Low InTensity Exercise Intervention in PAD
Phase: NA
Conditions: Peripheral Artery Disease
Sponsor: Northwestern University

PROTOCOL TITLE:  
Low InTensity Exercise intervention in PAD: The LITE 
Trial  
 
PRINCIPAL INVESTIGATOR:  
Mary McDermott, MD  
 
 
 
 
 
Northwestern University 
Department of General Internal Medicine  
312-503-6419  
mdm608@northwestern.edu  
 
VERSION NUMBER:  
 
Version #38  
 
VERSION DATE:  
 
 
8/16/2021 
 
NCT NUMBER: 
 
 
NCT02538900 

PROTOCOL TITLE: Low InTensity Exercise intervention in PAD:  The LITE Trial
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 PROTOCOL TITLE:
Low InTensity Exercise intervention in PAD:  The LITE Trial
PRINCIPAL INVESTIGATOR:
Mary McDermott, MD
Department of General Internal Medicine
312-503-6419
Mdm608@northwestern.edu 
VERSION NUMBER:
Version #38
VERSION DATE:
           8/16/2021
Table of Contents
1.0
Objectives .................................................................................................................3
2.0
Background...............................................................................................................4
3.0
Inclusion and Exclusion Criteria ..............................................................................9
4.0
Study-Wide Number of Subjects............................................................................11
5.0
Study-Wide Recruitment Methods .........................................................................11
6.0
Multi-Site Research ................................................................................................11
7.0
Study Timelines......................................................................................................11
8.0
Study Endpoints......................................................................................................11
9.0
Procedures Involved ...............................................................................................12
10.0
Data and Specimen Banking...................................................................................23
11.0
Data and Specimen Management ...........................................................................23
12.0
Provisions to Monitor the Data to Ensure the Safety of Subjects...........................26
13.0
Withdrawal of Subjects*.........................................................................................26
14.0
Risks to Subjects*...................................................................................................26
15.0
Potential Benefits to Subjects .................................................................................28
16.0
Vulnerable Populations...........................................................................................29
17.0
Community-Based Participatory Research.............................................................29
18.0
Sharing of Results with Subjects ............................................................................29
19.0
Setting.....................................................................................................................29
20.0
Resources Available ...............................................................................................30
21.0
Prior Approvals.......................................................................................................30
22.0
Recruitment Methods..............................................................................................30
23.0
Local Number of Subjects ......................................................................................32
24.0
Confidentiality ........................................................................................................32
25.0
Provisions to Protect the Privacy Interests of Subjects ..........................................32
26.0
Compensation for Research-Related Injury............................................................32
27.0
Economic Burden to Subjects.................................................................................33
28.0
Consent Process......................................................................................................33
29.0
Process to Document Consent in Writing...............................................................33
30.0
Drugs or Devices ....................................................................................................33
31.0
References...............................................................................................................34
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1. Objectives
1.1
Purpose/Objectives.
Clinical practice guidelines recommend supervised, high-intensity, ischemic-pain inducing treadmill 
exercise to improve walking performance in people with lower extremity peripheral artery disease 
(PAD) (1,2).  However, supervised exercise is not paid for by medical insurance.  Furthermore, the 
ischemic leg pain induced by high intensity exercise is a barrier to exercise for patients with PAD.  
Thus, fewer than five percent of the more than eight million men and women with PAD in the United 
States participate in supervised exercise (3,4). This proposed study will determine whether an alternative 
exercise intervention that avoids continuous supervision and exercise-related ischemic pain improves 
functional performance at 52-week follow-up in people with PAD.  Our intervention directly addresses 
two aspects of current practice guidelines that are major barriers to exercise for patients with PAD:  1) 
the recommendation for long-term supervised exercise and 2) the recommendation for high intensity 
ischemic-pain inducing walking exercise (1,2).
We will randomize 305 PAD participants to one of three parallel arms:  Group 1: Low-intensity, self-
paced walking exercise; Group 2: Standard high intensity, ischemic pain-inducing walking exercise; 
Group 3:  Non-exercising attention control group.  The low and high intensity exercise groups will 
attend center-based exercise sessions once per week for four weeks followed by transition to an entirely 
home-based exercise program for an additional 48 weeks (52 weeks total).  The low and high intensity 
exercise interventions will use identical self-regulatory and support strategies.  However, the low 
intensity exercise group will be instructed to exercise with minimal to no ischemic leg discomfort and 
the high intensity group will be instructed to exercise to maximal ischemic leg pain.  These two distinct 
exercise prescriptions will be reinforced during 48 weeks of home-based exercise, using a well-validated 
behavioral coaching model that can be delivered by telephone once weekly.  Our primary outcome is 
change in six-minute walk distance at 52-week follow-up.  If our hypotheses are correct, millions of 
people with PAD will benefit from this alternative exercise regimen which will be accessible to most of 
the 8 million people in the U.S. who suffer from PAD. 
1.2
Specific Aims/Hypotheses.
Primary Specific Aim. We will determine whether PAD participants randomized to a low 
intensity, self-paced home-based walking exercise intervention achieve greater improvement or 
less decline in six-minute walk performance at 52-week follow-up, compared to those 
randomized to a high-intensity, ischemic pain inducing home-based walking exercise 
intervention and as compared to the attention control group, respectively.  We hypothesize that 
PAD participants randomized to low-intensity exercise will achieve greater increases or less 
decline in six-minute walk distance at 52-week follow-up compared to those randomized to high-
intensity exercise and as compared to the attention control group, respectively.  
Secondary Specific Aim #1.  We will determine whether PAD participants randomized to a low 
intensity, self-paced walking exercise intervention achieve greater improvement or less decline in six-
minute walk distance, physical activity, patient-perceived walking performance (measured by the 
Walking Impairment Questionnaire (WIQ)), and health-related quality of life (measured by the short-
form 36 physical functioning (SF-36 PF)) score at 26-week follow-up, compared to PAD participants 
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randomized to the high-intensity exercise intervention and as compared to the attention control group, 
respectively.  We hypothesize that PAD participants randomized to low intensity exercise will achieve 
greater increases or less decline in six-minute walk distance, physical activity, WIQ distance and speed 
scores, and the SF-36 PF Score at 26-week follow-up, compared to those randomized to high-intensity 
exercise and as compared to the attention control group, respectively.     
Secondary Specific Aim #2. We will determine whether PAD participants randomized to a low 
intensity, self-paced walking exercise intervention achieve greater improvement or less decline in 
maximal treadmill walking time, physical activity, patient-perceived walking performance (measured by 
the Walking Impairment Questionnaire (WIQ) distance and speed scores), and health-related quality of 
life (measured by the short-form 36 physical functioning (SF-36 PF)) score at 52-week follow-up, 
compared to PAD participants randomized to the high-intensity exercise intervention and as compared 
to a control group, respectively.  We hypothesize that PAD participants randomized to low intensity 
exercise will achieve greater increases or less decline in maximal treadmill walking time, physical 
activity, WIQ, and the SF-36 PF Score at 52-week follow-up, compared to those randomized to high-
intensity exercise and as compared to the control group, respectively.     
Secondary Specific Aim #3.  We will determine whether participants randomized to low intensity 
exercise have greater adherence to the home-based exercise intervention compared to participants 
randomized to high intensity exercise. Adherence is defined as the proportion achieving at least 80% of 
the prescribed exercise frequency and duration during the final month of the intervention.  Exercise 
frequency and duration will be measured objectively with the ActiGraph and by patient self-report.  We 
hypothesize that participants randomized to low intensity exercise will have higher adherence to the 
prescribed exercise intervention than participants randomized to high intensity exercise.  
Secondary Aims #4 and #5 were added in March 2020, before any outcome data were analyzed.  These 
specific aims were added because randomized trials published since the LITE Study was designed, 
demonstrated no effect of a high intensity home-based walking exercise intervention on six-minute walk 
distance or other walking outcomes in people with PAD at 6 and at 9 month follow-up compared to a 
control group that did not exercise  (5, 6).  Since the LITE Trial studied the effect of a high intensity 
home-based walking exercise intervention on change in six minute walk distance at 6-month and 12-
month follow-up, compared to an attention control group, Secondary Specific Aims #4 and #5 are 
particularly important.
 
