions, recurrent stroke, possible fractures and new
medical events that may limit activities of daily living. At 8
weeks post-stroke, the participant returns to the study site
to confirm that gait speed is < 0.8 m/s, provide the phase 2
informed consent, and complete the exercise tolerance test.
The exercise tolerance test, the baseline assessments, and
the analysis of the most recent available CT or MRI scan are
completed prior to randomization. The CT or MRI scan is
reviewed by one of the study's consulting neurologists.

When the participant is a non-English speaker, an inter-
preter, either a family member, friend, or professional
who can communicate with the participant, is available
during screening, assessment and intervention sessions

Inclusion and Exclusion Criteria
Stroke Diagnosis
Participants are individuals with recent onset of ischemic
or hemorrhagic stroke. For purposes of inclusion in this
study, a stroke is defined according to the World Health
Organization definition as, "a rapid onset event of vascu-
lar origin reflecting a focal disturbance of cerebral func-
tion, excluding isolated impairments of higher function
and persisting longer than 24 hours [21]." Stroke diagno-
sis is confirmed by CT or MRI scan or, if scan is not avail-
able, by clinical criteria.

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Inclusion Criteria
Inclusion criteria for the trial include (1) age > 18, (2)
stroke within 30 days, (3) residual paresis in the lower
extremity (Fugl-Meyer lower extremity score < 34), (4)
ability to sit unsupported for 30 seconds, (5) ability to
walk at least 10 feet with maximum 1 person assist, (6)
ability to follow a three-step command, (7) physician
approval for patient participation, (8) provision of
informed consent, (9) self-selected 10 meter gait speed
less than 0.8 m/s at the 2 month assessment, (10) success-
ful completion of the bicycle ergometer exercise tolerance
test at the 2 month assessment (see below) and, (11) liv-
ing in the community at 2 months post-stroke or if they
are living in a nursing home they are expected to be dis-
charged to home and will be able to travel to the interven-
tion site to participate in the LTP program or will be able
to receive the HEP program in the nursing home facility.

Exclusion Criteria
Exclusion criteria for participation in this study include:
(1) Lived in nursing home prior to stroke, (2) Unable to
ambulate at least 150 feet prior to stroke, or intermittent
claudication while walking less than 200 meters, and (3)
Serious cardiac conditions (hospitalization for myocar-
dial infarction or heart surgery within 3 months, history of
congestive heart failure, documented serious and unstable
cardiac arrhythmias, hypertrophic cardiomyopathy,
severe aortic stenosis, angina or dyspnea at rest or during
activities of daily living). Anyone meeting New York Heart
Association criteria for Class 3 or Class 4 heart disease is
excluded. Those who have undergone coronary artery
bypass grafts (CABG) or have had mitral valve replace-
ments within the last 3 months are excluded if their par-
ticipation is not approved by 2 physicians. One of the
physicians making the determination must be a cardiot-
horacic surgeon and the other must be either a cardiolo-
gist or the participant's primary care physician.

Additional exclusion criteria include: (4) History of seri-
ous chronic obstructive pulmonary disease or oxygen
dependence, (5) Severe weight bearing pain, (6) Preexist-
ing neurological disorders such as Parkinson's disease,
Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis
(MS), dementia, or previous stroke with residual motor
deficits, (7) History of major head trauma, (8) Lower
extremity amputation, (9) Non-healing ulcers of a lower
extremity, (10) Renal dialysis or end stage liver disease,
(11) Legal blindness or severe visual impairment, (12) A
history of significant psychiatric illness defined by diagno-
sis of bipolar affective disorder, psychosis, schizophrenia
or medication refractory depression, (13) Life expectancy
less than one year, (14) Severe arthritis or orthopedic
problems that limit passive ranges of motion of lower
extremity (knee flexion contracture of > 100, knee flexion
ROM < 900, hip flexion contracture > 250, and ankle


plantar flexion contracture > 150, (15) History of sus-
tained alcoholism or drug abuse in the last six months,
and (16) major post-stroke depression as indicated by a
Patient Health Questionnaire (PHQ)-9 score of greater
than 10 in the absence of documented management of the
depression by a health care provider (either anti-depres-
sant medication or psychotherapy), (17) History of pul-
monary embolism within 6 months, (18) Uncontrollable
diabetes with recent weight loss, diabetic coma, or fre-
quent insulin reactions, (19) Severe hypertension with
systolic blood pressure greater than 200 mmHg and
diastolic blood pressure greater than 110 mmHg at rest,
that can not be medically controlled into the resting range
of 180/100 mmHg, (20) Previous or current enrollment
in a clinical trial to enhance stroke motor recovery, (21)
Residence more than 50 miles from the training sites, (22)
Inability to travel 3 times per week for outpatient training
programs; and (23) Intracranial hemorrhage related to
aneurysmal rupture or an arteriovenous malformation
(hemorrhagic infarctions will not be excluded).

Exercise Tolerance Test
The bicycle ergometry protocol used successfully in the
Kansas City Post-Acute Stroke Study[22] is used to assess
exercise tolerance in this trial. This exercise tolerance test
is conducted in cardiac stress test laboratories at the
respective sites. When sitting on the bicycle, the
participant's resting diastolic BP must be less than 100,
systolic BP less than 180, and heart rate less than 100 to
begin the testing session. The bicycle ergometry protocol
requires pedaling at 40-60 RPM with a workload increase
of 10 watts (from initial 0 watts) per minute. Testing con-
tinues until maximal effort is achieved. Maximal effort is
defined as achievement of 90% maximal predicted heart
rate (220-age). The test is terminated prior to achieving
90% maximum heart rate if the person experiences onset
of limiting symptoms or meets criteria for halting the test
due to blood pressure, oxygen desaturation or abnormal
electrocardiographic changes. Participants will be asked to
report their rate of perceived exertion, using the Borg
Scale, at 10 W increments. During the graded exercise test,
blood pressure readings are obtained every minute. Heart
rate is obtained from the 12-lead EKG. In patients who are
taking beta blockers the test is terminated if the partici-
pant reports a Borg score of greater than 18.

Assessments
Methods and Timing of Assessments
Measures selected have established reliability and validity
and are captured according to standardized protocols that
are defined in a manual of operations Per diem therapists
who are unaware of treatment assignment conduct 2
month baseline assessments and all follow-up
assessments.



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Table I: Timeline for Consent, Screening Processes and Assessments up to Randomization


Activity


Specific Tests and Procedures


5-30 days post-stroke


6 7 weeks post-stroke
8 weeks post-stroke


2 months post-stroke


HIPAA Waiver Screen


HIPAA Authorization

Chart Review

Screening Informed Consent

Participant/family interview



Physical and Cognitive
Screen















MD Approval


6-Week Phone Contact
Gait Velocity Re-check
Intervention Informed Consent


Exercise Tolerance Test
Lesion Analysis

Baseline Assessment


Chart review for diagnosis, age, medical co-
morbidities, life expectancy, discharge distance
from clinical site
Patient grants permission for study staff to
complete a comprehensive chart review
Demographics collected, inclusion and
exclusion criteria reviewed
Study staff review screening procedures, risks
and benefits
Study staff determine:
* Pre-morbid functional status
* Enrollment in another clinical trial
* Ability to attend therapy 3x/week
Study staff complete tests:
* 3-Step Command
* Sitting Balance
* Ability to walk 10 feet
* 10 meter walk test (when able)
* Functional Ambulation Category
* Fugl-Meyer Motor and Sensory Tests
* PHQ-9 Depression Scale
* ROM of Lower Extremities
* Contracture Assessment of Lower
Extremities
* MMSE
* SF-36 Physical Function
* Pre-morbid Barthel Index
* Orpington Prognostic Scale
* Modified Rankin Index
Confirmation by treating physician that patient
meets inclusion/exclusion criteria and is safe
for the study
Interview confirms continued eligibility
10 meter walk test confirm velocity <.8 m/s
Study staff review exercise tolerance test and
intervention procedures, risks, and benefits
Cardiologist approves eligibility
Study neurologist reads MRI or CT to
characterize lesion
See Table 2 for assessment tests


Two month baseline assessments are conducted prior to
randomization. Participants are subsequently educated to
refrain from discussing assignment group during evalua-
tions. In addition, posters are placed in the evaluation
labs to remind patients not to reveal their group assign-
ment. To determine the effectiveness of our single blinded
assessments, we ask both the per diem therapist-evalua-
tors and the participants to complete a brief assessment to
determine if group assignment was revealed during evalu-
ations. All follow-up measures are performed at times and
places where training does not occur.