Secondary Specific Aim #4.  We will determine whether participants randomized to the high intensity 
exercise intervention have greater improvement or less decline in six-minute walk distance, physical 
activity, patient-perceived walking performance (measured by the WIQ distance and speed scores), and 
health-related quality of life measured by the SF-36 PF score at 26 week follow-up, compared to PAD 
participants randomized to the control group.   We hypothesize that participants randomized to the high 
intensity exercise intervention will have greater improvement or less decline in each outcome at 26-
week follow-up compared to the attention control group.
Secondary Specific Aim #5.  We will determine whether participants randomized to the high intensity 
exercise intervention have greater improvement or less decline in six-minute walk distance, maximal 
treadmill walking time, physical activity, patient-perceived walking performance (measured by the WIQ 
distance score), and health-related quality of life measured by the SF-36 PF score at 52 week follow-up, 
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compared to PAD participants randomized to the control group.   We hypothesize that participants 
randomized to the high intensity exercise intervention will have greater improvement or less decline in 
each outcome at 52-week follow-up, compared to the control group.
Secondary Specific Aim # 6.  
Preliminary evidence suggests that ischemia-reperfusion, such as that experienced during high-intensity 
exercise in PAD, is associated with reduced muscle mitochondrial oxidative metabolism and increased 
oxidative stress (7-9).  Therefore, in a randomly selected subset of participants, we will determine 
whether participants randomized to low intensity exercise (N=50) have greater improvement in calf 
muscle mitochondrial oxidative metabolism and lesser increases in calf muscle oxidative stress at 52-
week follow-up, compared to the high-intensity intervention (N=50).  We will also determine whether 
those randomized to low intensity exercise (N=50) and those randomized to high-intensity intervention 
(N=50), respectively, have greater improvement in calf muscle mitochondrial oxidative metabolism at 
52-week follow-up, compared to the control group (N=50).  
Exploratory Specific Aim 1. We will use qualitative methods to explore participants’ perceptions of the 
exercise interventions in the high and low-intensity exercise groups, respectively, at 52-week follow-up.
Exploratory Specific Aim 2.  In an exploratory specific aim, in up to 15 people with PAD and a body 
mass index > 28 kg/M2 who previously participated in the LITE Study or who were evaluated for 
participation, we will test the feasibility and efficacy of a 16-week weight loss intervention combined 
with the LITE home-based exercise intervention.  The primary goals will be to determine whether it is 
feasible and effective give to add a weight loss intervention to the LITE home-exercise intervention in 
people with PAD who are overweight.  We will determine whether this modification of the LITE 
intervention (weight loss combined with the LITE home-based exercise intervention) can improve six-
minute walk distance in people with PAD.
Exploratory Specific Aim 3.  In an exploratory specific aim, in up to 30 people with PAD, we will determine 
whether, compared to placebo, nitrate-rich beetroot juice acutely improves six-minute walk distance or the short 
physical performance battery (SPPB), two-hours after nitrate-rich beetroot juice or placebo ingestion.  We will 
also collect preliminary data to determine whether, as compared to placebo and as compared to nitrate-rich 
beetroot juice, far-red light (approximately 660 nm) alone and the combination of far-red light + nitrate-rich 
beetroot juice acutely increase plasma nitrite and improve six-minute walk distance, four meter walking 
velocity at usual or fast pace, or the SPPB, approximately two to three hours after far-red light treatment alone 
and the combination of far-red light treatment with nitrate-rich beetroot juice.
2.0
Background
2.1
Relevant experience.
A. Our prior work supports the LITE Trial proposal.  Our multidisciplinary investigative team 
includes internationally renowned experts in PAD, behavioral change, exercise training, functional 
performance, and skeletal muscle metabolic function.  Our observational work, funded by the 
NHLBI, established that people with PAD have greater functional impairment, faster functional 
decline, and greater mobility loss than individuals without PAD (11-15).  These associations are 
present even in PAD patients who are asymptomatic or who do not have classic intermittent 
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claudication symptoms (11-15).  We have completed two NHLBI-funded randomized trials of 
exercise in people with PAD.  The Study to Improve Leg Circulation (SILC) (R01-HL073351) 
demonstrated that supervised treadmill exercise significantly improves six-minute walk in PAD 
participants both with and without claudication symptoms (55).  However, the SILC trial’s 
requirement for supervised exercise is burdensome.  Furthermore, our SILC trial showed that once 
supervised exercise is removed, PAD participants stop adhering to exercise and lose gains in 
walking performance (see Table 2 below).  Our Group Oriented Arterial Leg Study (GOALS) trial 
(R01-HL088589) demonstrated that a Group Mediated Cognitive Behavioral intervention 
significantly improved walking performance in patients with PAD (52).  However, the GOALS 
intervention required weekly attendance at group sessions, which is impractical for many patients 
with PAD and is not covered by medical insurance.  Furthermore, assembling a group of PAD 
participants can be difficult.  The LITE Trial overcomes all of these limitations and employs remote 
monitoring to promote home exercise and avoid regular visits to the exercise center.
B. Our SILC Trial showed that gains from a high intensity supervised treadmill exercise 
intervention are lost when supervision is no longer available.  In our SILC trial, PAD participants 
randomized to supervised treadmill exercise improved their six-minute walk at six-month follow-up 
by +20.6 meters, while the control group declined (-20.4 meters) (55).  After completing supervised 
exercise, participants in the intervention were asked to continue high-intensity exercise at home and 
were telephoned at regular intervals for an additional six months.  Although participants were 
encouraged to walk for exercise at least three times weekly, the mean frequency of home-based 
exercise was only 1.9 times per week and participants lost the gains they had achieved during 
supervised exercise as shown in Table 1.  
Table 1.  Changes in six-minute walk during the supervised and unsupervised phases of our SILC trial 
Supervised Exercise: Baseline to 6 month f/up
Unsupervised Exercise: 6 to 12 month f/up.
Treadmill Exercise 
Group (N=41)
Control 
Group 
(N=39)
P Value
Treadmill Exercise 
Group (N=41)
Control 
Group 
(N=39)
P Value
Change in 6-
minute walk.
+ 20.6 Meters
-20.4 Meters
<0.001
-24.5 Meters
+3.34 Meters
0.031
2.2
Significance of the research.
A. Lower extremity peripheral artery disease (PAD) affects eight million people in the United 
States (U.S.) (10).  PAD will be increasingly prevalent as the U.S. population survives longer with 
chronic disease.  Men and women with PAD have greater functional impairment and more rapid 
functional decline than those without PAD (11-15).  The functional limitations experienced by 
people with PAD are associated with increased rates of mobility loss, increased hospitalization rates, 
and poor quality of life (16-19). 
B. Clinical practice guidelines recommend high-intensity, ischemic-pain inducing supervised 
treadmill exercise to improve walking performance and prevent mobility loss in PAD (1,2).  
This Class I, Level of Evidence A recommendation originates from a meta-analysis of 21 studies of 
exercise for PAD patients, published in JAMA in 1995 (20).  In this meta-analysis, supervised 
treadmill exercise was associated with a 122% increase in maximal treadmill walking distance and a 
179% increase in pain-free treadmill walking distance, compared to control.  Participants who were 
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asked to walk to maximal ischemic leg pain achieved greater gains in treadmill walking distance 
than those who were asked to walk to onset of pain +(606.8 meters + 426.6 vs. +195.5 meters + 78.3, 
respectively, P=0.005).  Yet, our data (section C3e), and that of others (21-23) show that exercise-
related ischemic pain is a major deterrent to exercise in PAD.  Recent evidence from supervised 
exercise trials suggests that low-intensity exercise may be beneficial for people with PAD.
C. Three recent clinical trials of supervised low-intensity treadmill exercise suggest benefit for 
patients with PAD (24-26).  One trial demonstrated that low-intensity supervised exercise was 
more effective than a no-exercise control group in PAD (24).  Two trials (25,26) demonstrated 
increases in treadmill walking performance as compared to baseline in PAD patients randomized to a 
supervised low intensity exercise intervention (see Table 2).  
Table 2.  Summary of three trials showing that SUPERVISED low-intensity exercise is effective in PAD 
Author/year
Study Design
Results
Limitations
Mika P et 
al/2005 (24)
98 participants with PAD and 
claudication were randomized 
to 12 weeks of supervised 
treadmill exercise vs. control 
(no exercise).
Treadmill time to onset of 
claudication pain increased by 
119% in the supervised low-
intensity exercise group vs. 17% in 
the control group.
The study tested supervised 
exercise, which is not 
accessible to most PAD 
patients.
Gardner 
AW et 
al/2005 (25)
64 participants with 
claudication were randomized 
to 6 months of high-intensity 
supervised ischemic pain-
inducing exercise vs. 6 months 
of low-intensity supervised 
exercise.
Compared to baseline, maximal 
treadmill walking distance 
increased by 63% in the high 
intensity group compared to 
baseline (P<0.01) and by 61% in 
the low-intensity group compared 
to baseline (P<0.01).
The study tested supervised 
treadmill exercise, which is 
not accessible to most PAD 
patients. There was no control 
group. 
Mika P et 
al/2012 (26)
60 participants with 
claudication were randomized 
to 12 weeks of high-intensity 
supervised treadmill exercise 
vs. 12 weeks of low-intensity 
supervised exercise.
Maximal treadmill walking time 
increased by 98% in the low-
intensity supervised group and by 
100% in the high-intensity 
supervised group. 
The study tested supervised 
exercise, which is not 
accessible to most PAD 
patients. There was no control 
group that did not exercise.
All three studies shown in Table 1 tested a SUPERVISED exercise intervention. However, most PAD 
patients do not have access to supervised exercise (see section A4).  No studies have assessed 
whether an alternative home-based low intensity walking exercise intervention improves walking 
performance in PAD.
D. The importance of establishing an exercise program that is accessible and acceptable to PAD 
patients.  Few people with PAD participate in supervised high intensity exercise programs that are 
recommended by practice guidelines (1,3,4,27).  There are several reasons.  First, medical insurance 
does not pay for supervised exercise.  Second, transportation to a center three times weekly for 
supervised exercise is burdensome for people with PAD.  Third, ischemic leg pain is a major barrier 
to walking exercise activity in people with PAD (21-23).  Our proposed alternative exercise 
intervention that employs low-intensity, self-paced walking exercise carried out at home will be 
accessible to most PAD patients.  An effective exercise intervention that is accessible and acceptable 
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to most patients with PAD is urgently needed to improve walking performance and prevent disability 
in the large and growing number of patients suffering from PAD. 
E. Clinical practice guidelines state that evidence is insufficient to recommend home-based 
walking exercise for PAD patients (1,27).  Three small trials of home-based walking exercise in 
PAD patients using telephone coaching yielded contradictory results (28-30).  But sample sizes of 
these studies were small, ranging from N=16 to N=24 (26-28).  Two of these studies showed that 
telephone coaching did not increase home-based walking exercise in PAD (28,29).  The third trial 
randomized 21 patients with PAD to either a 24 week home-based walking exercise program or a 12 
week supervised exercise program followed by a 12 week home-based walking exercise program 
(total of 24 weeks for each arm).  At 24 week follow-up, both groups (24 continuous weeks of home 
based exercise vs. 12 weeks of supervised followed by 12 weeks of home exercise) significantly 
improved their treadmill walking time as compared to baseline.  There was no significant difference 
between the two groups (30).  However, there was not a non-exercising control group in this study.  
Treadmill walking distance, the study’s primary outcome, is associated with a significant learning 
effect in people with PAD (28).  None of these three studies (28-30) used proven behavioral 
techniques to promote home-based exercise (28-30).  Clinical practice guidelines state that there is 
insufficient evidence to support home-based exercise in PAD patients (1,27).  Most physicians do 
not recommend walking exercise for PAD patients (31,32).  A definitive trial is needed to establish 
that a home-based walking exercise program that does not require regular visits to an exercise center 
improves walking performance in people with PAD.
F. High intensity, ischemic pain-inducing walking exercise may adversely affect calf skeletal 
muscle in people with PAD.  Mitochondria are double membrane-enclosed organelles that generate 
adenosine triphosphate (ATP), the primary energy source for skeletal muscle cells (33).  In patients 
with PAD, high-intensity exercise is associated with ischemia and subsequent reperfusion of calf 
skeletal muscle (7,38,39).  Animal studies and preliminary human evidence show that re-perfusion 
of target tissue after ischemia increases oxidative stress, promotes mitochondrial dysfunction, and 
reduces ATP production (7-9,34-36).   Preliminary human evidence suggests that high-intensity, 
ischemia-inducing walking exercise has harmful effects on calf skeletal muscle (36-39).  We 
hypothesize that by avoiding the ischemia and re-perfusion associated with high intensity exercise, 
low-intensity exercise will promote more favorable calf muscle mitochondrial changes in PAD.  We 
expect these favorable muscle changes will facilitate improved functional performance.  Therefore, 
in our Secondary Aim #3, we will determine whether high-intensity, ischemic-pain inducing exercise 
increases calf muscle levels of oxidative stress and impairs calf muscle mitochondrial function, 
compared to low-intensity exercise.   We will also determine whether low-intensity exercise 
improves mitochondrial function, compared to the control group.  Because low intensity exercise is 
not associated with ischemia/reperfusion, we will not compare oxidative stress between the low 
intensity intervention and the control group.
G. Conceptual Model/Basis for our Study Design.  Walking-related leg pain is a major deterrent to 
exercise in PAD (21-23). This phenomenon is not surprising from a behavioral perspective.  
According to Social Cognitive Theory (40,41), people’s self-efficacy (confidence) in their ability to 
perform a health behavior and the behavior’s incentive (reward) value are major determinants of 
adherence to healthy behaviors (42).  Aversive physical symptoms (i.e. pain) that are associated with 
a behavior (i.e. walking) diminish the behavior’s reward value, result in avoidance of the behavior, 
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and undermine self-efficacy about the ability to perform the behavior (40,41).  Consistent with this, 
we observed in patients with knee arthritis that more intense knee pain is related to poorer 
performance on measures of both self-reported and objective measures of physical function (43,44). 
In a trial of 439 participants with knee osteoarthritis (mean age 68.6+ 6, 30% males), who were 
randomized to aerobic walking exercise, resistance training, or a control group, Rejeski and 
colleagues observed that improvement in knee pain in response to the intervention mediated the 
benefits of exercise on performance (45,46).  Among participants randomized to aerobic exercise, 
knee pain was reduced in participants who exercised at a low intensity but not in participants who 
engaged in high/maximal intensity exercise.  These findings in people with knee osteoarthritis are 
consistent with our hypothesis that self-paced walking exercise will be more acceptable and will 
achieve greater gains in walking performance compared to high-intensity ischemic-pain inducing 
exercise in people with PAD.  
A patient’s ability to cope with pain is an important predictor of physical disablement (47-49).  Pain 
acceptance is the ability to accept and deal with pain (49).  We recently modified McCracken and 
colleagues’ measure of pain acceptance (49) for use with PAD patients. We found that PAD patients 
with higher (more favorable) scores for pain acceptance walked significantly further in the six-
minute walk (48).  Pain acceptance was inversely related to number of depressive symptoms (r = -
0.53).These findings are consistent with our hypothesis that PAD patients who exercise at a low 
intensity with minimal pain will achieve greater gains than those randomized to the high intensity, 
ischemic pain inducing exercise intervention.
Prior studies of sedentary people without PAD demonstrate that a low-intensity exercise intervention 
improves physical activity levels and/or cardiopulmonary fitness (50,51).  However, a home-based 
low-intensity exercise intervention has not been previously tested in people with PAD.  We 
hypothesize that our low-intensity home-based walking exercise intervention will improve functional 
performance by encouraging adherence to a home-based walking exercise program and by 
improving calf muscle health (see Figure 1).
Figure 1. Theoretical Model for Association of a Low-intensity, Self-paced Exercise Intervention with 
Improved Functional Performance in People with PAD.
H.
I.
Lower extremity 
atherosclerosis 
(PAD)
Ischemic 
pain on 
walking
Functional 
impairment 
and decline
High Intensity 
Ischemic-Pain 
Inducing 
Exercise
Clinically 
meaningful 
improvement 
in functional 
performance
Exercise 
Intervention
Slight 
improvement 
or maintenance 
of functional 
performance
Continued 
decline in 
functional 
performance
Increased calf muscle 
oxidative stress.  No change 
in mitochondrial function. 
Reduced calf muscle 
oxidative stress.  Improved 
mitochondrial function.
High adherence to exercise
Low Intensity 
Self-Paced 
Exercise
Control
Low adherence to exercise
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H. Importance of the LITE Trial.  Few men and women with PAD participate in the high-intensity 
supervised exercise recommended by clinical practice guidelines (3,4).  Our proposed alternative 
exercise intervention overcomes two major barriers to exercise for patients with PAD:  1) the 
recommendation for supervised exercise and 2) exercise-induced ischemic leg pain.  If our 
hypotheses are correct, our results will have major implications for the 8.0 million men and women 
in the U.S. who suffer from PAD.       
2.3
Innovation of the research. 
A.  No prior studies have tested whether home-based low-intensity exercise improves functional 
performance in patients with PAD.  Three previous trials demonstrated that supervised low-intensity 
exercise improved treadmill walking in people with PAD (24-26).  These supervised exercise trials 
support our hypotheses.  However, home-based low-intensity exercise has never been studied in people 
with PAD.  Determining whether a home-based low-intensity exercise intervention improves outcomes 
is important, because most PAD patients do not have access to supervised exercise (see section A4 
above).
B.  No prior studies have used mobile devices to help PAD patients self-monitor exercise activity 
or intensity.  As mobile technology is increasingly accessible, it is an important tool to promote healthy 
behaviors in patients with chronic disease.  In the LITE Trial, PAD participants randomized to exercise 
will use an ActiGraph accelerometer to monitor their walking exercise frequency, duration, and 
intensity.  Uploaded data will be visible to participants and the study coach (see section C12c).  Using a 
mobile device to help PAD participants monitor walking exercise behavior is a highly innovative feature 
of the LITE trial.  
C.  No prior randomized trials have tested the ability of a 52-week home-based exercise 
intervention to improve outcomes in PAD.  Prior home-based exercise interventions in PAD have 
ranged from 12 weeks to six months duration (29-31,52-54).  Home-based exercise interventions that are 
sustainable over the long term are essential for populations with chronic disease, such as those with 
PAD.   No prior studies of PAD participants have employed a coach that remotely monitors exercise 
activity for 52 weeks.
D.  No prior studies have tested whether low-intensity exercise reduces calf muscle oxidative stress 
or increases calf muscle mitochondrial function compared to high intensity ischemia-inducing 
exercise.  During high intensity exercise in people with PAD, metabolic demands for oxygen exceed 
oxygen supply.  Calf muscle reperfusion occurs during rest, when blood supply becomes sufficient to 
meet calf muscle oxygen requirements.  However, animal data and preliminary human evidence suggest 
that re-perfusion after ischemia increases oxidative stress and impairs mitochondrial function (7-9,35-
39).  We hypothesize that an exercise intervention that avoids ischemia will protect calf muscle against 
oxidative stress and improve mitochondrial function.  This hypothesis has never been tested in people 
with PAD.
3.0
Inclusion and Exclusion Criteria
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3.1
Screening for eligibility.
Initial eligibility criteria will be assessed by telephone with a recruitment call script.  
Potential participants who remain eligible after the telephone screening will be scheduled 
for a baseline visit, where they will undergo additional testing to determine their eligibility 
for randomization.
A. Recruitment. We will randomize 305 PAD participants over 32-months, allowing for a 15% drop-out at 
52-week follow-up.  This drop-out rate is comparable to the 52-week drop-out rate in our GOALS and 
SILC trials (52,55).  We will identify participants using 1) Northwestern’s Enterprise Data Warehouse to 
identify patients with PAD; 2) radio and newspaper advertising; and 3) bulk mailed postcards to people 
age 55 and older living in the Chicago area.  We have successfully used each method in our prior 
clinical trials.  Based on our previous work involving participants with PAD, we anticipate that the 
average age will be approximately 70 years, that at least 33% of participants will be minorities, and that 
approximately 50% will be women.  For example, in our recently completed SILC randomized 
controlled clinical trial of exercise in patients with PAD (55), participants were average age 70.6 + 10.3 
and the average ABI was 0.61 + 0.17.  In SILC, participants included 52% women and 45% African-
Americans.  In general, patients with PAD have a high prevalence of comorbid diseases, particularly 
coronary artery disease, cerebrovascular disease, and diabetes mellitus.  Thus the patient population is 
likely to be of poorer health than that of similarly aged men and women without PAD in the general 
population.  
 