All participants undergo evaluation of primary and sec-
ondary outcome measures at baseline (2 months post-
stroke), 6 months and 12 months post-stroke. In addi-
tion, during the intervention phase assessments of gait


speed, walking endurance, and amount of daily walking
after 12, 24, and 36 training sessions are recorded. Table 2
provides a list of the measures and the timing of
assessments.

Measures
Primary Measure of Walking: Gait Speed
Gait speed at one year has been selected as the primary
outcome measure for this study and is measured during a
10-meter walk. Individuals are given a 3 meter warm-up
distance for walking, preceding the 10 meter distance and
3 meters beyond the 10 meters to continue walking. The
time that it takes to traverse the 10 meters at the partici-
pant's usual pace is recorded. Increasing walking speed is
critical for community ambulation and measures reserve
and adaptability [2] Gait speed is related to the severity of



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impairment in the home and the community. Perry et
al.[2] placed study participants into one of 6 functional
walking categories to relate social outcomes of patients
with gait impairments. The most significant difference
between groups was preferred walking speed, with mean
speeds ranging from < 0.4 m/s for household walkers, 0.4
- 0.8 m/s for limited community walkers, and > 0.8 m/s
for community walkers. Schmid, Duncan, Studenski et al.
recently demonstrated that transitioning from one ambu-
lation class to another was correlated with improvement
in physical functioning and quality of life [23]. They con-
cluded that outcomes assessments based on transitions
within a mobility classification scheme that is rooted in
gait velocity yields meaningful indicators of clinical bene-
fit. Additionally, in a geriatric population Studenski, Dun-
can et al. revealed that gait speed < 0.6 m/s is a strong
indicator of future health care utilization and functional
decline [24]. Excellent (ICCs > .97) interrater and intra-
rater reliability estimates for self-paced timed forward
walking using a stopwatch have been reported [17].

Secondary Measures of Walking
In addition to walking speed, the distance a person can
walk and the amount of daily walking that a person is able
and willing to do are strong indicators of his or her health
and condition [171. Thus, LEAPS also obtains a 6-minute
walk test and monitors community ambulation using a
step activity monitor. The six-minute walk is a measure
that was originally developed to assess cardiopulmonary
function [25,26], but it has been used extensively as an
endurance measure in the elderly and in individuals with
stroke [171. Participants perform the 6-minute walk using
a previously standardized protocol [17]. In this test, par-
ticipants are allowed 6 minutes to walk as far as they can
at their usual pace. During the 6-minute walk test, the par-
ticipants use their customary assistive devices and orthot-
ics. The distance they cover in 6 minutes is recorded.

To measure the amount of self-selected walking over an
extended period of time, LEAPS uses a Step Activity Mon-
itor (SAM). The device is safe, highly accurate, unobtru-
sive for the wearer, capable of continuously recording data
in short time increments, and capable of withstanding
daily home and community use [27]. The device has a
99% accuracy for recording steps with a variety of gait pat-
terns [27-29]. The device has also been successfully tested
in monitoring ambulatory activity in persons with mild to
moderate impairments post-stroke [30]. High test re-test
reliability (r = 0.81) has been demonstrated across three
separate 4-day weekday recording epochs conducted
within a 3-week period in persons with chronic stroke
[30]. A demonstration and written instructions are pro-
vided to participants in appropriate use of the device. Fol-
low-up phone calls by the therapists are made during the


4-day intervals to enhance compliance and respond to
any problems.

Functional Ambulation Classification
This functional ambulation classification system catego-
rizes participants according to basic skills necessary for
functional ambulation, without assessing the factor of
endurance. The screening therapist uses standardized def-
initions to classify the participant according to one of six
categories during the 6 minute walk. The participants are
rated at their most independent level of function with
regard to supervision or physical assistance needed from
another person [31].

Sensory and Motor Control
Fugl-Meyer Motor Assessment
The Fugl-Meyer sensory motor assessment is probably the
most widely known scale of motor and sensory recovery
after stroke [32,33]. It is used for both clinical and
research purposes. The Fugl-Meyer includes items of
upper and lower extremity function that require progres-
sively more complex movements, hand grasps, and meas-
ures of speed, coordination, light touch, and
proprioception. Each item is graded on a three-point scale
(0 cannot perform, 1 performs partially, and 2 performs
fully). Standardized protocols for administration are
followed [32].

Balance
Balance is measured by the Berg Balance Scale [34]. The
scale consists of 14 items that require participants to
maintain positions of varying difficulty and perform spe-
cific tasks such as rising from a chair and timed stepping.
Each item is graded 0 to 4. A standardized protocol for
administration is followed [34]. The Berg Balance Scale
has been tested in a stroke population and has well-
established reliability and validity [34].

Cognitive Measures
The Mini Mental Status Examination (MMSE) is used to
assess cognitive function [35-37]. The Digit Symbol -
Coding from the WAIS III [38] and Trail Making Test A
and B [39,40] are additional cognitive measures.

For Digit Symbol-Coding the participant copies symbols
that are paired with numbers. Using a key, the participant
draws each symbol under its corresponding number. The
participant's score is determined by the number of sym-
bols correctly drawn within the 120-second time limit.

The Trails A measure requires the patient to sequence
numbers in a specified manner under the pressure of a
time. Trails B requires the patient to alternate between two
sets of different information while under the pressures of
time.


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Table 2: Summary of baseline and follow-up assessments for all subjects at each time point


Assessment

10-meter Walk
(orthotic and
assistive device)
Functional
Ambulation
Category Level

6-minute Walk
Test
Step Activity
Monitor
Fugl-Meyer Motor
and Sensory
Berg Balance Scale
Anthropometric
Measurements
Trail Making Test
A and B
Digit Symbol -
WAIS
MMSE
ABC Confidence
Scale
Stroke Impact
Scale
SF-36 Physical
Function
Co-morbidity and
Functional Impact
Index
PHQ-9
Depression Scale
Medication
Information

Past
Hospitalization
Modified Rankin
Scale


Baseline 2
months

X


X


6 months

X


X


12 months

X


X


Post- 12
sessions*

X


X


Post-24
sessions*

X


X


Post-36
sessions*

X


X


* These assessments are completed between the baseline and 6 month assessment for LTP-Early and HEP participants and between the 6 month
and 12 months assessments for the LTP-Late group.


Balance Efficacy
The Activities-Specific Balance (ABC) Scale [41] is a self-
report measure and is used to assess perceived efficacy
(self-reported confidence) in maintaining balance while
performing a number of activities common in commu-
nity-dwelling older adults such as bending, reaching, and
walking both inside and outside the home. This measure
has good reliability and internal consistency [41].

Depression Screen
The Patient Health Questionnaire nine-item depression
scale (PHQ-9) is used to measure depression. The PHQ-9
is increasingly used in primary care and other medical
populations [42-44]. Its usefulness as a depression screen-


ing and diagnostic instrument has been recently estab-
lished for individuals with stroke [45]. The PHQ-9 is a
summed scale with scores ranging from 0 (no depressive
symptoms) to 27 (all symptoms occurring daily). Cutoff
points of 5, 10, 15, 20 represent the thresholds for mild,
moderate, moderately severe, and severe depression. A
PHQ-9 score of> 10 in individuals with stroke has 91%
sensitivity and 89% specificity for major depression [46].

Stroke Specific Disability Measure, the Stroke Impact Scale
The Stroke Impact Scale (SIS) is a comprehensive and psy-
chometrically robust stroke-specific outcome measure
[46-48]. The SIS was developed from the perspective of
patients, caregivers, and health professionals with stroke



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expertise [48]. In version 3.0, there are eight domains and
59 items. The domains are: strength, hand function, activ-
ities of daily living/instrumental activities of daily living,
mobility, communication, emotion, memory, and think-
ing, and social participation [49]. A comparison of the SIS
(physical and social functioning domains) and the Short
Form-36 (SF-36) has been completed [50]. The results of
the study indicated that the SIS is better at capturing phys-
ical functioning and social well-being in patients with
stroke then the SF-36 [51].