B. Our experience successfully enrolling PAD participants in NHLBI-funded studies: Since 2004, we 
have randomized 661 PAD participants from the Chicago-area into NHLBI-funded clinical trials.  Since 
1998, we have enrolled more than 1,800 participants with PAD into our NHLBI-funded studies.  Thus, 
we have the experience and expertise to successfully recruit the proposed 305 PAD participants for the 
LITE Trial.
C. Randomization. Participants will be randomized to one of three parallel arms using a SAS computer 
program.  Block randomization will be implemented to ensure balance between the three groups.  
Randomization will be stratified by according to whether the participants are eligible for (and consented 
to) muscle biopsy.
D. Rationale for focus on walking exercise.  Walking exercise is the only form of exercise that 
consistently improves walking performance in PAD and is the only exercise currently recommended by 
practice guidelines for PAD (1,2,27,64).   
3.2
Criteria.
Inclusion and exclusion criteria. All participants will have PAD. PAD will be defined as follows. First, 
an ABI < 0.90 at the baseline study visit is a well-accepted standard for the diagnosis of PAD and will 
be an inclusion criterion (59-62). Second, people with an ABI of >0.90 and <1.00 who experience a 20% 
ankle systolic pressure drop after the heel-rise test will also be included. Third, potential participants 
with an ABI > 0.90 who have vascular lab evidence of PAD* or angiographic evidence of PAD** who 
have ischemic symptoms during the six-minute walk and/or treadmill exercise stress test will be eligible. 
In addition to meeting a criterion for PAD, all participants must be symptomatic, defined by one of the 
following criteria:;  a) ischemic leg symptoms (primarily assessed with the San Diego Claudication 
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Questionnaire); b) report ischemic leg symptoms at the end of the six-minute walk; c) report ischemic 
leg symptoms at the end of the baseline treadmill stress test; d) walking impairment questionnaire 
results, e) interview with the potential participant about the presence and nature of leg symptoms during 
walking activity. Exclusion criteria are listed in Table 3.
* If the only criterion by which a participant is eligible to participate is a toe pressure, the toe pressure 
must be < 70 or the toe brachial index ratio must be < 0.60 if asymptomatic or < 0.70 if symptomatic.
** Angiographic criteria of PAD consist of a stenosis of 70% or greater in a lower extremity artery.
Table 3.  Summary of exclusion criteria and justification for each criterion.
List of specific exclusion criteria
Justification for exclusion criteria
1. Above or below knee amputation, critical limb 
ischemia, wheelchair confinement, or foot ulcer.
1. Inability to fully participate in the intervention.
2. Individuals whose walking is limited by a condition 
other than PAD. 
2. The intervention is designed to improve PAD-related 
walking impairment.
3. > Class II NYHA heart failure or angina. Increase in 
angina, angina at rest, or abnormal baseline treadmill 
stress test. 
3. Exercise may not be safe for these potential 
participants.
4. Major surgery including lower extremity 
revascularization or orthopedic surgery during the prior 
three months or anticipated in the next twelve months.
4. Surgery may influence change in functional 
performance, independent of study interventions.
5. Major medical illness including renal disease 
requiring dialysis, lung disease requiring oxygen, or 
cancer (other than non-melanoma skin cancer) requiring 
treatment in the prior three years. Note: Potential 
participants may still qualify if they have had treatment 
for an early stage cancer in the past three years and the 
prognosis is excellent. Patients who use oxygen at night 
may still qualify.
5. These conditions may interfere with the ability to 
fully participate and complete the study.
6. Mini-mental status examination score <23 (63), 
dementia, or psychiatric illness including severe 
depression or anxiety. However, investigator
discretion may be used to allow some people with an 
MMSE below this threshold to participate, if the 
investigator determines there is another reason for their 
lower score, including lack of sufficient familiarity with 
the English language or lack of sufficient education to 
achieve a score of 23 or higher. Note that the MMSE 
includes some spelling and English writing proficiency.
6. May interfere with ability to fully engage in the 
study.
7. Currently walking regularly for exercise at a level 
comparable to the amount of exercise prescribed in the 
intervention.
7. The interventions may not further improve 
functioning.
8. Currently enrolled in another clinical trial, exercise 
trial, or in cardiac rehabilitation. Currently enrolled in a 
clinical trial or participation in cardiac rehabilitation or a 
8. Interference with ability to determine whether study 
interventions are responsible for improved outcomes. 
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trial of a therapeutic intervention within the past three 
months. For a clinical trial of a stem cell or gene therapy 
intervention, potential participants will be potentially 
eligible immediately after the final study visit for the 
clinical trial, so long as long as at least six months has 
passed since the participant received  their final treatment 
in the stem cell or gene therapy intervention. For a 
clinical trial involving open-label therapy in which the 
treatment is not related to functional performance and 
will not change during the LITE Trial, participants may 
still qualify for the LITE Trial based on investigator 
discretion.
.
9. Individuals with PAD who have a history of lower 
extremity revascularization and currently have a normal 
ABI.
10.Potential participants who are unable to walk for 
exercise at a sufficiently slow pace to avoid ischemic leg 
symptoms.* 
9. We are seeking participants who currently have 
ischemia
10. Participants randomized into the low intensity 
intervention must be able to walk slowly enough to 
avoid ischemic leg symptoms.
*All individuals who are unable to walk for three minutes during a modified Gardner protocol or for 
one minute on a Gardner protocol exercise stress test will be interviewed by the study Principal 
Investigator (PI) or another physician investigator to determine whether they are able to walk 
sufficiently slowly to avoid ischemic leg symptoms during exercise activity.
3.3
Special Populations.
Vulnerable populations (fetuses, pregnant women, children, prisoners, and institutionalized persons) and 
adults unable to consent will not be included in this study.
4.0
Study-Wide Number of Subjects
NA
5.0
Study-Wide Recruitment Methods
NA
6.0
Multi-Site Research
To maximize recruitment rate for the LITE Trial, the University of Pittsburgh and the University of 
Minnesota will also serve as recruitment sites.  
7.0
Study Timelines
7.1
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
The duration of an individual subject’s participation in the study.
Each participant’s part in this study will last approximately 52 weeks. During the first four 
weeks, participants will attend four weekly on-site visits to orient them to the intervention 
followed by transition to entirely home-based exercise, using identical behavioral 
techniques, for an additional 48 weeks. 

The duration anticipated to enroll all study subjects.
We anticipate that we will enroll all study subjects over 32 months.

The estimated date for the investigators to complete this study (complete primary 
analyses).
We anticipate that we will complete data collection over 44 months.  See study timeline 
below.
Study Timeline
Months
2
3
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46     47
48
Start-up
Recruitment & 
enrollment
Intervention and 
follow-up measures
Data analyses & 
manuscript writing
8.0
Study Endpoints
8.1
Primary and secondary study endpoints.
We selected the Six-minute walk as the primary study endpoint because ability to walk long distances 
was the most common outcome that PAD patients wanted to improve.  The six-minute walk is an 
objective and well-validated measure of walking endurance that is well accepted in the scientific 
community (3-8,11,17,46-48). Change in the six-minute walk has been linked to clinically meaningful 
outcomes, including mobility loss, mortality, and meaningful declines in quality of life (49,50).  
Therefore, the six-minute walk, an objective measure, is our primary outcome. We have substantial 
experience measuring the six minute walk (2-8,11,17).  Most prior clinical trials of PAD patients used 
treadmill walking as their primary outcome measure.  However, PAD patients in our focus groups report 
that treadmill walking is not a natural form of walking for them.  Published studies from older patients 
confirm this, and demonstrate that treadmill walking is associated with balance problems and anxiety 
(51-53).  The intra-class correlation coefficient for the test-retest reliability of the six-minute walk test 
among 156 PAD participants in our laboratory was 0.90 (p<0.001) when two six-minute walk tests were 
completed one to two weeks apart (46).  For all of these reasons, the six-minute walk test will be our 
primary outcome measure.
Additional endpoints include a) treadmill walking performance; b) seven day physical activity levels; c) 
calf muscle biopsy measures; d) patient perceived walking ability (WIQ distance and speed scores); e) 
Health-related quality of life (SF-36 PF); f) adherence to exercise; g) qualitative interviews 
(exploratory). In addition, some participants may be asked questions about their interest in supervised 
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treadmill exercise programs, barriers to their participation in supervised exercise programs, and their 
ability to participate in supervised treadmill exercise programs.  Blood samples will be collected for 
potential later analyses.  The WIQ stair climbing score will also be measured.
9.0
Procedures Involved
9.1
Study design.
LITE TRIAL OVERVIEW.   305 participants with PAD will be randomized to one of three parallel 
arms:  Group 1: low-intensity, self-paced walking exercise; Group 2:  high intensity, ischemic pain-
inducing walking exercise; Group 3:  Non-exercising attention control group.  Groups 1 and 2 will 
attend four weekly on-site sessions to orient them to the intervention followed by transition to entirely 
home-based exercise, using identical behavioral techniques, for an additional 48 weeks (total 
duration= 52 weeks). 
A. Data collection overview.  Table 4 shows outcome measures planned at each time point.
Table 4.  Data Collection Plan
Study Measure
Baseline
26 week follow-up
52 week follow-up
Six minute walk distance (Primary 
Outcome)
X
X
X
Treadmill walking performance
X
X
Blood collection
X
X
Seven day physical activity levels
X
X
X
Calf muscle biopsy measures
X
X
Patient perceived walking ability (WIQ 
scores)2
X
X
X
Health-related quality of life (SF-36 PF)
X
X
X
Adherence to exercise1
0
X
X
Qualitative interviews1
0
X
Figure 2.  Overview of the LITE Trial Study Design.
ActiGraph-monitored intensity, frequency, duration of home-based exercise in Groups 1 and 2
Home based low 
intensity exercise
Home based high 
intensity exercise
Home based 
attention control
Phase II.  48-week home based 
exercise or attention control
26-week and
52-week 
follow-up 
measures
(See Table 7)
PAD 
participant
Baseline 
measures 
(see Table 7)
Group 1: Home based low 
intensity exercise with 4 
weekly center visits
Randomized 
Group 2: Home based high 
intensity exercise with 4 
weekly center visits
Group 3: Four weekly 
attention control visits
Phase I.  4 weekly on-site 
sessions or attention control
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1These outcomes will be measured at 52-week follow-up in participants randomized to high or low 
intensity exercise.2 The WIQ distance and speed scores are secondary outcomes.  The WIQ stair 
climbing score is a pre-specified additional outcome.
In addition, some participants may be asked questions about their interest in supervised treadmill exercise 
programs, barriers to their participation in supervised exercise programs, and their ability to participate in 
supervised treadmill exercise programs.  These additional questions will be collected as pilot data for a 
subsequent study and may be administered at any time point during the LITE Trial.
Following final follow-up testing, participants may be called and asked to complete a questionnaire about their 
current walking activities. The trial demonstrated an important and unanticipated finding, that walking exercise 
that induced ischemic leg symptoms significantly improved walking ability more than walking exercise that did 
not induce ischemic leg symptoms.  Despite its benefits, it was more difficult for participants to engage in high 
intensity exercise in this trial.   In order to determine the long term effects of the intervention, we will ask study 
participants who completed the trial about their current exercise activity.  Specifically, we will telephone 
individuals who have completed the study and ask them approximately five to ten minutes of questions about 
their current mobility, exercise activity, and physical activity.  In addition to providing additional information 
about the exercise intervention, this information may be used to support a grant application. We will administer 
a verbal consent form prior to completing the study questionnaire. Only participants who agree via verbal 
consent will be asked the questionnaire.  
9.2
Research procedures.
A. Exercise intervention overview.  Drs. Jack Rejeski and Bonnie Spring, internationally recognized 
experts in behavior change, will direct the exercise interventions in the LITE Trial.  Their expertise 
is complementary.  Dr. Rejeski has specific expertise promoting exercise for patients with chronic 
health conditions (43,44,65,66).  Dr. Spring has specific expertise in telephone-delivered behavioral 
interventions for diet and activity change that incorporate mobile technology.  She pioneered the use 
of mobile transmission of participants’ behavioral data to telephone coaches in behavioral 
intervention trials (67).  This connective approach to behavioral interventions enables the coach to 
offer responsive, highly tailored interventions efficiently and allows participants to feel supported 
but also held accountable and avoids the need for regular visits to the exercise center. 
Participants randomized to low-intensity exercise will be advised to walk at a low, self-paced 
intensity that feels comfortable, maintaining a pain level of < 2 on the 1-5 Likert claudication pain 
scale, where ‘1’ indicates no pain and ‘5’ indicates maximum, severe pain (Figure 3).  Participants 
randomized to low-intensity exercise are told that the important goal is total time exercised at a 
comfortable, self-selected pace.  Participants randomized to high-intensity exercise will be asked to 
maintain a pain level of 4-5 on the 1-5 Likert pain scale (Figure 3).  These participants are told that 
to benefit from exercise training they must exercise at a level inducing moderate to high levels of 
ischemic pain (1,2).   
Figure 3. Claudication symptom severity for the low intensity and high intensity exercise 
No leg symptoms
1
2
3
4
5
Maximum leg symptoms
Moderate leg symptoms
Range for low intensity exercise
Range for high intensity exercise
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B. Phase I of the intervention (weeks 1-4):  In Phase I, participants randomized to either one of the 
two exercise groups will be asked to attend a total of four weekly visits to the exercise center over a 
four week period. If the sessions cannot be completed at weekly intervals over four weeks, the 
participant will have eight weeks to complete all four sessions to allow for make-up sessions.  At the 
first session, participants will be asked to begin walking for exercise at home at least five days 
weekly.  Our exercise facility has a 1/8 mile indoor track that participants will use to help them “get 
started” on a regular walking exercise regimen.  During Phase I, participants will learn to use the 
ActiGraph to collect and upload data regarding their walking exercise activity.  They will be taught 
to distinguish between high and low intensity exercise, using the ActiGraph to define activity counts 
corresponding to their low and high intensity exercise, respectively. They will meet and bond with 
the coach.  Based on our pilot studies, the four weekly exercise center visits will be sufficient to 
teach participants to use the ActiGraph to monitor their exercise and get started on home-based 
walking exercise.  Limiting Phase I to four weeks (four visits) will ensure that Phase I is not 
burdensome or difficult for participants.  Phase I is less demanding, for example, than a typical 
course of physical therapy prescribed for a patient suffering from low back pain (68).   
C. Phase II of the intervention (weeks 5-52).  Phase II will consist of entirely home-based exercise.  
Participants will be asked to wear the ActiGraph while they are exercising.  The ActiGraph records 
duration, frequency, and intensity of exercise.  The ActiGraph Bluetooth mechanism, available in the 
ActiGraph model that we will use in the LITE Trial, automatically uploads data to the study website, 
whenever participants walk within 15 feet of their home computer/tablet.  Participants without a 
home computer suitable for uploading ActiGraph data will be provided with a computerized tablet 
with wireless internet access for the duration of the study.  Our pilot data, collected in 150 
consecutive PAD participants in our ongoing studies, show that 65% own a home computer and that 
50% have home internet access.  Dr. Spring’s technology team will build the user-friendly website 
that participants and the coach will access to remotely monitor all aspects of home-based walking 
exercise.  Because we successfully taught 10 consecutive PAD patients to upload ActiGraph data on 
their home computer during one visit to our exercise center, we anticipate no difficulty teaching 
participants this method in the LITE Trial. 
D. Monitoring intensity of home-based walking exercise.  We will use the ActiGraph to objectively 
monitor fidelity to group assignments of high or low intensity exercise.  We selected the ActiGraph 
because data output is in raw form without proprietary equations, it has become the standard among 
researchers for physical activity measures, and it has accumulated a wealth of excellent validation 
data documenting its sensitivity to movement speeds and intensity (56-58).  As in our pilot study 
(section C3b), we will use the ActiGraph to establish individualized definitions of high vs. low 
intensity exercise for each participant at home.  We will define ActiGraph measured activity counts 
for high and low intensity exercise at home, because the environment in which participants exercise 
can influence their activity counts during high and low intensity exercise.  In addition, defining 
intensity in the home environment avoids visits to the exercise center.  To define activity counts for 
high intensity exercise at home, the coach will read this script over the telephone while the 
participant is in their home exercise setting wearing the ActiGraph, “I would like you to walk for 
five minutes at a high intensity pace so that you are experiencing moderate to severe discomfort.  
Once you reach moderate to severe discomfort, please continue walking for as long as you can. If 
you must rest, please begin walking again as soon as you are able.”  Participants will then put down 
their telephone and walk at a high intensity for approximately five minutes while the ActiGraph 
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records activity counts corresponding to high intensity exercise.  For low intensity exercise, the 
coach will read this script over the telephone while the participant is in their home exercise setting, 
“I would like you to walk for five minutes at a comfortable pace, so that you are not experiencing 
any pain or discomfort.  If you begin to experience pain or discomfort, please slow your pace so that 
it becomes comfortable again.”  Participants will then put down their telephone and walk at a low 
intensity for approximately five minutes while the ActiGraph records activity data corresponding to 
low intensity exercise.  ActiGraph-recorded activity count values for high vs. low intensity exercise 
will be used to determine whether the participant is adhering to their assigned intensity level.  We 
successfully used these methods in our pilot study. Table 5 shows two theoretical participants and 
how their ActiGraph-measured walking intensity would be used to ensure fidelity to their assigned 
group.
Table 5.  Examples of how the ActiGraph will be used to ensure fidelity to the assigned exercise intensity.
Theoretical participants
Mean and range of defined 
low intensity exercise
Mean and range of defined 
high intensity exercise
Actual mean exercise 
intensity
Participant #1- assigned 
to low intensity.
 2,900 activity counts 
(range 2,000-3,500)
5,000 activity counts
(range 4,500-5,500)
2,700 activity counts
Participant #2- assigned 
to high intensity.
2,000 activity counts 
(range 1,500 to 2,500)
4,500 activity counts
(range 4,000-5,000)
3,500 activity counts
For the theoretical participants in Table 9, the coach will counsel Participant #1 that they are exercising 
within their target  (low intensity) and encourage them to continue.  The coach will counsel Participant 
#2 that they are exercising below their target intensity range and will push them to increase their 
walking exercise intensity. We did not add ecological momentary assessment to the ActiGraph measure 
because of concern that wearing two devices combined with regular prompting for the ecological 
momentary assessment measures may be overly burdensome for PAD participants.  
E. Re-measuring high and low- intensity definitions during the intervention. Exercise intensity 
definitions for an individual may change over time.  Therefore, we will repeat the ActiGraph defined 
walking intensity measures at specified intervals during the study.  In supervised walking exercise 
interventions for PAD participants, the greatest improvements in walking performance occur during 
the first 8-12 weeks of the intervention (70).  Therefore, ActiGraph intensity definitions will be 
performed at baseline, and after one month, three months, six months, and nine months of the 
exercise intervention.  We will also define the ActiGraph intensity definitions after hospitalizations 
or inter-current illnesses.  Since the exercise definitions will be carried out at home, with the coach 
reading the study script by telephone, these calibrations will not be burdensome.
F. Weekly telephone coaching.  The coach will contact participants randomized to an exercise 
intervention by telephone once weekly for a five to fifteen minute coaching session.  Both the coach 
and participant will have access to the website showing the participant’s exercise duration, 
frequency, and intensity.  Each coaching contact will have a structured format.  Adherence to this 
format (treatment fidelity) will be monitored by the coach using a check-list (see Table 10). Either a 
subset or all telephone coaching calls will be audiotaped, enabling additional monitoring by an 
independent rater who is blinded to the intervention condition (see section C12f).  The components 
of each session, recorded on the check-list, are as follows: a) Checking in:  Review ActiGraph data, 
including the frequency, duration, and intensity of home-based exercise.  This will be reviewed in 
the context of the participant’s assigned group (high vs. low intensity) and walking exercise goals 
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established during the prior weekly telephone contact with the coach; b) Ensuring adherence to 
assigned low vs. high intensity exercise.  The coach will review the participant’s actual exercise 
intensity, based on ActiGraph recordings and provide feedback on intensity, using the established 
ActiGraph definitions of high and low intensity exercise for each participant.  c)  Discussion of 
challenges encountered during the past week and strategies for overcoming them.  Potential 
challenges we may encounter, based on our experience, include adverse weather affecting outdoor 
walking, difficulty finding time to exercise, and inter-current illness.  d) Discuss My Action Plan 
(MAP) for the coming week.  Participants will be asked to set exercise goals for the coming week.  
Goals will be written down and serve as a reference for the next weekly contact;   e) Wrap-
up/questions- mindful reflection with focus on successes and challenges. 
G. Intervention checklist.  The coach will use a checklist to guide each call.  A ten to fifteen percent 
subsample of audiotaped calls will be reviewed each quarter by investigators Drs. Spring, and 
Rejeski to ensure fidelity to the intervention.  Particular attention will be paid to fidelity to the 
exercise intensity the participant was randomized to receive.  No mention of high-intensity exercise 
will be permitted for participants in the low-intensity group.  No mention of low-intensity exercise 
will be permitted for participants randomized to high intensity exercise.  When the coach deviates 
from the protocol, the coach will be re-trained and certified.  
Table 6.  Study Checklist Components for Monitoring Fidelity to the Study Intervention.
Component
Low intensity, 
High intensity
Checking in-adherence to transmitting exercise 
frequency/duration
X
X
encouragement of self-paced, low-intensity walking exercise
X
0
Encouragement of high-intensity, ischemic pain inducing 
exercise
0
X
Discuss challenges encountered with solutions to overcome 
them
X
X
Discussion of My Action Plan (MAP)
X
X
Wrap-up, conclusion
X
X