Other Measures
SF-36 Physical Function
The physical functioning portion of the SF-36 consists of
10 items and assesses the impact of a participant's health
on their physical functioning. Participants are asked to
answer the questions regarding activities that they might
do in a typical day and whether or not their health limits
these activities. This information is collected at baseline
assessment and at the 6-month and 12-month assess-
ments. During screening phase the physical functioning
portion of the SF-36 is administered in relation to the par-
ticipant's pre-morbid functioning at one month prior to
stroke onset. The measure is used during post-randomiza-
tion assessments to measure the participant's current
functioning.

Co-Morbidity and Functional Impact Scale
A disease and symptom co-morbidity index developed
and tested in a stroke population by Rigler, Studenski,
Wallace, Reker and Duncan to predict post-stroke func-
tion is administered at baseline [52].

Anthropometric Measures
Measures of height, weight and waist circumference are
taken. Height is a major indicator of general body size and
bone length. It is important in the interpretation of
weight. Weight is a composite measure of total body size.
Strictly, this measurement is of mass rather than weight,
but the latter term is well-established in the common
lexicon. Waist circumference is an index of deep adipose
tissue and is related to fat-free mass. These measures are
taken at baseline (2 months post-stroke) 6 month and
12 month post-stroke assessments.

Falls
All participants are asked to keep a falls diary. Each partic-
ipant is given a definition of falls and a supply of 30-day
calendars on which to keep a record of falls. Each partici-
pant is given a packet of self-addressed postcards to mail
if he or she experiences a fall. If a postcard is received, the
participant receives a structured phone call to obtain
information about the location and conditions of the fall
as well as about any injuries. These methods have been


utilized in previous studies by Studenski and Duncan
[53,54].

Usual Care Intervention Logs
The purpose of the Usual Care Intervention Log is to track
the amount of physical and occupational therapy LEAPS
participants receive during enrollment in the trial (2
months to 12-months post-stroke) from outside sources.
Participants are instructed to write in the time (in min-
utes) of occupational or physical therapy they receive out-
side of their participation in the LEAPS clinical trial on
monthly calendars provided for them. They turn in a
monthly calendar to the intervention therapist during the
intervention period indicating any additional physical or
occupational therapy during that time. When the partici-
pants are not actively enrolled in the intervention they are
provided stamped, addressed envelopes to return their
monthly calendar via mail to the clinical site for the dura-
tion of LEAPS follow-up. Participants are prompted to
return these calendars at the monthly phone call. Partici-
pants turn in a calendar monthly, even if no occupational
or physical therapy was received.

Medication Information
Information on the medications taken by a participant are
recorded at baseline and at the 6- and 12- month assess-
ments. Participant's are asked to bring a list, or the actual
medication containers, of all over-the-counter and pre-
scription medications that they have taken in the past
week. The list of medications, the overall number of med-
ications and whether dizziness is a side effect of any of the
medications is recorded.

Standardization of Assessments
Standardization of data collection methods is achieved
through a systematic training and competency assessment
program for all per diem physical therapists masked to the
intervention. The assessors are introduced to each of the
outcome measures in a lecture and demonstration style
educational setting. This is followed by practice on volun-
teers (usually persons with stroke) under the supervision
of the study's clinical research coordinators and site team
leaders. The assessor must pass a competency-based eval-
uation, which is videotaped. At least 90% achievement of
standardized skills must be documented for all primary
outcome measures, including the Fugl-Meyer Motor and
Sensory Assessment, and the Berg Balance Test. Perform-
ance of all outcome measures is reviewed and approved
by the study clinical research coordinators to ensure
standardization. Continual training and feedback is pro-
vided to ensure sustained quality of outcome measures.


Randomization Methods
A total of 400 participants
one of the three groups: (1)


are randomly assigned to
LTP-early; (2) LTP-late; or


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(3) HEP. Treatment allocation occurs when a participant
is eligible for the intervention, baseline assessments at
2 months post-stroke are complete, and the consent for
randomization has been obtained. The study coordinator
registers the patient, enters the baseline data into the web-
based database system, and then obtains group assign-
ment from the data management and analysis center.

Because of concern that a simple randomization might
yield significant imbalance in baseline impairment sever-
ity within the three treatment groups at each site, an adap-
tive treatment allocation procedure has been adopted.
Participants are stratified by the baseline impairment
severity rating into two strata (< 0.4 m/s and > 0.4 < 0.8
m/s), and for each severity stratum within each clinical
site, they are randomly assigned to the LTP-early, LTP-late
and HEP groups in the proportions of 140:140:120. As
each participant is presented to the web-based system for
random allocation, the system determines the difference
between the true accumulations and the target distribu-
tion across the three groups. If there is imbalance, a partic-
ipant is assigned to the underrepresented group with 80%
probability and to the other two groups with 10% proba-
bility each. As an example, we may define imbalance as di
= maxj |f F, I being larger than three, where fi and F, are
the realized and expected frequencies of participants from
the ith stratum in the jth treatment group within the site.
Rules and cutoffs are determined by the DMAC.

Interventions
Participants are randomized to 1 of three intervention
groups, each receiving 3 treatment sessions per week for
12 to 16 weeks (36 total sessions):

1. Early Locomotor training (LTP-early) High intensity
locomotor training program that includes both walking
training on a treadmill with partial body weight support
and overground provided 2 months after stroke.

2. Late Locomotor training (LTP-late) High intensity
locomotor training program that includes both walking
training on a treadmill with partial body weight support
and overground provided 6 months after stroke.

3. Home-based exercise (HEP-early) -, Low-intensity exer-
cise program focused on strength, balance and coordina-
tion provided in the home 2 months after stroke.

In addition to the LTP and HEP interventions, all partici-
pants receive any prescribed usual and customary care
during the intervening periods. There are several reasons
to allow individuals to receive usual and customary care.
First, facilities may be less likely to refer clients to this trial
if they believe they will lose revenues from outpatient or
home health treatments. Second, participants may be


inhibited from enrolling if they believe trial participation
will reduce their opportunities to participate in other ther-
apy. However, participants are required to abstain from
any therapeutic intervention during the full period of
their enrollment and participation that uses a treadmill or
body weight support device (either over a treadmill or
overground) unless under the supervision of the trial.
Usual care interventions are monitored with participant
self report logs.

Prior to initiating the intervention, each participant is pro-
vided a Participant's Guide for orientation to the study
team, intervention, and expectations. The trainer reviews
the guide content with the participant across several ses-
sions. The guide content covers contact information for
the primary PT, schedule, falls calendar, an overview of
the responsibilities and role of the training team and par-
ticipant, and overview of the LTP or HEP and how to make
the most of gains after the program is completed. Partici-
pants are asked to identify their primary walking goal, i.e.
"I want to walk my dog in the park", "I want to be able to
drive my lawnmower equipment". At each training ses-
sion, specific training goals are reviewed with the partici-
pant and in the context of achieving the participant's goal.
As the participant's skills progress during the training, the
trainers also ask the participant, "what is limiting you
from achieving your goal relative to walking?". Trainers
may use the response to tailor the goals and parameters of
the training session.

Locomotor Training Program
Because the overall goal of the LTP is to achieve independ-
ent community walking within the range of normal walk-
ing speed using an optimal stepping pattern. The
structured LTP, by training across two environments: the
treadmill with a body weight support and treadmill
(BWST) system (see Figure 2) [55] and overground (see
Figure 3), targets the essential control and functional
requirements of walking: (1) a reciprocal stepping pat-
tern, (2) dynamic equilibrium during propulsion, and (3)
adaptability to behavioral goals of the participant and
environmental constraints.