H. Interventionist training and certification. Prior to beginning the study, the coach will undergo 
formal training in cognitive behavioral interventions by Dr. Rejeski.  Our coach, Mr. Al Rego, is an 
exercise physiologist who has served as an interventionist for our successful GOALS Study and for 
the LIFE Study at the Northwestern Field Center.  Training will include an overview of social 
cognitive theory, the conceptual background for the intervention, and an overview of PAD-related 
ischemic leg pain and optimal exercise programs for PAD.  Mr. Rego will role-play telephone 
coaching sessions, and receive feedback.  Management of “difficult” participants and challenging 
scenarios will be reviewed.  Once training is complete, the coach will perform telephone counseling 
calls with five mock participants.  A certification checklist will be used to ensure that the 
interventionist follows the protocol.  Once certified, Drs. Rejeski, Spring, and McDermott will hold 
monthly telephone calls with the coach to discuss problem participants or challenging issues that 
arise in the delivery of the intervention.  A back-up coach is available if needed during the study.
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I.
Attention control group.  Our attention control group controls for the possibility that regular 
contact with the study team may improve outcomes in participants randomized to the intervention.  
Participants randomized to the control group will attend weekly one-hour educational sessions at 
Northwestern University for the first four weeks of the intervention (Phase I). If the sessions cannot 
be completed at weekly intervals, the participant will have eight weeks to complete all four sessions. 
These sessions are on topics of interest to the typical PAD patient and are led by physicians and 
other health care workers.  Topics include Medicare Part D, nutritional supplements, and cancer 
screening.  During Phase II (weeks 5-52), the attention control group will receive weekly telephone 
calls, lasting 5-15 minutes, with information on a health-related topic.  We have substantial 
experience delivering these sessions in our prior randomized trials (52,55).      
J.
Six-minute walk test.  The primary outcome is change in six-minute walk distance between 
baseline and 52-week follow-up.   We have selected the six-minute walk as our primary outcome for 
several reasons.  First, the six-minute walk is a well validated measure of walking endurance that 
better represents walking during daily life than treadmill walking performance in older people 
(15,71-76).  Second, our prior work demonstrates that poorer six-minute walk performance is 
associated with higher rates of mortality and mobility loss in people with PAD (15,71).  Third, 
treadmill walking performance is associated with a significant learning effect (77-80).  However, the 
six-minute walk does not have this limitation (72,80).  In the six-minute walk, participants walk back 
and forth along a 100-ft hallway for six minutes after standardized instructions to complete as many 
laps as possible (15,52,55,71,72).  Distance covered in six minutes is recorded.  The intra-class 
correlation coefficient for the test-retest reliability of the six-minute walk test among 156 PAD 
participants in our laboratory was 0.90 (p<0.001) when two six-minute walks were completed one 
week apart (55,72). 
K. Four-Meter Walk. Participants are timed walking a four-meter distance in a corridor at their usual 
and fastest pace. Each walk is performed twice, and the fastest walk in each pair is used in analyses.
L. Short Physical Performance Battery (SPPB). Repeated chair rises: Participants sit in a straight-
backed chair with arms folded across their chest and are timed standing from the seated position five 
times consecutively as quickly as possible.  Timing begins with the word, “go”, and ends when the 
participant stands upright for the fifth time.  Standing balance:  This measure is also a component of 
the summary performance score.  Participants are asked to hold three increasingly difficult standing 
positions for ten seconds each:  standing with both feet together side-by-side and parallel (side-by-
side stand), standing feet parallel with the toes of one foot adjacent to and touching the heel of the 
opposite foot (semi-tandem stand), and standing with one foot directly in front of the other (tandem 
stand).  
M. Maximal treadmill walking time and treadmill time to onset of leg symptoms.  The Gardner 
graded treadmill exercise test is the standard, accepted protocol for measuring change in maximal 
treadmill walking time in response to interventions in PAD (77-78).  Maximal treadmill walking 
time and treadmill time to onset of leg symptoms are secondary outcomes in the LITE Trial.  In the 
Gardner protocol, speed is maintained at 2.0 miles per hour (mph) and treadmill grade increases by 
2.0% every two minutes (77-79).  If patients cannot walk at 2.0 mph, treadmill speed is started at 
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0.50 mph and increased by 0.50 mph every 2 minutes until the participant reaches 2.0 mph, after 
which the treadmill grade is increased every 2 minutes.  
N. Blood collection and long-term storage.  At each study visit, participants will have 45 mls of blood 
drawn for processing and long-term storage at -70 degrees Celsius. Approximated 10% of 
participants selected by chance will have an additional set of blood drawn for quality assurance, for a 
total of 90 mL at each visit. Blood obtained will be collected in serum, plasma EDTA, and plasma 
citrate tubes.  Stored blood will await later analyses for inflammatory biomarkers and other 
emerging blood markers that may change in response to the intervention.  Genetic testing may also 
be performed on stored blood samples.      
O. Health Related Quality of Life will be assessed with the Short Form-36 physical functioning 
domain (SF-36 PF) (81).  Perceived walking ability will be measured with the Walking Impairment 
Questionnaire (WIQ) (82-87).  These measures document changes in quality of life, health status, 
and perceptions of walking in response to our intervention.  We have substantial experience with 
them (52,55,85).  The WIQ distance and speed scores are secondary outcomes.  The WIQ stair 
climbing score is a pre-specified additional outcome.
P. COVID-19 Questionnaire. Currently enrolled and past participants may be called to see if they are 
willing to complete a questionnaire related to the COVID-19 pandemic. The questionnaire will be 
completed over the telephone and will help investigators determine how the pandemic is affecting 
older adults with PAD and how physical activity levels are affected during this time. 
Q. Measuring physical activity.  Physical activity will be measured in all participants over 10 days at 
baseline and follow-up, using the ActiGraph accelerometer (56-58).  Participants are asked to wear 
the ActiGraph on the right side of their beltline for 10 days, removing it only for bathing or sleeping.  
After 10 days, participants mail the accelerometer back in a stamped, pre-addressed envelope 
provided to them at their study visit.  We also contact participants by telephone to ensure monitors 
are returned.  Although activity data will be collected over 10 days, the first seven days of data will 
be used in analyses.  In addition, a consecutive subset of up to 50 LITE Trial participants and up to 
50 participants excluded from the LITE because of absence of PAD will wear an additional 
Actigraph strapped to their thigh for 10 days in order to measure the number of times that they stand 
up and sit down during the 10 day period.  Again, our interest will primarily be in the first seven 
days of data collection.
R. Measuring adherence to the exercise intervention.  For patients randomized to high or low 
intensity exercise, we will use the ActiGraph to objectively measure exercise adherence.  As 
delineated above (see section C12c), the ActiGraph is an extremely well validated and well accepted 
measure of physical activity (56-58).  Adherence will be defined as achieving at least 80% of the 
prescribed exercise frequency and duration during the final month of the intervention.  Exercise 
frequency and duration will be measured based on the ActiGraph data combined with patient self-
report. Specifically, participant report is used to estimate daily exercise, which is confirmed with 
ActiGraph data.  However, participant report is used for people who do not wear the ActiGraph for 
an exercise bout or to resolve discrepancies between ActiGraph and participant reported data.   
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S. Calf muscle biopsy measures.  Muscle biopsies will be obtained on consecutive participants who 
provide informed consent for muscle biopsies until the required number of muscle biopsies is 
completed.  Muscle biopsies may be obtained in up to 30 participants who are found to have a 
normal ABI consistent with the absence of PAD at their baseline visit.  Muscle biopsies will be 
performed by co-investigator Robert Sufit MD, a neurologist with > 30 years of experience 
performing muscle biopsies.  Dr. Sufit completed all muscle biopsies for our pilot study (Section 
C3f).  The biopsy will be performed in the medial head of the gastrocnemius muscle, at the point that 
is 67% of the distance between the medial malleolus and the medial aspect of the proximal tibia.  
This site represents greatest calf muscle diameter in >95% of individuals (88).  Anesthesia is 
achieved with subcutaneous lidocaine.  Subcutaneous and adipose tissue are dissected until muscle is 
identified.  Approximately 250 mgs of muscle tissue is removed and immediately frozen at -70 
degrees Celsius. The fascia is closed with absorbable suture. The wound is closed with subcuticular 
sutures and steri-strips.  Participants return for a wound check one week later.  At 52-week follow-
up, we will repeat the measurement using identical techniques, at the site adjacent to the baseline 
incision.  In the open biopsy, muscle tissue is directly visualized, ensuring an optimal muscle tissue 
sample and providing substantial advantages over the blind needle biopsy.  If a participant refuses 
the open biopsy at either baseline or follow up, a Bergstrom needle biopsy will be offered, which 
involves using a Bergstrom needle to remove muscle.  The Bergstrom needle biopsy method requires 
a small skin incision.  Lidocaine is injected into the skin and subcutaneous tissue.  A small incision 
of the diameter of the needle (5 mm) is made through the skin and superficial fascia of the muscle.  
The Bergstrom needle is a side-cut tool with a sharp end that includes an inner needle that obtains 
the muscle specimen. After the Bergstrom needle is advanced directly into the muscle, the inner 
needle is first withdrawn and then reinserted cutting the muscle that has pushed through the side cut 
of the outer needle.  The entire apparatus is then removed and the specimen is examined.  If that 
tissue is of insufficient size the technique can be repeated.  The wound is closed with steri-strips.  
The biopsy will be performed at the same site as the planned open biopsy.  This method avoids the 
long incision and need for sutures, but has the disadvantage of obtaining a smaller quantity of 
muscle tissue and has the disadvantage that the physician cannot directly see what tissue he/she is 
obtaining during the biopsy.  Multiple passes with the Bergstrom needle will be required to obtain 
the amount of tissue usually obtained through the open technique.  Specimens are shipped to the 
Univ. of Florida for measuring 3-nitrotyrosine with Western Blot (89) mitochondrial content 
(mtDNA copy number) measured by RT-PCR  (90)  and cytochrome c oxidase (COX) and citrate 
synthase activities using established methods (91-93). Muscle specimens may be sent to the 
Universities of Florida and University of Kentucky for analyses that include inflammatory 
biomarkers, markers of oxidative stress, measures of mitochondrial function and quantity, and 
muscle myofiber typing. Analyses may also be tested for protein measures of mitochondrial 
function, macrophages, satellite cells, and PCR/gene expression. Other measures related to skeletal 
muscle quality and function may also be performed. 
In addition, in a subset of participants we will obtain a muscle biopsy on the left and the right legs, 
respectively.  These bilateral biopsies could be obtained at baseline, at 12-month follow-up, or both 
time points.  The first biopsy will be performed as per our current procedures.  The second biopsy 
will be performed seven days later when the participant returns for their incision site checks.  It will 
be necessary for these individuals to remain off of their anti-platelet therapy for 14 days.  Physician 
approval will be required.  If the participant prefers to schedule the second biopsy at a later date (i.e. 
more than seven days after the initial biopsy), that will also be acceptable. In this case, anti-platelet 
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therapy will be held seven days prior to the contra-lateral biopsy.  Participants will receive $100 for 
their time and effort for each biopsy performed.  
T. Qualitative measures.  To achieve our Exploratory Aim, we will perform digitally recorded 
qualitative interviews among participants in the low and high exercise intensity interventions, 
respectively.  We will assess participants overall perceptions of the exercise intervention and 
participant-identified facilitators and barriers to exercise behavior that is consistent with the study 
goals. Interviews will be performed under the direction of Dr. Kenzie Cameron, a nationally-
recognized expert in qualitative research.  Prior work shows that theoretical saturation, or the point 
of redundancy at which no new themes emerge, often occurs in interview studies within the first 12 
interviews; basic elements for themes may be present as early as six interviews (94). We will 
interview 15-20 randomly selected participants in each of the low- and high-intensity groups.  
Following transcription, responses to these open-ended items will be independently coded by the 
qualitative interviewers and Dr. Cameron using content and constant comparative analysis (95-97).
U. Other measures.  As in our previous trials, patient report will be used to document comorbidities.  
Patient report is highly correlated with comorbid disease measured with medical record review (98-
101).  Participants are asked to bring their medication bottles to each visit to assess medication use.  
V. Quality control of outcome measures.  Health interviewers are trained by senior health 
interviewers and certified by Dr. McDermott in all aspects of data collection including the ABI, 
patient interviewing, and six-minute walk.  Health interviewers are re-certified every six months.  
For quality control of calf muscle measures, a commercially available standard muscle specimen, 
with known characteristics, is included in each set of analysis, to monitor the quality of each protein 
measurement.  Dr. Cameron will train selected assessment staff and monitor the fidelity of the 
qualitative assessments.
W.
Weight Loss + LITE Exercise Intervention in PAD.  We will obtain informed consent from up to 15 
participants with PAD who have body mass index (BMI) > 28 Kg/M2 for a study of weight loss combined with 
home-based exercise.  This study will be conducted in people who completed the LITE Trial or in people who 
were evaluated for the LITE Trial, but who were not able to participate in the LITE Trial (for example if they 
were not willing to commit to a 12-month study for example).  This component of the LITE Trial addresses the 
Exploratory Aim #3 of the LITE Trial and will last for up to 16 weeks.  This phase of the LITE study is similar 
to the LITE exercise intervention but will include a weight loss intervention and is limited to people with a BMI 
> 28 Kg/M2.  
Participants will be asked to attend weekly group sessions at Northwestern Medical Center, meeting with other 
participants with PAD, a Registered Dietician, the LITE exercise coach, and a behavioral change expert.  These 
on-site sessions will last approximately 60 to 90 minutes.  These on-site sessions will be similar to the LITE 
exercise sessions and will include some walking exercise activity, discussion of walking exercise goals, and 
behavioral change strategies to meet the exercise goals.  In addition, during these sessions, participants will be 
helped to adopt healthy lifestyle behavior changes to achieve weight loss, by receiving instruction about dietary 
change and healthy eating.  Participants will receive instruction about behavioral techniques (such as goal 
setting and self-monitoring) to help them achieve weight loss while they participate in regular walking exercise 
activity.  Participants will also be helped to develop behavioral change strategies to help them engage in regular 
walking exercise at home. These methods consist of those described elsewhere in this protocol for the LITE 
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Trial intervention. The group on-site sessions may be audio recorded and reviewed by study investigators to 
monitor the quality of the intervention.   Participants will be asked to walk for exercise approximately five 
days/week for up to 50 minutes per session.  Only people who have completed an exercise stress test in the past 
year that shows no evidence of coronary ischemia will be eligible.  Potential participants who have not 
completed an exercise stress test in the past year will have one as part of their study participation, using the 
methods described elsewhere in this protocol.  Potential participants with exertional chest pain that has recently 
increased will not be eligible for this phase of the study. 
To assist with weight loss, participants will be asked to use a weight loss APP to monitor their food intake. If 
necessary, they will be lent an iPAD for the duration of this phase of the LITE Trial.  Participants will also 
receive a wireless scale for monitoring their daily weight.  Participants will receive a FitBit activity monitor to 
help monitor their walking exercise activity.  Information from the FitBit and wireless scale will automatically 
be uploaded (with Bluetooth) onto the participant’s computer device or telephone and the data will be visible to 
both the study participant and the study coaches.  Information about the participant’s eating behavior, weight, 
exercise activity, and goals will be discussed by the coach with the participant at the weekly meetings during a 