The program consists of 20-30 minutes of step training
using the BWST modality with manual assistance pro-
vided by trainers, followed by 15 minutes of overground
assessment and ambulation training 3x/week for 36 ses-
sions. A 20-30 min period of actual stepping is the goal
for the intervention sessions on the treadmill with rest
periods as needed. Each training session may last up to 1
hour and 30 minutes including time for warm-up, stretch-
ing, and cool down. The overall goal is to enable the par-
ticipant, by the end of training, to walk independently a
total of 20 minutes in four, 5 minute bouts at 0.89 1.2
m/s (2.0 2.8 mph) and 0% BWS with good stepping kin-


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ematics. Good stepping is defined as walking with (1) an
upright trunk with pelvic rotation to achieve limb load-
ing, (2) symmetrical stride length, (3) symmetrical swing
and stance time, (4) hip and knee flexion moments dur-
ing swing initiation and swing, and (5) hip and knee
extensor moments during stance and push-off with
proper stance and swing kinematics.

Parametric training targets include: (1) gradually decreas-
ing BWS from 40% to 0%, (2) initiating treadmill speed
in the range of normal walking speeds and increasing as
tolerated, and (3) providing manual assistance initially
when the participant is unable to independently step or
control upright posture, and decreasing manual assistance
to afford skill and control progression by the participant.
One to three trainers assist the participants with verbal
instructions and manual assistance to practice and achieve
good stepping and posture. The progression of LTP train-
ing parameters during the course of the intervention are
listed in Table 3. When bout duration of 5 minutes and
total step time of 20 minutes are achieved, then the
number of bouts may be decreased and the length of each
bout increased. The target exercise capacity is 20 minutes
of continuous, independent, good stepping on the tread-
mill at 0% BWS.

Goals for each session address achieving training duration
of 20 minutes, a minimum target training speed of 2.0
mph, and maximal body weight load while maintaining
the kinematics and posture associated with walking. An
early training priority is to achieve an upright symmetrical
posture with spatial-temporal symmetry of the stepping
pattern. Initially, the participant may walk with a shorter
step length for the non-paretic limb and the step centered
in the middle of the treadmill as a means to compensate
for deficits in paretic limb and trunk control. A trainer
thus initially works with the participant to verbally cue or
manually assist with foot placement of the non-paretic
limb.

The next phase of training continues repetitive practice of
walking, but also provides opportunity for the participant
to control his/her trunk and limb control. The priority is
to gain trunk control first, then limb control. Achieving
trunk/pelvic control is a necessity for overground walking.
The speed may be decreased or BWS increased to allow
independent practice of trunk control, limb control, or
the entire stepping pattern. Errors will occur as partici-
pants tests their control abilities. As independence and
control are achieved, the treadmill speed is increased and
BWS decreased to continue to challenge the individual
and to progress. As independence and control are
achieved with minimal BWS and walking speed of 2.0
mph, then the last phase of training is introduced. Adapt-
ability is challenged both in the treadmill and overground


environments. Specifically, the participant adapts to con-
ditions such as changes in the treadmill speed from slow
to fast to slow again, sudden stops or starts, turning the
head while walking, uneven terrain, or obstacles in the
environment.

Step training using the BWST modality is followed by fif-
teen minutes of assessment and community ambulation
training in the overground environment. The aim of com-
munity ambulation training is to transfer stepping capacity
and skills from the BWST environment to overground
walking. Participants stand and walk in the overground
environment with guarding and/or manual assistance of
trainers as transfer of stepping skills is assessed.
Dimensions of stepping in the BWST environment that fail
to transfer to overground walking are identified and appro-
priate instructions provided. The trainer and participant
identify daily activities that support the overall goal of
walking to be incorporated on a daily basis at home or in
the community. Goals for the next treatment session using
the BWST modality are set, based on the overground per-
formance. Practice instructions for home may include use
of an AFO or assistive device/support. As the stepping pat-
tern and dynamic equilibrium improve and independence
is achieved, the particular challenges of community ambu-
lation are addressed by targeting performance of transi-
tions (start and stopping), techniques to maximize
endurance, walking over variable terrain, and negotiating
obstacles. Evaluations and recommendations are made at
the 12th, 24th, and 36th training sessions regarding spe-
cific use of assistive devices or braces.

For participants with poor proximal upper extremity mus-
cle control, the hemiparetic arm may feel heavy and
potentially painful during locomotor training. Addition-
ally a heavy, flaccid upper-extremity can pull the trunk
forward inhibiting good stepping. During training, the
arm may be supported using a humeral cuff sling or with
hand-hold support from a trainer. If shoulder range is
available and voluntary movement is present and pain-
free, armswing is encouraged.

Home Exercise Program
An exercise intervention designed to improve upper and
lower extremity strength, sitting and standing balance,
and coordination was designed for the home exercise
group, incorporating techniques used in previous low-
intensity and gait preparatory exercise programs (see
Figure 4) [12-14]. The purposes of the home exercise pro-
gram are to provide (1) an exercise-based intervention
that is expected to have little or no effect on the primary
outcome, gait speed, (2) an equal number of interactions
and time spent with a physical therapist to minimize any
potential for bias due to differential exposure and mini-
mize the risk for differential loss to follow-up, and (3) a


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Figure 2
Locomotor Training Program (LTP) Body weight support
with treadmill training. Figure 2 reprinted with permission
from Sage Publications [55].




credible training program so that the participants would
consider themselves involved in meaningful therapy
activity. To match the LTP group, the home exercise group
receives 36 therapy visits (3 times per week for 12 weeks)
with length of HEP and LTP training sessions the same.
Cardiovascular response monitoring during exercise is
identical to that done in the LTP groups. In these ways, the
HEP intervention will plausibly control for Hawthorne
effect but exclusively through interventions that have
been shown to have little or no impact on gait speed.

The exercise program is divided into three 4-week phases
to provide the participants with a sense of progression.
The first phase consists of upper extremity resistance
exercise, lower extremity active exercises against no resist-
ance, and sitting balance tasks. Each major joint of the
upper and lower extremities is addressed. The second
phase adds minimal resistance to the lower extremity,
strengthening exercises, coordination tasks and static
standing balance exercises. The third phase adds low rep-
etitions of sit-to-stand practice and dynamic standing bal-


ance activities. At the end of each session, participants are
encouraged to walk every day. Each participant is individ-
ually progressed according to their ability within each
phase. Table 4 outlines examples of progression of exer-
cises/activities. To ensure that all groups receive the same
advice regarding the use of assistive devices for walking,
the home exercise group participants are evaluated for
assistive device needs after the 12th, 24th, and 36th
session.

Vital Sign Monitoring for LTP and HEP Interventions
Blood pressure (BP) and heart rate (HR) are monitored
prior to a session, during a session, and at the completion
of each session. BP and HR must be within normal range
for the participant prior to initiating each training session.
HR must be less than 100 bpm to begin the training
session. Participants' resting diastolic BP must be less than
100 and systolic BP less than 180 to begin the training ses-
sion [56]. During the 20-30 minute training sessions, BP,
HR, blood oxygen saturation, and the Borg scale Rate of
Perceived Exertion are monitored every 5 minutes initially
to assure that they remain within acceptable limits. The
American College of Sports Medicine criteria for terminat-
ing an in-patient exercise session are followed according
to guidelines shown to be effective for persons post-stroke
with multiple comorbidities [56]. Persons that are on beta
blockers are identified prior to initiating the training.
Exercise tolerance for these individuals is specifically
assessed using the Borg scale Rate of Perceived Exertion.

The criteria for termination of a training session include
complaints of light-headedness or moderate or severe dys-
pnea, or the development of paleness and excessive sweat-
ing or confusion; complaints of feeling ill; onset of
angina; pressure changes (systolic BP greater than 200
mm Hg, diastolic BP greater than 110 mm Hg), drop in
systolic BP greater than 20 mmHG and inappropriate
bradycardia (drop in heart rate greater than 10 beats per
minute). In addition, should the participant's HR exceed
80% of the predicted maximum HR (220 age) or
the participant report a Borg exertion rate of greater than
12-13, then the training ceases. Should training be halted,
the participant is asked to rest (sitting or standing) while
BP and HR are monitored and training will resume only
when vital signs have returned to within an acceptable
range and excessive dyspnea or chest pain have resolved.
If any of these conditions persist after rest, the patient's
primary physician is called and the patient referred for
evaluation. If the patient complains of angina at rest, loss
of consciousness occurs, or cardiac arrest, emergency med-
ical services through 911 are called immediately. All train-
ers are CPR certified and aware of signs of cardiac
complications. All trainers and assistants are trained in
procedures to afford quick and safe removal of a patient
from the BWST system in the case of an emergency.


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Figure 3
Locomotor Training Program (LTP) Overground training.


Standardization for the Interventions
The LTP and HEP interventions are standardized to
achieve consistent implementation of the intervention
across clinical sites. Standardization assures that the
training teams successfully implement a common
intervention through application of six critical elements:
(1) knowledge of the protocol; (2) goal setting, decision-
making and progression; (3) participant safety and moni-
toring; (4) equipment use; (5) hands-on training skills;
and (6) participant's role and participation. Documenta-
tion procedures are standardized across sites and require
trainers to record in a computerized database all training
parameters for the BWST and overground training.

A competency-based training program was used to train
the trainers across all sites. The intervention teams met
together for a 5-day training course, returned to their clin-


ical sites for 2-3 months of pilot training, with follow-up
sessions at each of the 5 sites to complete competency-
based training and testing. Competency is required in
each of the six knowledge and application domains and
includes both written and practical components.

After individual therapists/trainers and the site achieve
competency status, they are approved to admit partici-
pants to the RCT. Competency status is maintained
throughout the trial by each trainer at every site and is
systematically reviewed during the first participant's
training after 1, 4, 8, and 11 weeks; then every 3 months
by the Co-PIs (or an independent reviewer).

Turnover in trainers across sites is anticipated across a
3 year span of participant entry and training. The inter-
vention site team leader is responsible for training new


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Table 3: Locomotor Training Progression


Training
Priorities on the
Treadmill


Phase I (1-12) I. Intensity 2.
Speed 3.
Independence at
non-paretic leg


Phase II (13-24)








Phase III (25-36)


I. Intensity at 2.0
mph and decrease
BWS 2. Progress
independence at
trunk/pelvis with
short bouts
(decrease speed,
increase BWS as
needed)
I. Intensity to 30
mins 2. Progress
independence with
increased bout
length, then
increase speed,
decrease BWS. 3.
Adaptability
(speed variations,
stop/starts, incline)


Treadmill (TM)
Speed

1.6 mph minimum
(goal of 2.0 mph)



2.0 2.8 mph








2.0 2.8 mph and
increasing speeds


Body-Weight
Support


30 -40%




20%- 35%








0 -20%


Intensity/
Endurance


Four 5-minutes
bouts to attain 20
mins of stepping


Increase bout
duration with
decrease in
number of bouts
to attain 20 mins
of stepping



Increase total
stepping time to
30 mins


As needed at
trunk, paretic and
nonparetic leg.
Decrease assist at
non-paretic leg.
Decrease assist to
first trunk/pelvis,
then paretic leg


I. Attempt skills
observed/trained
on the treadmill 2.
Educate on use
beyond clinic
I. Attempt skills
observed/trained
on the treadmill 2.
Transfer skills/
speed 3. Introduce
assistive device
and orthosis, as
needed


Removed I. Transfer skills/
speed 2.
Adaptability to
environment:
stairs, curbs,
terrain and change
speed, stops,
turns.


Figure 4
Home Exercise Program (HEP).


staff. The trainer, in accordance with her/his specific role
and responsibilities in the trial, must achieve intervention
competency before joining the site training team in treat-
ing enrolled participants. Any deviation from established
competency standards requires immediate remediation
and reevaluation. No trainer is allowed to conduct treat-
ment without established and maintained competency.
The Clinical Research Coordinator and co-PIs are respon-
sible for maintaining standardization and competency
throughout the trial.

Communication between site lead trainers, clinical
research coordinators, and the co-PIs is maintained
through weekly conference calls. A web-based, discussion
board specific to each intervention provides timely
responses to questions from the training teams with
responses available to all training personnel. This list of
questions and responses is recorded throughout the trial
and used to refine or clarify the training manual. The Clin-
ical Research Coordinators conduct weekly to bi-monthly
visits to each site and relay any intervention-related con-
cerns to the Co-PIs. As a follow-up to site visits or interim
standardization reviews of training session videos and
training session documentation, pertinent aspects of the
HEP and LTP interventions are highlighted and discussed
on conference calls to maintain consistency in decision-
making and progression. Finally, the investigators have
prepared an intervention training manual for therapists
available on the LEAPS website. In addition, all


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Phase and
Sessions


Overground/
Manual Community
Assistance Ambulation


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Table 4: Home Exercise Program

Upper and Lower Extremity Exercises


Sitting Balance


Static Standing Balance


Dynamic Standing Balance


Progression

Gravity eliminated, active assistive
Gravity eliminated, active
Against gravity, no Theraband
Against gravity, yellow Theraband
Against gravity, red Theraband
Against gravity, green Theraband
Against gravity, blue Theraband
Against gravity, black Theraband
Against gravity, silver Theraband

Progression

Equal weight bearing on ischial tubersosities
Weight shift, lifting opposite leg from chair
Ipsilateral anterior diagonal reaching, NP* UE**
Ipsilateral posterior diagonal reaching, NP UE
Contralateral anterior diagonal reaching, P* UE
Contralateral posterior diagonal reaching, P UE
Contralateral anterior diagonal reaching, NP UE
Contralateral posterior diagonal reaching, NP UE
Ipsilateral anterior diagonal reaching, P UE
Ipsilateral posterior diagonal reaching, P UE

Progression

Shoulder-width stance 30 sec, eyes open
Shoulder-width stance 30 sec, eyes closed
Feet together 30 sec, eyes open
Staggered stance, P leg in front, eyes open
Staggered stance, P leg in front, eyes closed
Feet together 30 sec, eyes closed
Staggered stance, P leg behind, eyes open
Staggered stance, P leg behind, eyes closed
Staggered stance, P leg in front on step, eyes open
Staggered stance, P leg in front on step, eyes closed
Staggered stance, NP leg in front on step, eyes open
Staggered stance, NP leg in front on step, eyes closed

Progression

Catching ball straight on
Catching ball thrown towards NP side
Catching ball thrown towards P side
Turning towards P side
Turning towards NP side


*P = paretic; NP = nonparetic
**UE = upper extremity


participants received a Participant Manual for the LEAPS
trial specific to either the HEP or LTP intervention to
inform them of what to expect, goal-setting, progression
across the sessions, and the role of the participant and
trainers throughout the training.


Statistical Analysis
Sample Size and Participant Accrual
LEAPS is powered to detect a difference of 20% in the
proportion of participants achieving a successful locomotor
recovery (defined as >0.4 m/s gait speed for participants


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with initial severe impairment, and >0.8 m/s for those with
moderate impairment) between the locomotor training
groups (LTP-early and LTP-late) and the HEP group, and a
0.1 m/s mean difference in gait speed change between the
two locomotor training groups (LTP-early and LTP-late).

Power calculations indicate that a total of 340 participants
are needed (120 in each of the two LTP training groups and
100 in the HEP group) in order to detect with 85% power
a difference of 20% between each of the LTP treatment
groups and the HEP group at the significance level = 0.05.
In addition, with a sample size of 120 in each of the two
LTP training groups, LEAPS will have 85% power to detect
a difference of 0.1 m/s between each of the LTP groups
using a two-sample t-test at the 0.05 significance level (two
sided).

Because LEAPS is anticipating a 15% attrition rate at 1-year
post-stroke, we plan to recruit and randomize 400 partici-
pants (140 in each of the two LTP training groups and 120
in the HEP group) in order to achieve our sample size goal.
To achieve our recruitment goal of 400 participants from 5
sites in 2.5 years (32/site/year), LEAPS expects that for each
year, each site will be able to train 24 participants with a
BWST modality for 36 sessions.

Primary Statistical Analyses
Baseline
Demographic and baseline levels of clinical variables will
be compared between the three randomized groups using
analysis of variance (ANOVA) for comparison of means
and chi-square tests for comparison of proportions. Vari-
ables found to be significantly different between the treat-
ment groups will be considered in the endpoint analyses,
in addition to the pre-specified covariates (e.g., severity,
clinical site, age, stroke type, lesion location, and
depression).