brief individual encounter outside of the group interaction.  The coaches will also telephone the participant 
during the week to assist them with their exercise and weight loss goals.  
The six-minute walk, physical activity level for up to 14 days, and the short physical performance battery will 
be measured prior to the start of this pilot study and these measures will be repeated at the end of this phase of 
the LITE Trial.  Pain-free and maximal treadmill walking time may be measured before and after this weight 
loss + exercise intervention phase of the LITE Trial.  Participants will be invited to return to the medical center 
to meet in a group with other participants and provide feedback to study investigators about their experience in 
this study. All participants from the pilot will be contacted over the phone and invited to participate in the focus 
group. The additional group visit will take approximately 60 to 90 minutes.
X. Potential problems and solutions.  First, we recognize that a subset of PAD patients do not own 
computers or have home-internet capability.  We have budgeted for the costs of a home computer 
tablet and internet capability for participants who require these. Additionally, low cost items that 
may help participants better adhere to study procedures may be purchased. Examples include 
chargers for telephones or computers, which will allow participants to communicate with the study 
coach. In no instance will the cost exceed $50 per participant. Participants who provide a reason for 
poor adherence to study protocol (i.e. “I cannot take the study coaching telephone calls because I do 
not have a charger for my telephone”) and if on further questioning the participant indicates that they 
cannot afford to purchase a charger, then study staff will potentially pay for this. With increasing 
availability of computer technology and internet access, we anticipate that our intervention will be 
accessible to the majority of PAD patients in the near future.  Second, we recognize that some PAD 
participants will change medication or undergo revascularization procedures during the LITE Trial. 
As in our previously completed randomized trials in PAD participants, we will systematically collect 
data on changes in medications and new revascularization procedures throughout the study.  If there 
is imbalance regarding medication changes or revascularization procedures across the three study 
groups, we will repeat our analyses, adjusting for these changes.  In our prior trials, medication 
changes and revascularization procedures have not meaningfully influenced our results.  
Some or all study measures may need to be repeated at baseline or follow-up testing for data 
quality purposes. In some cases, it may be necessary to take an additional, unscheduled blood 
pressure measurement. For instance, if a participant has high blood pressure during the ABI 
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and investigators would like to double check their arm pressure measurement before 
performing the six-minute walk either at the same visit or at a subsequent visit.  
Determinations about blood pressure checks will be made on a case-by-case basis in 
consultation with Dr. McDermott or Dr. Lloyd-Jones or other qualified personnel.
Y. Pilot Data Collection. Some participants may be asked to complete a short questionnaire to 
allow investigators to better understand whether and how people with peripheral artery 
disease prefer to carry out walking exercise, and to collect data on whether weight loss is an 
important goal for people with peripheral artery disease.  
Z. Pilot Data Collection 2.  To understand how people completing the LITE Trial metabolize 
nitrates, we will perform a preliminary study in which people who have completed follow-up 
testing are asked to drink one serving of “Beet It”, an all-natural beet root juice.  This product 
is available for purchase on Amazon (https://www.beet-it.com/product/beet-it-sport-shot/).  It 
contains 98% concentrated beet root juice and 2% lemon juice.  Nutritional ingredients 
consist of 97 Kcal, 20 grams of carbohydrates, four grams protein, and 0.2 grams of total fat.  
Participants will be asked to attend a visit at the medical center after data collection for LITE 
is completed (this may often be an additional visit) and will be asked to drink one serving of 
the beet root juice (70 mL, 2.4 ounces).  A blood draw will be performed prior to drinking 
the beet root juice and 2-3 hours after the participant consumes the beet root juice, for 
measurement of nitrates and nitrites. The amount of blood collected will be 16 ml total before 
and after consuming the beet root juice. Our goal is to determine the proportion of 
participants who achieve a concentration of nitrates of 400 nM after consuming the single 
serving of beet root juice.  Variability has been demonstrated in metabolism of nitrate 
containing products, and we aim to determine inter-individual variability in metabolism in 
participants who have completed the LITE Trial.
AA.
In follow-up to the above, and for exploratory aim #3, we will assess the acute effects of nitrate-
rich beetroot juice, compared to placebo, on change in six-minute walk distance, four-meter walking 
velocity at usual pace, four-meter walking velocity at fast pace, and the SPPB.   Participants who 
sign written informed consent will be assigned to either nitrate- rich beetroot juice, described above, 
a matching placebo that is made by the same company that does not include the nitrate-rich beetroot 
juice, or 10 minutes of light therapy with a 660 nm light.  They will be asked to perform a six-minute 
walk, four meter walking velocity at usual and fastest pace, and the SPPB without consuming any 
beverage at the first visit for this substudy.  Approximately 1-5 weeks later, they will return for 
repeat measures.  However, prior to the repeat measures, performed approximately 1-5 weeks after 
the initial measure, they will either consume one drink of nitrate-rich beetroot juice, consume the 
matching placebo, or receive light therapy.   Blood will be obtained prior to the intervention (drink 
or light therapy) and at approximately 2.5 hours after ingesting the drink or 10 minutes after the light 
therapy.  The blood will be obtained for measurement of nitrate and nitrite and potentially other 
blood measures for research.  Participants assigned to light therapy will receive up to 10 minutes of 
light therapy with a 660 nm light (https://mitoredlight.com/products/mitomid) prior to the second 
blood draw at the second visit.  The six-minute walk, the four-meter walk at usual and fastest pace, 
and the SPPB will be performed immediately after the blood draw.    Participants may be asked to 
return for a third visit, in which they receive both nitrate-rich beetroot juice and the light therapy.  At 
this third visit, participants will undergo a blood draw.  They will then receive the nitrate-rich 
beetroot juice.  Approximately 2.5 hours later, they will receive the 10 minutes of light therapy.  
Immediately after the light therapy they will have plasma measured for  nitrite and they will undergo 
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functional performance measures (six-minute walk, four meter walks, and SPPB) immediately after 
the blood draw. In statistical analyses, the degree of change in each outcome (six-minute walk 
distance, four-meter walking velocity at usual pace, four-meter walking velocity at fastest pace, or 
the SPPB) between the initial measure and the measure obtained approximately 1-5 weeks later after 
consumption of the study drink and/or the light therapy, will be assessed and compared with those 
who received placebo. We will also analyze the association between the combination of the therapies 
(nitrate-rich beetroot juice + light therapy) and the individual therapies for the outcomes of  
increases in plasma nitrite and the degree of improvement in the functional measurements. 
Specimens may be shipped to Wake Forest University for measurement of nitrates and nitrites, for 
participants who agreed to the optional beetroot juice portion of the study.  
Procedures performed to lessen the probability or magnitude of risks.
A. Adequacy of protection against risks and methods to minimize potential risks.  Overview of 
protection against risks.  Prior to beginning data collection, all study coordinators undergo training 
and are certified by Dr. McDermott using a detailed checklist for each data collection element (see 
Appendix C).  Research coordinators are certified in each element of the study visit including 
obtaining informed consent, administering questionnaires, protecting confidentiality of collected 
data, performing the six-minute walk, and performing the ankle brachial index. Dr. McDermott re-
certifies coordinators every six months to ensure continued adherence to protocol.  Those not 
adhering to all aspects of the protocol undergo additional training followed by re-certification. 
All research staff members have completed human subjects training required by Northwestern’s 
institutional review board (IRB).  This training includes education about the importance of 
maintaining confidentiality of personal health information.  The study principal investigator or a co-
investigator is available to answer questions that arise during the informed consent process as 
needed.  
Participants are asked to sign a study consent form at each on-site visit.  The research coordinator 
reviews study procedures, including risks and benefits associated with study participation.  The 
research coordinator answers participants’ questions.  Dr. McDermott and other study investigators 
are available to answer participants’ questions.  Both the participant and the individual administering 
the consent form will sign the consent form.  Dr. McDermott’s pager, direct telephone line, and 
home telephone number are provided to participants.  
B. Minimizing risks related to exercise.  According to current clinical practice guidelines (1), all 
participants will undergo baseline exercise stress testing prior to randomization.  Potential 
participants with an abnormal baseline exercise stress test will be excluded.  A safety manual will be 
developed prior to beginning the exercise intervention and will be reviewed and approved by the 
Data Safety Monitoring Board (DSMB) before implementation.  In addition, participants will be 
monitored during supervised exercise for development of chest discomfort, new dyspnea, or new 
fatigue during exertion.  Dr. McDermott will be promptly notified when this occurs (by pager).  Our 
exercise physiologists have significant experience working with populations of participants with 
PAD and have been trained in CPR, ACLS, and use of the automatic external defibrillator.  During 
transition to the home-based exercise program, participants are educated on important symptoms to 
watch for during exercise, such as chest discomfort or dyspnea.  Participants are instructed to 
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immediately contact their physician should these symptoms occur. During their first on-site exercise 
session, the coach discusses information regarding safety during exercise. Dr. McDermott’s cellular 
telephone number, pager, and direct line are provided in the informed consent form so that they can 
reach Dr. McDermott easily with any questions or concerns.
C. Minimizing risks related to muscle biopsy.  The muscle biopsy procedure will be performed by 
Dr. Robert Sufit who has more than 30 years of experience performing these muscle biopsies, 
primarily as part of his clinical practice as a Board-Certified Neurologist.  As in our pilot study, 
completed in preparation for this proposal, the muscle biopsy procedures will be performed under 
sterile conditions using sterile technique.  Local anesthesia will be obtained using subcutaneous 
lidocaine.  All participants will be provided with written and verbal instructions about wound care 
and will be advised to contact Dr. McDermott immediately if any signs of wound infection occur.  
All participants will return for a one-week follow-up check of their incision site.
Many PAD participants take anti-platelet therapy to prevent cardiac and cerebrovascular events.  If 
potential participants are taking anti-platelet therapy, they will be asked to either hold their anti-
platelet therapy (if they are taking 81 mgs of aspirin or less per day) or switch to a low dose (81 
mgs) of aspirin therapy (if they are taking clopidogrel or an equivalent medication or > 81 mgs of 
daily aspirin at study entry) during the seven days leading up to the muscle biopsy procedure.  
Participants who are taking warfarin or other anti-coagulant therapy will be excluded from the 
muscle biopsy procedure.  
D. Minimizing risk related to baseline and follow-up testing.  All study coordinators undergo 
baseline training and are certified by Dr. McDermott before beginning data collection.  Training and 
certification involves ensuring that coordinators are trained in methods to help minimize falls.  Dr. 
McDermott re-certifies coordinators every six months to ensure continued adherence to study 
protocol.  Those who are not adhering to protocol undergo additional training followed by re-
certification.    
E. Minimizing risk related to loss of confidentiality.  The following methods will be employed to 
maintain confidentiality of participants.  First, study recruitment letters will be mailed, using IRB-
approved methods, only after receiving written permission from the participant’s physician.  The 
personal physician of each study participant will have the option of not allowing investigators to 
contact the potential participant.  Lists of potentially eligible participants will be obtained by 
individuals who normally have access to these lists as part of their daily work requirements.  
Recruitment letters for potential participants identified from hospital and outpatient lists are prepared 
by research staff members whose job is to assist study investigators with recruitment.  These 
research staff members have completed training in the ethical conduct of human subject research, 
including maintaining participant confidentiality.  Recruitment letters to potential participants 
identified from medical center lists are mailed in sealed envelopes and addressed to the potential 
participant.  All potential participants who receive mailed information about the study after the 
approval from their physician will have the opportunity to call a voice-mail system to ask NOT to be 
further contacted about this study.  Secondly, only study investigators and key research staff will 
have access to the study database.  Third, participants will be assigned a unique study identifier.  
Individual names will ultimately be removed from the study database and only the unique study 
identifier will be used to distinguish participants in the database.  Fourth, collected data will be 
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maintained in locked computer files and file cabinets to which only study investigators have access.  
Collected data will be used only for research purposes.  Any published data will not contain any 
individual identifiers.
F. Minimizing risk related to loss of confidentiality during qualitative interviews.  Participation 
includes a risk of loss of confidentiality regarding personal health information.  However, all 
research staff have undergone formal human subjects training.  They are trained to protect the 
privacy of research subject participants.  Each qualitative interview will be digitally recorded to 
reduce the need for note taking and to facilitate analysis. When participants consent to the study, we 
will use a staged consent to ask permission to record the qualitative portion of the interviews to 
better capture qualitative data. If a participant does not give permission for audio-recording, s/he 
can still participate in the study. In those cases, the designated interviewer will enter as much of the 
participant’s responses as possible. Digital recordings of the interviews will be permanently erased 
from the server five years following the end of the data collection period. We will retain de-identified 
transcripts of participant responses.
G. Minimizing risk related to the weight loss intervention.  Individuals who lose > 1.36 kilograms 
per week for three weeks in a row will be contacted by study staff.  Calorie goals will be increased 
and Dr. McDermott will interview the participant to determine whether additional medical 
evaluation is warranted.  Second, to avoid dehydration, participants will be advised early on in the 
trial of the importance of maintaining adequate hydration.  Participants will be reminded regularly of 
the importance of adequate hydration. 
H. Data and Safety Monitoring Board (DSMB).  As per NHLBI guidelines, the DSMB will be 
appointed by the NHLBI.  The DSMB will meet at least every six months during the study.  The 
DSMB will meet to review and approve the protocol prior to beginning data collection.  They will 
decide on specific stopping criteria for the study. The biostatisticians and data manager will work 
closely with the DSMB to perform interim analyses. Adverse events and hospitalizations will be 
monitored monthly via telephone call and will be reported to the DSMB and IRB in a timely manner 
according to pre-specified requirements.  Analyses will be done according to the requests of the 
DSMB. In addition, for each major adverse event, the group assignment of the patient will be 
provided.  In this way the DSMB can determine whether the event is intervention related.  Adverse 
event rates and interim study results will be reviewed and discussed by the DSMB at the DSMB 
meetings.  At least four categories of adverse events will be defined:  a)  Death; b) cardiovascular 
events (myocardial infarction, stroke, and coronary arrhythmias) c) musculoskeletal outcomes 
(muscle soreness, foot ulcer, joint aches and pains).  We will also include adverse events for the 
muscle biopsy, including a) infection and b) bleeding requiring a visit to a healthcare provider.  We 
will report all hospitalizations to the DSMB in a timely fashion.  We will use a designated data 
collection form to record these events and they will be reported immediately to the Institutional 
Review Board and DSMB.  Note that to date, however, exercise programs have been demonstrated 
to be safe in patients with PAD (1,52,55).

All drugs and devices used in the research.
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Participants will be asked to wear the ActiGraph while they are exercising.  The ActiGraph 
records duration, frequency, and intensity of exercise.  The ActiGraph Bluetooth 
mechanism, available in the ActiGraph model that we will use in the LITE Trial, 
automatically uploads data to the study website, whenever participants walk within 15 feet 
of their home computer/tablet.  Participants without a home computer suitable for 
uploading ActiGraph data will be provided with a computerized tablet with wireless 
internet access for the duration of the study.  

Source records that will be used.
Sources of material.  Primary and secondary outcome measures that will be collected for this study 
are shown in Table 7 and include the six-minute walk test, treadmill walking performance, 
physical activity measured by the ActiGraph accelerometer, calf muscle biopsy measures, quality 
of life questionnaire data (SF-36 PF score), and patient-perceived walking ability (WIQ scores).  
In addition, adherence to the prescribed exercise intervention will be measured during the final 
four weeks of the intervention in the two exercise groups using the ActiGraph.  Qualitative 
interviewing will be conducted to obtain information about participants’ perceptions of their 
walking exercise experience.   We will also administer questionnaires to participants at baseline 
and at each follow-up visit to assess their medical history, including presence of comorbidities, 
medication use, smoking status, and other health characteristics.  Data collection will not make use 
of existing records or data.  The prevalence of comorbid disease will be measured using patient 
report, based on previous study (98-101).  
9.3
Data collected.
Please see section 9.2 above.
10.0
Data and Specimen Banking
10.1 Storage of specimens.
Blood specimens for long-term storage will be stored in a freezer belonging to Dr. McDermott's 
research program at Northwestern University, in the freezer farm in the basement of Olson 
Pavilion.
Specimens will be stored for up to 70 years, after which they will be destroyed.
10.2 Data to be stored or associated with each specimen.
Specimens will be coded; meaning that a key will exist that can link the codes back to the direct 
subject identifiers. Each participant will be assigned a unique study ID number that can be traced 
back to the study participant.  The blood samples that are maintained in long-term storage will be 
labeled with this unique identifier and the date and time of the blood collection. 
10.3 Procedures to release data or specimens.
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Only Dr. McDermott has control over release of study data or specimens.  Any investigators 
seeking to analyze blood specimens must contact Dr. McDermott for permission.  Each request, if 
it occurs, will be considered on a case-by-case basis.  Dr. McDermott will obtain IRB approval 
prior to releasing any blood specimens for analysis, other than those tests specifically named in 
this application.
11.0
Data and Specimen Management
11.1 Data analysis plan. 
A. Data management.  We will use data management methods in place for our ongoing NHBLI-
funded PAD studies.  Data from baseline and follow-up study visits are acquired on paper forms and 
processed using the Teleform system by Cardiff Software.  We have successfully used this system 
for over 8,000 patient visits in our previous and ongoing studies.  Data are backed-up on multiple 
hard drives and copied to CDROM for secure off-site storage.
B. Data Safety Monitoring Board (DSMB).   We have identified nationally recognized experts to 
serve on the DSMB.
Statistical Analyses.  Analyses will be performed according to the intention to treat principle.  Data 
will be analyzed according to each participant’s originally assigned group, irrespective of whether 
the participant adheres to his/her assignment. Prior to analyses, the distributions of the variables 
(changes) will be examined and necessary transformations will be performed. The balance of socio-
demographic factors and prognostic factors (such as age, sex, race, ABI, comorbidities, and relevant 
medication use) will be compared between the three groups using ANOVA or chi-square tests.  If 
there is any indication of major imbalance, proper analysis of covariance adjustments will be 
performed in data analyses.   
NOTE:  The original plan to use two sample two-tailed t-tests was changed to a mixed model for 
repeated measures analysis on 8/27/2020 prior to analyzing any data.  This change was made 
because as of 8/27/202, investigators are projecting an approximately 16% loss to follow-up rate at 
52 week follow-up.  The mixed model for repeated measures will be used to adjust for missing data.
For our Primary Aim, we will use  mixed model for repeated measures (MMRM) analysis to 
compare changes in six-minute walk performance at 52-week follow-up between the low  vs. the 
high-intensity exercise group and between the low-intensity exercise group vs. the control group, 
respectively. To this end, the 26-week and 52-week changes of six-minute walk from baseline are 
treated as correlated outcomes, and independent variables include visit (26-week and 52 week), 
treatment (low-intensity, high-intensity, control), visit/treatment interactions and baseline six-minute 
walk performance.  Unstructured variance-covariance matrix will be used to model the within-
person correlations. In addition, we will also adjust for potentially imbalanced baseline confounders 
such as age, sex and baseline six-minute walk performance. When there is evidence that the 
normality assumption for the distribution of measures of interest is severely violated, we will 
perform Wilcoxon rank-sum test for the comparison. The nonparametric adjustment for the 
imbalance in mean difference of baseline covariates will be employed, when needed.  
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For Secondary Aim #1, we will use MMRM analysis to compare changes in six-minute walk,  
physical activity, and SF-36 PF and WIQ distance and speed scores at 26-week follow-up between 
the low- and high-intensity exercise groups and between the low-intensity exercise and control 
group, respectively. 
For our Secondary Aim #2, we will use MMRM analysis to compare changes in maximal treadmill 
walking time, physical activity, and SF-36 PF and WIQ distance and speed scores at 52-week 
follow-up between the low- and high-intensity exercise groups and between the low-intensity 
exercise and control groups, respectively.
For our Secondary Aim #3, we will use normal approximation for binomial distribution to compare 
the proportion of participants who achieve adherence (as defined in section C18) between the low vs. 
high intensity exercise groups.  We will also use logistic regression to compare the adherence rate 
between these two groups, adjusting for potentially imbalanced baseline confounders such as age, 
sex, and baseline six-minute walk performance.  We will also use two sample two-tailed t-tests to 
compare adherence to the exercise intervention overall and at the prescribed intensity between the 
high vs. low intensity groups at 52-week follow-up.  
For our Secondary Aim #4, we will use MMRM analysis to compare changes in six-minute walk 
distance, physical activity, and SF-36 PF and WIQ distance and speed scores at 26-week follow-up 
between the high-intensity exercise and control groups. 
For our Secondary Aim #5, we will use MMRM analysis to compare changes in six-minute walk 
distance, maximum treadmill walking time, physical activity, and SF-36 PF and WIQ distance and 
speed scores at 52 week follow up between high intensity exercise and control groups.
For our Secondary Aim #6, we will use two sample two-tailed t-tests to compare changes in COX, 
citrate synthase, and mitochondrial DNA at 52-week follow-up between the low intensity vs. the 
high-intensity exercise group and between the low-intensity exercise and control groups.  We will 
also compare change in nitrotyrosine muscle measurements between the high-intensity exercise and 
the control groups.  We will repeat these comparisons for the participants who adhere to their 
prescribed exercise intensity, measured by the ActiGraph.  
For our Exploratory Aim #1, we will use two sample two-tailed test compare patients’ perception to 
exercise at 52-week follow-up between high and low-intensity groups.  For our Exploratory Aim #2,  
we will evaluate the effect of modified combo intervention (weight loss + LITE home-based 
exercise) on six-minute walk distance at approximately 12 week follow-up.  This pilot study was 
completed in 2018.
The significance level for the Primary Aim will be 0.05/2 to adjust for two comparisons between 
low-intensity and high-intensity arms and between low-intensity and control arms. 
The significance level will be 0.05 for all secondary aims.  Furthermore, Secondary Aims #4 and #5 
were pre-specified but added after the LITE Trial was underway in response to two negative trials of 
home-based exercise in patients with PAD demonstrating that a high-intensity walking exercise 
program did not improve six-minute walk or other outcomes in people with PAD (5, 6).   
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Missing data occur when participants are lost to follow-up.  First, we will make every effort to 
ensure that participants return for the 52-week follow-up. We will use proxies to help us locate 
participants we are unable to reach and we will mail reminder letters when participants are not 
responsive to telephone calls.  We will encourage participants who do not adhere to their assigned 
groups to return for the 52-week follow-up by providing transportation and monetary incentives. 
Thus, we anticipate that the proportion of participants without 52-week follow-up data will be small.  
Second, MMRM analysis is valid under the missing at random assumption.  In case the proportion of 
missing data at 52-week follow-up is not small (>25%), we will additionally employ the multiple 
imputation approach to account for missing data as sensitivity analysis. If there is evidence for the 
possibility of missing not at random, we will perform additional analyses using pattern-mixture and 
shared-parameter models (105).
11.2 Power analysis.
Power estimates. For all primary and secondary aims, we anticipate a 15% drop-out rate at 52-week 
follow-up, based on 12-month follow-up rates in our GOALS and SILC trials (52,55). We will 
randomize 305 participants.  Of these, 120 will be randomized to the low-intensity intervention, 120 
will be randomized to the high-intensity exercise intervention, and 65 will be randomized to the 
control group. We will enroll more participants in each exercise group than the attention control 
group because we anticipate that the effect size of the low vs. high intensity exercise comparison 
will be lower than the effect size of the low intensity vs. the control group.  For our Primary Specific 
Aim, we will have 80% power to detect a minimum difference of 0.43 standard deviations (SD) 
between the low intensity vs. high intensity exercise groups and a difference of 0.52 SD between the 
low-intensity and the attention control groups, in change of six-minute walk distance at 52-week 
follow-up, using two-sided two-sample t-tests with a significance of 0.025 to adjust for the two 
comparisons. Low intensity exercise will be considered effective if either comparison (i.e. with high 
intensity exercise or with the attention control group) is statistically significant.  The SD of the 
change in six-minute walk in our GOALS and SILC trials was approximately 60 meters.  Therefore, 
our sample size allows us to detect a difference in change in six-minute walk of 26 meters and 31 
meters, respectively, between the low vs. high intensity groups and between the low intensity and 
control groups.  Prior studies have defined clinically meaningful changes in the six-minute walk as 
30 meters (small meaningful change) and 50 meters (large meaningful change) (102,103). Thus, our 
power should be adequate to detect a clinically meaningful difference.  For our Secondary Aim #1, 
we will have 80% power to detect a difference of 0.39 SD between the high vs. low intensity 
exercise interventions and a difference of 0.47 SD between the low-intensity intervention vs. control 
group, respectively, in changes of six-minute walk, physical activity,  WIQ scores, and SF-36 scores 
at 26 –week follow-up using two-sided two-sample t-tests with a significance of 0.05.  For our 
Secondary Aim #2, we will have 80% power to detect a difference of 0.39 SD between the high vs. 
low intensity exercise interventions and a difference of 0.47 SD between the low-intensity 
intervention vs. control group, respectively, in changes of maximal treadmill walking time, physical 
activity, and WIQ and SF-36 scores at 52-week follow-up, using two-sided two-sample t-tests with a 
significance level of 0.05.  In our SILC trial, the observed differences between the intervention and 
control groups are 0.61 SD, 0.59 SD and 0.61 SD in changes of maximal treadmill walking time, 
WIQ distance, and SF-36 physical functioning scores, respectively (52). In a study by Gardner et al 
of supervised exercise in participants with PAD (73), the observed improvement in physical activity 
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level as measured by accelerometer in the exercise group was more than 0.86 SD greater than that 
for the control group. Thus we should have adequate power to detect similar effect sizes.  For our 
Secondary Aim #3, we will compare rates of ActiGraph-measured adherence to the prescribed 
exercise intervention (five exercise sessions per week for 45 minutes of walking exercise per 
session) between the low vs. high intensity exercise groups.   Adherence will be defined as achieving 
at least 80% of the prescribed exercise intervention (see section C18).  Based on the home-based 
component of our SILC trial, we expect the adherence rate in the high intensity exercise group will 
be about 30%. Our sample size provides 80% power to detect a minimum difference of 19% in the 
proportion of adherence between the low intensity and high intensity groups, based on the two-sided 
Z test with pooled variance using normal approximation for binomial distribution with a significance 
level of 0.05.  For our Secondary Aims #4 and #5, we will have 80% power to detect a difference of 
0.52 SD between the high-intensity intervention vs. control groups, in changes of six-minute walk 
distance, physical activity, and WIQ and SF-36 scores at 26-week and at 52-week follow-up, and in 
change of maximal treadmill walking time at 52-week follow-up, using two-sided two-sample t-tests 
with a significance level of 0.05.  Therefore, we have adequate power for detecting differences 
similar to those observed in SILC trial.  For our Secondary Aim #6, we will randomly select 50 
participants from each of the three study groups.  We will have 80% power to detect a difference of 
0.61 SD between the low vs. high intensity exercise interventions, between the low-intensity 
exercise intervention and the control group, and between the high-intensity exercise intervention 
group vs. control group, respectively, in changes of citrate synthase, COX, and mitochondrial DNA 
at 52-week follow-up, using two-sided two-sample t-tests with a significance level of 0.05.  In a 
randomized trial, Timmers et al reported observed differences in citrate synthase, COX, and 
mitochondrial DNA of 3.17 SD, 2.12 SD, and 0.75 SD, respectively, between a treatment and 
control group (104). Thus we should have adequate power.
11.3 Steps to secure data to maintain confidentiality during storage, use, and transmission.
First, all research assistants must complete training in protection of subject privacy and prevention 
of disclosure of identifying information.
Second, all data collection forms are maintained in a secure office space.
Third, our study databases are maintained in locked computer files or on secure hard-drives that 
are password protected; to which only authorized staff have access. Dr. McDermott or a study 
manager must provide permission for programmers and research assistants to access study 
databases.
Fourth, a study identification number will be assigned to each participant. This identification 
number will be used to label blood specimens, for example. In addition, most pages of our data 
collection forms will have only the study identification number listed (and not the participant's 
name, for example).
11.4 Describe any procedures that will be used for quality control of collected data.
Quality Control.  As in our prior studies, health interviewers will be trained by a senior 
coordinator and certified by Dr. McDermott in each component of data collection, using a 
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detailed checklist developed for this trial.  Health interviewers are rigorously evaluated for 
adherence to protocol, prior to beginning data collection and every six months after initial 
certification.  
12.0
Provisions to Monitor the Data to Ensure the Safety of Subjects
Serious adverse events will be reported to the DSMB within seven days of each serious adverse 
event.  Adverse event data will be reported to the DSMB every six months during the study, 
and/or as requested by the DSMB.  The DSMB will have the ability to stop the study at any time 
if there are concerns about safety.
13.0
Withdrawal of Subjects*
Subjects may withdraw from the research at any time. If they decide to leave the research, they should 
contact the investigator, Dr. Mary McDermott.
If they stop being in the research, already collected data may not be removed from the study database. 
They will be asked whether the investigator can collect data from their routine medical care. If the 
subject agrees, this data will be handled the same as research data.
14.0
Risks to Subjects*
14.1 Foreseeable risks.
A. Risks associated with the exercise program.   First, the exercise program might be associated with 
an increased risk of heart attack, arrhythmia, or death.  In addition, patients may develop ischemic 
chest pains during exercise.  If participants develop chest pain while at a study visit, Dr. McDermott 
or Dr. Lloyd-Jones will be notified immediately.  Dr. McDermott will oversee arrangement of 
appropriate follow-up (including immediate transport to the emergency room if appropriate).  The 
exercise physiologist is certified in Cardiopulmonary Resuscitation (CPR) and use of an Automatic 
External Defibrillator (AED).  As recommended by clinical practice guidelines (1), all potential 
participants will undergo a baseline exercise stress test.  Those with an abnormal baseline exercise 
stress test will be excluded from participation and will be asked to follow-up with their physician.  
These tests on the heart may lead to the need for procedures to improve the blood flow to your heart 
or hospitalization if the result on the exercise stress test shows a particularly worrisome result. A 
treadmill exercise stress test may also be associated with an irregular heartbeat or a heart attack.  In 
addition, those randomized to one of the two home-exercise programs will be educated regarding 
symptoms to watch for during exercise that should be reported immediately to their physician. 
Safety manuals and protocols will be developed prior to beginning the intervention. Dr. 
McDermott’s direct line, pager, and cellular telephone number will be provided to all participants.  
Second, chest pain during exercise may result in additional cardiac work-up that may lead to 
procedures to improve coronary blood flow.  As indicated above, subjects will be screened for active 
heart problems with a baseline exercise treadmill test prior to enrollment, according to currently 
recommended standards of screening PAD patients for coronary artery disease prior to their 
beginning an exercise program (1).  These exercise stress tests will be performed as part of our 
protocol and interpreted by board-certified cardiologist and co-investigator Dr. Lloyd-Jones.  
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Participants must have a normal 12-lead exercise stress test to be eligible.  Abnormal baseline 
exercise stress tests may also lead to additional cardiac work-up by the participant’s physician that 
may lead to coronary angiography or coronary revascularization.  
Third, exercise may be associated with muscle fatigue or soreness.  This typically resolves with rest.  
Fourth, it is possible that walking may contribute to foot sores when shoes are poorly fitting. 
Additionally, walking may worsen or slow healing of foot sores or ulcers in PAD. 
Fifth, risks associated with baseline and follow-up testing include loss of balance and falling during 
the walking tests, chair rises, and standing balance testing.  However, the research assistant who will 
collect these data has been trained to prevent falling.  The risk of falling is less than 1 in 200.  
Falling during these tests may be associated with fracture.  The risk of a fracture secondary to a fall 
during the walking tests is less than 1 in 5,000.   
B. Risks associated with the muscle biopsy.  The muscle biopsy is associated with several potential 
risks.  These include discomfort during the muscle biopsy procedure, scarring from the muscle 