Specific Aims
Specific Aim I
To determine if a structured locomotor training program
(LTP) delivered early (2 months) or late (6 months) post-
stroke is more successful in achieving clinically significant
gains in locomotor recovery at 1-year post-stroke than the
home exercise program (HEP) intervention.

Hypothesis I
At 1-year post-stroke, there will be a clinically significant
difference between each of the training groups (LTP-early,
LTP-late) and the HEP group in the proportion of partici-
pants who successfully recover walking ability. Successful
recovery of walking is defined as having achieved a 0.4 m/
s gait speed or greater for persons with initial severe gait
impairment (< 0.4 m/s) or as having achieved a 0.8 m/s
gait speed or greater for persons with initial moderate gait


impairment (> 0.4 m/s < 0.8 m/s). A clinically
significant difference will be defined as a greater than 20%
difference in the proportion of participants who achieve
successful recovery. We expect that both the LTP-early and
LTP-late groups will have more success than the HEP
group.

Analysis Plan
The purpose of this analysis is to test the hypothesis that
there will be a clinically significant difference in successful
recovery between the three randomized groups (LTP-
early, LTP-late and HEP). First, we will provide summary
statistics on the success proportions for each of the three
groups by severity. Then, we will conduct a logistic regres-
sion with successful recovery of walking (yes/no) as the
dependent variable, and two independent variables (XI,
X2) indicating each of the training groups (LTP-early, LTP-
late, and the HEP as the reference group). Other explana-
tory factors will include severity, clinical site, age, stroke
type, lesion location, and depression. The odds ratios for
achieving successful outcome for each treatment relative
to the HEP group will be estimated. As indicated in the
sample size section, the 20% difference in success propor-
tions translates into an odds ratio of 2.33 for each treat-
ment. Formally, if we let p, denote the probability of
successful recovery at one year post-stroke for the jth par-
ticipant in the ith treatment group, and define Z, as the
baseline covariates for the corresponding participant,
then the regression model can be written as follows: log
ir(,p. ') = a+ X1 + ,#X2 + Zjy. The Hochberg step-up pro-
cedure [xx] will be used to test two individual null
hypotheses A = 0 and, ,2 = 0, after controlling for severity
and other covariates. Start with the larger p value p(2), if
P(2) <0.05, then stop testing and reject both hypotheses
thus we conclude that both LTP groups are significantly
different from the HEP group; otherwise the LTP group
corresponding to the larger p value is claimed to be not
significantly different from the HEP and continue to check
the smaller p value P(i) ; if P(i) < 0.025, then the
corresponding hypotheses is rejected and we conclude
that the corresponding LTP group is significantly different
from the HEP group; otherwise none of the two LTP
groups is significantly different from the HEP group. In
addition, we will perform post-hoc tests to determine
whether the differences occurred in the severely impaired
participants, the moderately impaired participants, or
both. The particular value of using this logistic regression
approach to test this hypothesis is that it allows us to put
all independent variables of potential importance into the
model without making any a priori assumptions about
the presence or absence of time of treatment effects, or
effects related to clinical site, age, stroke type, lesion
location, or presence of depression. LTP can be justified
only if a clinically significant difference between LTP and
HEP participants can be demonstrated. Only when such a


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difference has been established does it make sense to ask
when the treatment should take place and whether sever-
ity of impairment influences optimal timing of treatment
(the foci of specific Aim 2).

Specific Aim 2A
To determine if the timing of LTP delivery (early vs. late)
affects the improvement in gait speed at 1 -year post-stroke.

Hypothesis 2A
The improvements of gait speed from baseline to 1-year
post-stroke for participants trained at 2 months will
be significantly greater than for participants trained at
6 months

Specific Aim 2B
To test whether initial locomotor impairment severity
interacts with the timing of LTP delivery to affect the
improvement in gait speed at 1-year post-stroke.

Hypothesis 2B
The timing of LTP delivery will interact with baseline loco-
motor impairment severity such that (1) individuals with
more severe initial walking impairment will demonstrate
greater improvements in gait speed from LTP-late than
LTP-early and (2) individuals with less severe initial walk-
ing impairment will demonstrate greater improvements
in gait speed with LTP-early than LTP-late.

Analysis Plan
The rationale behind this analysis is that, once a clinically
significant difference between the LTP and HEP groups
has been established (Specific Aim 1), then any statisti-
cally significant difference in timing effect or in timing by
severity interaction effect will become clinically relevant.
If at least one of the two individual null hypotheses
is rejected in the analysis for Specific Aim 1, we will con-
duct formal statistical inference to compare the two treat-
ment groups (trained during the sub-acute or chronic
periods post-stroke) based on improvement in gait speed
from 2-month baseline assessment to 1-year post-stroke.
This second primary analysis will fit a linear model for the
gains of gait speed. The explanatory factors will include
study group, severity, clinical site, age, stroke type, lesion
location, and depression. Let Yi denote the improvement
in gait speed at 1-year follow up for jth the participant in
the ith treatment by severity group, where i = ES, LS; EM,
LM. (ES, early severe; LS, late severe; EM early moderate;
LM, late moderate). We define Zi3 as the baseline
covariates for the corresponding participant. The linear
model can be written as follows: Y, = q + ZfJ + cy,. In this
model, o is the mean of gait speed improvement within ith
treatment by severity group and 8 is the covariates effect
on response. The error term eij is assumed to have normal
distribution with zero mean and variance d. Similar to


the Specific Aim 1, we will employ the Hochberg step-up
procedure [xx] to test two individual null hypotheses as
= qs and M = q., with the larger p value compared to
0.05 and the smaller p value compared to 0.025. If the
null hypothesis q s = as is rejected, we would
conclude that the timing of intervention delivery affects
mean 1-year outcome for the severe group. Similarly, we
may conclude am # q M which indicates a timing effect for
the moderate group. In addition, we would perform post-
hoc tests to determine whether the timing effects are the
same for the two severity levels.

Secondary Statistical Analyses
Specific Aim 3A
For each LT group, to determine if the number of locomo-
tor training sessions affects the outcome of gait speed
immediately following the 12th, 24th, and 36th sessions.

Hypothesis 3A
There will be a significant increase in gait speed for partic-
ipants when assessed following increasing numbers of
training sessions, such that gait speed after the 24th ses-
sion will be greater than after the 12th session and gait
speed after the 36th session will be greater than after the
24th session.

Specific Aim 3B
To test whether initial locomotor severity interacts with
the number of treatment sessions to affect the gait speed
immediately following the 12th, 24th, and 36th sessions.

Hypothesis 38
The number of locomotor training sessions will interact
with baseline locomotor impairment severity such that
(1) individuals with more severe initial walking impair-
ment will demonstrate greater improvements in gait
speed from an increasing number of training sessions and
(2) individuals with less severe initial walking impair-
ment will not benefit from more extended training.

Analysis Plan
For each LTP group, a longitudinal analysis will be con-
ducted using gait speed before the training and following
the 12th, 24th, and 36th sessions, taking into considera-
tion the dependence of repeated measurements at differ-
ent time points for each participant. The model will
include baseline impairment severity, categorical assess-
ment time and their interactions. It will be performed
using the MIXED procedure of SAS software. The
regression coefficient associated with assessment time
represents the average rate of change in gait speed. Treat-
ment group differences in the estimated gait speed change
rate will be tested.




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Tertiary Statistical Analysis
Additional analyses will assess the differences in improve-
ments between the three groups in the Fugal-Meyer Motor
Scores, the Berg Balance Score, distance walked in 6 min-
utes, community ambulation (as measured by the step
activity monitor), and self-reported quality of life
(as measured by the Stroke Impact Scale -Participation
domain). We will also assess differences in the incidence
of depression between the three groups. A multivariate
ANOVA (or ANCOVA) will be conducted to compare the
2-month to 12-month change scores between the three
groups: LTP-early, LTP-late and HEP. If there are signifi-
cant differences among the three groups, then linear con-
trast tests will be employed to detect pairwise differences.
We will conduct a logistic regression with incidence of
depression (yes/no) as the dependent variable. In addi-
tion, a Poisson regression will be conducted to assess
whether the intervention reduces the number of falls.
Lastly, a regression analysis will be conducted with gait
speed change from 2-month to 12-month post-stroke as
dependent variable for the HEP group. The explanatory
factors will include severity, clinical site, age, stroke type,
lesion location and depression.

Missing data
For participants who drop out and cannot complete the
one-year evaluation, we will impute outcome based on
the last available assessment value, with the proviso that,
for those who dropped out due to a related adverse event,
the dichotomous outcome will be imputed as failure in
the logistic regression analysis and the improvement in
gait speed as the minimum of zero and the change from
the baseline and last assessment in the linear regression
analysis. More precisely, the change in gait speed will be
defined as A = min(0, gastobs gIstobs) for those who
dropped out due to a related adverse event, and as A = g s
trobs Sstobs for all other "non-completers"; the successful
recovery of walking (yes/no) is defined correspondingly.

In addition, we will perform sensitivity analyses by com-
paring results from the intent-to-treat analyses described
above with the subgroup of participants with one-year fol-
low-up data, as well as those obtained using different
imputation procedures, including: (1) missing one-year
outcome predicted by participant gait speed trajectory; (2)
missing one-year outcome predicted by participant gait
speed trajectory, plus baseline demographic and clinical
factors, and (3) missing one-year outcome predicted by a
model that takes into account participant dropout bias.
For this last model, we will evaluate participant dropout
bias through the following four steps: (1) determine
demographic and clinical variables that characterize
differences between "completers" and "non-completers";
(2) develop a model predicting outcomes for the "compl-
eters" using the significant independent variables from


the previous step; (3) use the resulting model to predict
outcomes for the non-completers; and (4) redo the pri-
mary analyses for the full dataset.

Adverse Event Monitoring and Reporting
Adverse events are carefully monitored at every level of the
LEAPS trial. The teams at the clinical intervention sites
monitor and report all minor and serious adverse events
that occur with any participant from the point of enroll-
ment through the 12-month final follow-up assessment.

The LEAPS trial is supported by an NIH appointed Medi-
cal Safety Monitor, independent of the study executive
committee, who reviews all serious adverse events. An
NIH appointed Data Safety Monitoring Board provides
oversight and meets biannually. All adverse events are
reported to the DSMB every 6 months.

The LEAPS clinical intervention sites report adverse events
to their local Institutional Review Boards (IRBs). All seri-
ous, unexpected and related events at any site are reported
to every IRB within one week. Some of the site IRBs
require reporting of all serious adverse events, regardless
of whether or not they were expected or related, within the
one week timeframe. Other site IRBs allow for the report-
ing of expected and/or unrelated serious adverse on a
yearly basis. All minor adverse events are reported to the
site IRBs once a year at the time of renewal of IRB
approval.

Definitions for adverse event monitoring
Serious Adverse Events
Using general IRB guidelines the LEAPS trial has specifi-
cally defined what constitutes a serious adverse event: The
following events are considered serious: death, life-threat-
ening adverse event (stroke, MI, fracture), inpatient hospi-
talization, a persistent or significant disability or
incapacity that lasts more than 48 hours and limits
activities of daily living.

Serious adverse events are reviewed to determine whether
or not the event is expected. An expected adverse event is
one that is part of the normal disease progression or one
that is listed in current investigator brochure, protocol, or
informed consent form. The initial determination of
whether or not an event is expected is made by the site
medical director. The medical safety monitor also judges
whether or not the event is expected.

The LEAPS trial also considers whether or not an event is
related to the trial. A "related" adverse event reflects a real-
istic chance of a causal relationship between the study
intervention and the adverse event, as suggested when an
event occurs within a short time after the intervention
(i.e., 24 hours), follows a pattern consistent with the study


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intervention, and improves when the study intervention
has stopped and/or reappears when the intervention is
resumed. As with expectedness, whether or not an event is
related to the screening, exercise tolerance test, the study
assessments or the study intervention is initially judged by
the site medical director. The medical safety monitor also
judges whether or not the event is related to any of the
study procedures. Information on whether or not an event
is deemed related to the LEAPS trial is forwarded to the
Institutional Review Boards according to their individual
regulations.

In some cases a relationship with the trial can not be ruled
out. Such a relationship exists when the reaction follows a
pattern consistent with the study intervention and
improves when the intervention is stopped, but could
have been caused by the condition being treated or by
other interventions. This is also judged by the site medical
director and the medical safety monitor.

Minor Adverse Events
The following events are considered minor adverse events:
(1) Fall with no fracture, (2) Dyspnea, (3) Open sore or
blister, cuts (break of skin), (4) Muscle soreness or pain
that persists for more than 48 hours, (5) Dizziness/faint-
ing, (6) Diaphoresis, (7) hypertension during exercise that
requires stopping the intervention for the day, (8) Low
blood pressure that requires stopping the intervention for
the day, (9) Deep venous thrombosis. Minor adverse
events are reported to the site IRBs once a year at the time
of renewal.

Reporting Procedures
The LEAPS trial utilizes a web-based data entry system and
all Adverse Events are input into this system as soon as the
site team becomes aware of the event. The LEAPS data
entry system then employs an automated notification sys-
tem that sends an email regarding all serious and minor
adverse events to the site team leaders, the site research
assistants, the clinical research coordinators, the co-prin-
cipal investigators, the principal investigator, the project
manager and the medical safety monitor.

When an adverse event occurs, the site team leader imme-
diately fills out an initial adverse event report. If the event
is minor, a second minor adverse event form is com-
pleted. In the case of a serious adverse event, the team
notifies the site medical director immediately and then
confirms the event within 3 business days. Once the event
is confirmed as a serious adverse event, the team, includ-
ing the site medical director, completes a serious adverse
event confirmation form. Serious adverse events are con-
firmed by review of medical records or by contacting the
participant's primary care physician.


The Medical Safety Monitor fills out a report adjudicating
the event and determining whether the event is, in his
opinion, related to the trial. The Medical Safety Monitor
also provides a recommendation as to whether the
participant should remain in the trial. All sites have online
access to the completed adverse event reports and are
responsible for reporting the events to the individual
Institutional Review Boards that oversee the clinical inter-
vention sites.

The site's Medical Director, the study PI and the Medical
Safety Monitor will review all serious adverse events
immediately and determine if the participant is to be dis-
continued from the trial. If the adverse event is related and
precludes continuation, the participant will be officially
dropped from the study. If the adverse event is unrelated
or a temporary condition and the patient is medically
cleared to continue in the trial, she/he will not be
dropped.

The Data Management and Analysis Center provides
monthly reports of all serious adverse events. These
reports are sent to each site and to the administrative coor-
dinating center for review. This allows for the review of all
adverse events and to ensure that all events are followed
to conclusion and that participants are appropriately
maintained or discontinued from the study.

Data Management and Quality
Data Management and Quality Control Procedures
The Data Management and Analysis Center (DMAC) has
developed and implemented a secure LEAPS database and
web-based data entry system. The LEAPS database system
facilitates data entry with built in quality control checks
(e.g., range checks, checking for missing data for required
data points). In addition, the LEAPS web-based system
provides (1) a public website including study informa-
tion, background and responsibilities of key personnel,
news items, employment opportunities, publications, and
(2) a secure website information housing the Manual of
Procedures, data collection forms, reports to the Steering
Committee, minutes of conference calls with study inves-
tigators, reports and updates on recruitment status, report-
ing of SAEs, and reports to the Data Safety and Monitoring
Board (DSMB).

Additional quality control procedures include: (1) ran-
domly selected comparison of data points between the
paper records and the electronic records in the SQL
database at each study site, and (2) frequency distribu-
tions checks of key outcome variables (overall, not strati-
fied by treatment assignment) along with a list of
participant IDs associated with possible outliers or ques-
tionable data points. Quality control summary reports are
also housed on the secure LEAPS website.