biopsy skin incision, bleeding, and infection.  Potential participants who are asked to hold or reduce 
their anti-platelet therapy or anti-coagulation therapy during the week leading up to the muscle 
biopsy procedure may experience a cardiovascular event related to the temporary reduction or 
discontinuation of the anti-platelet or anti-coagulant therapy.  
To minimize risk, all participants undergoing muscle biopsy will receive a written hand-out 
regarding signs to watch for of wound infection after the muscle biopsy.  They will also be verbally 
instructed in this.  The participant will be instructed to call Dr. McDermott immediately if any signs 
of infection occur.  In addition, permission from the participant’s primary care physician will be 
required before switching participants on anti-coagulant therapy to low-dose aspirin therapy for the 
seven days prior to the procedure.  If the potential participant’s primary care physician does not 
provide permission for switching to low-dose aspirin for patients taking anti-coagulant therapy, the 
potential participant will not be eligible for the study.  However, based on our pilot study, we 
anticipate that the number of these exclusions will be very small.
C. Six-minute walk test.  The six-minute walk test may be associated with the risk of falling or 
coronary ischemia or dyspnea due to heart failure or lung disease.  Rarely, falling during the six-
minute walk test may result in a fracture.  However, the research assistant who will collect these data 
has been trained to prevent falling.  The risk of a fracture secondary to a fall during the six-minute 
walk test is less than 1 in 5,000.   
D. Risks associated with ABI measurement.  The ankle brachial index measurement consists of 
measuring systolic blood pressure in each extremity using a hand-held Doppler.  The ABI is non-
invasive, safe and does not have any known lasting side effects.  During the ankle brachial index 
test, participants may experience discomfort from the inflated blood pressure cuff.  However, this 
discomfort resolves immediately when the cuff is released.
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E. Risks associated with drawing blood: The potential risks of drawing blood include a bruise at the 
site of vein puncture, inflammation of the vein, and infection. Care will be taken to avoid these 
complications.
F. Risks associated with questionnaire administration and qualitative interviewing.  Participation 
includes a risk of loss of confidentiality regarding personal health information.  However, all 
research staff have undergone formal human subjects training.  They are trained to protect the 
privacy of research subject participants.  Each qualitative interview will be digitally recorded to 
reduce the need for note taking and to facilitate analysis. When participants consent to the study, we 
will use a staged consent to ask permission to record the qualitative portion of the interviews to 
better capture qualitative data. If a participant does not give permission for audio-recording, s/he 
can still participate in the study. In those cases, the designated interviewer will enter as much of the 
participant’s responses as possible. 
G. Risks associated with exposing the legs to far-red light for approximately 10 minutes.  There are 
no known risks associated with the light exposure.  The light is bright and can be uncomfortable if 
the participant looks directly into the light.  The light will be directed away from the eyes and the 
participant will be provided with goggles to wear during the light treatment
14.2 If applicable, indicate which procedures may have risks to the subjects that are currently 
unforeseeable.
Either exercise intervention may have risks that are currently not foreseeable.
15.0
Potential Benefits to Subjects
15.1 The potential benefits that individual subjects may experience from taking part in the 
research. 
A. Potential benefits of the proposed research.  Lower extremity peripheral artery disease (PAD) 
affects eight million people in the United States (U.S.) (10).  PAD will be increasingly prevalent as 
the U.S. population survives longer with chronic disease.  We previously demonstrated that men and 
women with PAD have greater functional impairment and more rapid functional decline than those 
without PAD (11-15).  The functional impairment experienced by people with PAD is associated 
with loss of independence, increased hospitalization rates and poor quality of life (16-19).  Yet few 
therapies exist for improving functional performance and preventing mobility loss in people with 
PAD.
B. Clinical practice guidelines recommend supervised, high-intensity, ischemic-pain inducing treadmill 
exercise to improve walking performance in people with lower extremity peripheral artery disease 
(PAD) (1,2).  However, supervised exercise is not paid for by medical insurance.  Furthermore, the 
ischemic leg pain induced by high intensity walking exercise is a barrier to exercise in patients with 
PAD.  Fewer than five percent of the more than eight million men and women with PAD in the 
United States participate in supervised exercise (3,4).  This proposed study will determine whether 
an alternative exercise intervention that employs remote monitoring, avoids continuous supervision, 
and avoids ischemic-pain improves functional performance at 52-week follow-up in people with 
PAD.  Our intervention directly addresses two aspects of current practice guidelines that are major 
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barriers to exercise for patients with PAD:  1) the recommendation for long-term supervised 
exercise and 2) the recommendation for ischemic-pain inducing walking exercise (1,2).  If our 
hypotheses are correct, millions of people with PAD will benefit from our proposed alternative 
exercise regimen which will be accessible to most of the eight million people in the U.S. who suffer 
from PAD. 
C. Importance of knowledge to be gained.  Lower extremity peripheral arterial disease (PAD) is 
common.  Currently 8 million men and women in the United States (U.S.) have PAD (10).  The 
number of individuals with PAD is expected to increase as the U.S. population lives to older ages 
with chronic disease.  Our prior work and that of others shows that patients with PAD have greater 
functional impairment, increased rates of functional decline, and increased mobility loss compared to 
persons without PAD (11-15).  Older patients with functional impairment are less likely to remain 
independent in the community, have higher rates of hospitalization, and have poorer quality of life 
than those without functional impairment (16-19).  Yet few therapies have been identified that 
improve lower extremity functioning or prevent functional decline or mobility loss in persons with 
PAD.  Only two FDA-approved medications improve functional performance in patients with PAD.  
Although supervised treadmill exercise is recommended by clinical practice guidelines to improve 
functional performance in PAD, fewer than five percent of PAD participants are actively engaged in 
supervised treadmill exercise (3,4). If our hypotheses are correct, millions of people with PAD will 
benefit from our proposed alternative exercise regimen which will be accessible to most of the 
eight million people in the U.S. who suffer from PAD.  Remote monitoring is a highly innovative 
feature of our proposed trial that has not been tested previously in people with PAD and is expected 
to facilitate adherence to home-based walking exercise.  
16.0
Vulnerable Populations
NA
17.0
Community-Based Participatory Research
NA
18.0
Sharing of Results with Subjects
Participants will receive results of their ankle brachial index (ABI) test results immediately after this 
testing is completed.  They will be provided with a “result letter” at the end of their baseline visit.  They 
will not be provided with other study results.
19.0
Setting
The research will be conducted at Northwestern Memorial Hospital, 680 North Lake Shore 
Drive, and 750 North Lake Shore Drive. If a participant is unable or unwilling to come back to 
our site for a follow-up visit or if they are unable or unwilling to come to the medical center for 
an intervention visit, we may go to their home to collect follow-up data or carry out the 
intervention visit.  
Exercise intervention sessions will be conducted at either L.A. Fitness (355 E. Grand Ave. or 55 
E. Randolph St.) or at 680 N. Lake Shore Drive. Heath education sessions will take place at 750 
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N. Lake Shore Drive.
20.0
Resources Available
20.1 Qualifications of staff.
Collaborating sites.  Dr. Christiaan Leeuwenburgh is an internationally recognized expert 
in skeletal muscle biology and mitochondrial function.  Dr. Leeuwenburgh’s laboratory 
will measure mitochondrial oxidative metabolism measures and oxidative stress proteins in 
muscle biopsy samples obtained in the LITE Trial.  Dr. Leeuwenburgh’s laboratory 
performed all of the measures from our muscle biopsy pilot study.  Dr. Leeuwenburgh’s 
laboratory has demonstrated success measuring respirometry.  Dr. Walter Jack Rejeski of 
Wake Forest is an internationally recognized leader in behavior change interventions in 
patients with chronic disease.  Dr. Rejeski led the successful group mediated cognitive 
behavioral intervention for our GOALS Trial (52).  Drs. Michael H. Criqui (University of 
California at San Diego), Jack M. Guralnik (University of Maryland), and Luigi Ferrucci 
(National Institute on Aging) have worked with Dr. McDermott on PAD studies of 
functional impairment for over eleven years and bring expertise in functional assessment, 
PAD, and clinical trials to the study team.  
21.0
Prior Approvals
NA
22.0
Recruitment Methods
22.1 When, where, and how potential subjects will be recruited.
PAD participants will be identified from among consecutive patients diagnosed with PAD 
in the non-invasive vascular laboratory of Northwestern Memorial Hospital (NMH). Study 
co-investigator, Dr. Mark Eskandari, is medical director of the non-invasive vascular 
laboratory at NMH and will assist with identifying potential participants from the non-
invasive vascular laboratory. As director of the vascular laboratory at NMH, Dr. Eskandari 
formally reads many of the non-invasive vascular laboratory tests. He maintains all non-
invasive vascular test results in his vascular laboratory. As director of the vascular 
laboratory, Dr. Eskandari could conceivably contact the patients whose test results are 
maintained in his laboratory. However, Dr. Eskandari prefers that the contact of potential 
participants in studies come from the physicians referring him for testing. Lists of patients 
who have undergone lower extremity arterial testing in the non-invasive vascular 
laboratory are generated monthly and e-mailed by Dr. David Leibovitz from Northwestern 
Memorial Hospital to Dr. McDermott using an encrypted file. Dr. Leibovitz is the Director 
of Clinical Information Systems at Northwestern Memorial Hospital and he is Chief 
Medical Information Officer at Northwestern Medical Faculty Foundation. A research 
assistant, working on behalf of Dr. Eskandari, will contact referring physicians of potential 
participants identified from the vascular laboratory via fax, phone, page, or e-mail, to ask 
for permission to contact their patient about the study. Physicians will be advised that if 
they do not contact us to tell us to advised us NOT to contact their patient, we will send 
their patient a study recruitment letter from Dr. McDermott on behalf of the patient's 
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physician. We have substantial experience with our proposed recruitment methods, which 
are IRB approved for our previous or ongoing studies. 
We also propose to obtain lists of consecutive patients with a diagnosis of lower extremity 
peripheral arterial disease who are seen in our vascular surgery practice, cardiology 
practice, and general internal medicine practice in the Northwestern Medical Faculty 
Foundation (NMFF). Co-investigator Dr. Mark Eskandari is a member of the vascular 
surgery practice at NMFF. Co-investigator Dr. Lloyd-Jones is a member of the cardiology 
division at NMFF. Dr. McDermott is a member of the general internal medicine practice at 
NMFF. We also propose to obtain lists of consecutive patients with a diagnosis of lower 
extremity peripheral arterial disease who are patients in our vascular surgery, cardiology, 
geriatrics, and general internal medicine practices at NMFF. Again, similar methods will be 
used as those described above, in which the patient’s physician will be contacted to obtain 
permission to send a recruitment letter to their potentially eligible patient from Dr. 
McDermott on behalf of the patient's physician. We will contact the physicians and if after 
the physician does not advise us NOT to contact their patient within three weeks of sending 
the letter, three weeks, we will contact their patients. 
Up to four recruitment letters will be mailed, three weeks apart. We may also contact by 
telephone (after three weeks) those who do not respond to the first mailing within three 
weeks. Lists of patients at NMFF will be obtained using the EDW system. These lists will 
be obtained by an individual who is employed by the Division of General Internal 
Medicine who has received training and permission to obtain the lists from the EDW. 
In the recruitment letters, recipients are asked to call our voice mail line if they are 
interested in participation or if they do not want to be contacted. Potential participants who 
do not call us within three weeks of the first mailed recruitment letter may be telephoned 
by study staff and invited to participate. 
In addition, we may use internet advertising, public transportation advertising, newspaper 
advertising, and radio advertising to identify potential participants for this study. A draft 
newspaper ad and a radio advertising script are included in this IRB submission. We will 
also use brochures/flyers that we will post in relevant office practices. 
The EDW will be used to identify patients with peripheral arterial disease and other 
conditions which put them at risk for PAD (diabetes, coronary artery disease) using 
diagnosis codes. The patient will be contacted via a previously IRB approved recruitment 
letter signed by the principal investigator on behalf of the patient's physician.
On February 21, 2017, IRB approval was obtained at the Jesse Brown VA Medical Center.   Dr. 
William Pearce, a vascular surgeon at the Jesse Brown VA Medical Center and a study co-
investigator will provide lists of patients who have undergoing lower extremity arterial testing for 
PAD and lists of PAD patients seen in the vascular surgery clinic using IRB approved methods.  A 
research coordinator from Northwestern University who has obtained Without Compensation 
status at Jesse Brown VA Medical Center (JBVAMC) will mail recruitment letters to patients with 
PAD identified at the Jesse Brown VA Medical Center.  Letter recipients who do not telephone the 
investigators to indicate whether or not they are interested in study participation may be 
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telephoned by the study coordinator who will describe the study, assess the patient’s interest, and 
perform initial telephone eligibility screening at the Jesse Brown VA Medical Center.  Patients 
interested in participating who are deemed potentially eligible using telephone screening will 
attend a baseline visit at the Jesse Brown VA Medical Center, where they will sign a VA consent 
document and will undergo initial study testing. If the participant remains eligible after this initial 
testing, they will be scheduled for subsequent testing and interventions at Northwestern University. 
Eligible participants will be asked to sign the Northwestern University consent form at the start of 
their visit at Northwestern University. 
22.2 Describe the source of subjects.
Please see details regarding “source of subjects” in section 22.0 and 22.1.
22.3 Describe the methods that will be used to identify potential subjects.
Please see details regarding methods used to identify potential subjects in sections 22.0 and 
22.1.
22.4 Amount, timing, and method of any payments to subjects.
If the participant agrees to a muscle biopsy and is randomly selected to undergo a biopsy, 
s/he will receive $100 cash for each muscle biopsy that s/he undergoes. If the participant 
participates in two muscle biopsies, the total s/he could receive for study participation is 
$200. If the participant withdraws from the study, s/he may still retain payment for the 
portions of the study that s/he completed. Study payments are considered taxable income 
and reportable to the IRS. A Form 1099 will be sent to the participant if total payments 
from Northwestern University are $600 or more in a calendar year. We will pay up to 
$110.00 to reimburse participants for travel per study visit.
23.0
Local Number of Subjects
Recruitment. We will randomize 305 PAD participants over 32-months, allowing for a 15% drop-
out at 52-week follow-up. We will identify participants using 1) Northwestern’s Enterprise Data 
Warehouse to identify patients with PAD; 2) radio and newspaper advertising; 3) bulk mailed 
postcards to people age 55 and older living in the Chicago area; and 4) the CAPriCORN network, 
which is PCORI-funded network of medical centers in the Chicago area designed to assist 
investigators with recruitment for clinical trials. CAPriCORN has its own IRB (CHAIRb). The 
LITE Study has CHAIRb IRB approval for recruitment from individual sites that are part of 
CAPriCORN. Patients with PAD identified at these medical centers receive a recruitment letter 
that describes the LITE trial and invites the PAD patients to participate.
24.0
Confidentiality
NA
25.0
Provisions to Protect the Privacy Interests of Subjects
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25.1 Steps that will be taken to protect subjects’ privacy interests and to make the subjects feel 
at ease with the research situation.
Questionnaires will be administered in an enclosed space by a trained and certified research 
assistant.  Dr. McDermott personally certifies study participants in data collection to help 
ensure that participants are treated with the highest level of professionalism.  
25.2 Indicate how the research team is permitted to access any sources of information about the 
subjects. 
All research staff undergo training (human subjects training) in the protection of participant 
confidentiality and privacy.  Research staff have access to medical records only for the purpose of 
conducting research that is approved by the IRB.
26.0
Compensation for Research-Related Injury
26.1 If the research involves more than Minimal Risk to subjects, describe the available 
compensation in the event of research-related injury.
If the subject needs medical care because of taking part in this research study, they should contact 
the investigator and medical care will be made available. Generally, this care will be billed to the 
subject, their insurance, or other third party. Northwestern University has no program to pay for 
medical care for research-related injury.
27.0
Economic Burden to Subjects
NA
28.0
Consent Process
The “SOP: Informed Consent Process for Research (HRP-090)” will be followed. Participants 
will be consented by a research assistant who has been trained and certified by Dr. McDermott in 
obtaining informed consent. Prior to attending their first study visit, a research assistant will 
explain the study to potential participants by telephone. When a potential participant arrives to 
the medical center for study participation, the research assistant will explain the full details of the 
research study, including risks and benefits. The informed consent process will take place first at 
initial study visits. Data will be collected on the 11th floor of Galter in a private area. The 
research assistant will be collecting the signed consent form.
Potential participants will be provided plenty of time to read the consent form. The research assistant 
will answer study questions. However, if the participant would like more time to discuss the research 
study with their physician or family member, they will be allowed to do so. In this case, the study visit 
will not proceed. Dr. McDermott or another study investigator at Northwestern is also available to 
answer any questions that participants may have about the research.
Non-English Speaking Subjects
Potential participants who do not speak English will not be eligible for study participation.
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Subjects who are not yet adults (infants, children, teenagers)
Children will not be involved in this research.
Cognitively Impaired Adults
Participants who are cognitively impaired will not be eligible.
Adults Unable to Consent
Written consent will be required from all study participants. Participants who cannot 
provide informed consent are not eligible for participation. 
29.0
Process to Document Consent in Writing
The “SOP: Written Documentation of Consent (HRP-091): will be followed. 
30.0
Drugs or Devices
30.1 Plans to store, handle, and administer drugs or devices.
Actigraphs. Participants will be asked to wear the ActiGraph while they are exercising.  We will 
provide the ActiGraph for the participant to use. 
31.0
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