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Study Organization and Management
The LEAPS Trial is managed by an executive steering com-
mittee. This committee is responsible for the overall trial
management including oversight of participant recruit-
ment, execution of the trial, ethical conduct of the trial,
study publications and ancillary studies. The steering
committee includes the Principal Investigator Dr. Pamela
Duncan, the Co-principal Investigators, Dr. Andrea Behr-
man, and Dr. Kathy Sullivan. Dr. Stephen Nadeau and Dr.
Bruce Dobkin are the study Neurologists and Neuroreha-
bilitation consultants. Dr. Stanley Azen is the Director of
the Data Management and Analysis Center and Dr. Sam
Wu is the study lead statistician. Ms. Sarah Hayden is the
Project Manager. Dr. Duncan, the study principal investi-
gator chairs the committee. The executive steering com-
mittee has conference calls every week and meets once a
year in person. There is a subcommittee of clinical site
medical directors. This committee has a monthly phone
call with the executive steering committee. Each clinical
intervention site receives oversight from a Clinical
Research Coordinator. The Clinical Research Coordina-
tors for this trial are Julie Tilson, DPT and Dorian Rose,
Ph.D., P.T. The Clinical Research Coordinators have a
weekly conference call with the site team leaders and visit
the clinical facilities at least on a biweekly basis. The clin-
ical research coordinators and the study principal and co-
principal investigators have weekly conference calls to
ensure that all assessment, intervention, and patient
recruitment issues are dealt with in an efficient and con-
sistent manner across sites.

There is an NINDS appointed Data Safety Monitoring
Board (DSMB) to oversee the trial. The DSMB is responsi-
ble for assuring NINDS that the study is safe and con-
ducted according to high scientific and ethical standards.
The DSMB assesses participant recruitment, retention and
follow-up, and data quality. The DSMB also reviews all
adverse events and monitors safety issues. It reviews all
proposed protocol changes and all ancillary study propos-
als. Then DSMB meets with Dr. Duncan, Dr. Azen, Dr.
Wu, and an NINDS representative twice a year. A sum-
mary of the DSMB meeting and subsequent recommenda-
tions are forwarded to NINDS, the principal investigator,
and respective IRBs.

This trial also has an NINDS appointed Medical Safety
Monitor, who is independent of the trial investigators and
reviews all serious adverse events as they occur.

The DMAC is co-directed by Dr. Stanley Azen, Dr. Steven
Cen and Dr. Samuel Wu. The co-directors oversee the
operation of the DMAC, including data management and
analysis of all data sources. Dr. Wu is responsible for con-
ducting the primary statistical analyses for the Specific
Aims, reviewed by Drs. Azen and Cen. All three Co-direc-


tors will be responsible for running secondary and tertiary
statistical analyses.

The Co-directors are assisted by the Bioinformaticist and
Web Manager (James Baurley MS and James Gardner),
who developed and oversee the LEAPS database system
and website. In addition, Dr. Cen interacts with the Data-
base Manager (Chris Hahn, MS) in producing recruit-
ment, follow-up and compliance reports, quality control
reports, and biannual Data and Safety Monitoring Board
(DSMB) reports. Dr. Cen also oversees the training proc-
ess of LEAPS study personnel in using the database sys-
tem, the randomization process, and the reporting of
SAEs.

The DMAC members meet biweekly and two executive
committee calls each month are lead by Stan Azen. During
these calls Dr. Azen reports on all data acquisition, data
management, and analysis issues to the executive
committee.

Discussion
This multi-site RCT is designed to determine the impact of
LTP compared to a home exercise program on clinically
and functionally meaningful changes in function for
patients with acute and sub-acute stroke. Stroke results in
disabling limitations for patients. These patients turn to
rehabilitation specialists for evidence-based care that will
maximize their recovery. The results of this RCT will pro-
vide a significant addition to our body of knowledge
regarding LTP post-stroke and more broadly to our under-
standing of how to conduct large scale, multi-site clinical
trials of rehabilitation interventions.

This trial will make several unique contributions to the
practice of locomotor therapy after stroke. First and fore-
most, it will test the value of a clinically practicable loco-
motor training program in a sufficient number of
participants of sufficient variety to provide a reasonable
basis for confident inference to clinical practice. The pri-
mary endpoint of the trial is clinically relevant and meas-
ured one year post-stroke to assesses the sustainability of
any immediate post treatment benefit.

The value of LTP will be tested against a home exercise
program (HEP) intervention that not only incorporates
usual and customary care but also provides a sufficiently
intensive intervention to provide a plausible control for
Hawthorne effect. The trial will help to determine the
optimal timing of intervention. Optimal timing of neu-
rorehabilitation remains a subject of scientific dispute and
even precisely controlled animal studies have not settled
the issue [57]. The trial will provide a start in the process
of understanding the optimal dose of treatment for any
given participant. Finally, the trial will examine the


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impact of treatment on a sufficient number of ancillary
functional measures to make its outcomes readily compa-
rable with those of other trials.

Current study status: Enrolling Patients

Abbreviations
RCT Randomized Controlled Trial; LTP Locomotor
Training Program; HEP Home Exercise Program; BWST
- Body Weight Support and Treadmill; BWS Body
Weight Support; DMAC Data Management and Analysis
Center; DSMB Data Safety Monitoring Board; SAE -
Serious Adverse Event

Competing interests
The authors) declare that they have no competing inter-
ests.

Authors' contributions
PWD led the conceptualization, design, and implementa-
tion of this research protocol. She was the primary author
for this manuscript.

KJS was a leader in the conceptualization, design, and
implementation of this research protocol. She is a contrib-
uting author for this manuscript.

ALB was a leader in the conceptualization, design, and
implementation of this research protocol. She is a contrib-
uting author for this manuscript.

SPA led the development of the data management proto-
col and statistical analysis plan. He is a contributing
author for this manuscript.

SSW has been a leader in the development of the analysis
plan and was a leader in the conceptualization and design
of this research protocol. He is a contributing author for
this manuscript.

SEN and BHD assisted in the design of this protocol.

DKR and JKT assisted in the design of the protocol for
interventions and assessments, as well as all data collec-
tion procedures. They contributed to writing of this man-
uscript.

All authors reviewed and approved this manuscript prior
to submission.

Acknowledgements
This work supported by funding from National Institute of Neurological
Disorders and Stroke and the National Center for Medical Rehabilitation
Research (ROI NS050506).


The author would like to acknowledge the contribution of the participants
who are pictured in our figures. Written consent for publication of photos
was obtained from each participant.

The author's would like to acknowledge the contributions of the following
members of the investigative team:

Site Medical Directors

Deborah Stewart, MD Brooks Rehabilitation Hospital, Jacksonville, FL

Trevor Paris, MD Brooks Rehabilitation Hospital, Jacksonville, FL

David Alexander, MD Centinela Freeman Regional Medical Center, Ingle-
wood, CA

Mitchell Freed, MD Florida Hospital, Orlando, FL

Michelle Dolske, Ph.D. Florida Hospital, Orlando, FL

H. Richard Adams, MD Long Beach Memorial Hospital, Long Beach, CA

Diehma Hoang, MD Long Beach Memorial Hospital, Long Beach, CA

Jerome Stenehjem, MD Sharp Rehabilitation Center, San Diego, CA

Roxanne Hon, MD Sharp Rehabilitation Center, San Diego, CA

Site Team Leaders

Joann Gallichio, PT Brooks Rehabilitation Hospital, Jacksonville, FL

Julie Hershberg, PT, DPT- Centinela Freeman Regional Medical Center,
Inglewood, CA

Craig Moore, PT Florida Hospital, Orlando, FL

Anita Correa, PT Long Beach Memorial Hospital, Long Beach, Ca

Molly McLeod, PT Sharp Rehabilitation Hospital, San Diego, CA

Project Manager

Sarah Hayden, Duke University


Data Management and Analysis Center


Steven Cen, Ph.D., University of Southern California

Consultants

Anatole D. Martin, Ph.D., University of Florida


Richard Schofield, MD, University of Florida

Medical Safety Monitor

Alexander Dromerick, MD from Georgetown University School of Medi-
cine is the current LEAPS Medical Safety Monitor.

Larry Goldstein, MD from Duke University served as the Medical Safety
Monitor for the LEAPS Trial from August I, 2005 through April 31, 2007.




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Data Safety Monitoring Board

The LEAPS Data Safety Monitoring Board consists of the following
members:

David G. Sherman, MD (Chair), University of Texas Health Science Center
at San Antonio

Elizabeth A. Noser, M.D., University of Texas

Michael Parides, Ph.D., Columbia University

Steven Wolf, Ph.D., PT., Emory University.

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