Telmisartan Plus Exercise to Improve Functioning in Peripheral Artery Disease
Phase: NA
Conditions: Peripheral Artery Disease
Sponsor: Northwestern University

PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
Page 1 of 51
Revised Template: January 1,2015
PROTOCOL TITLE:
Telmisartan Plus Exercise to Improve Functioning in PAD:  The TELEX Trial
PRINCIPAL INVESTIGATOR:
Mary McDermott, MD
Department of General Internal Medicine
312-503-6419
mdm608@northwestern.edu
VERSION NUMBER:
Version #29.
VERSION DATE:
 2/3/2022
IRB #: STU00200954 Approved by NU IRB for use on or after 11/7/2022 through 11/6/2023.

PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
Page 2 of 51
Revised Template: January 1,2015
Table of Contents
1.0 Objectives……………………………………………………………… 3
2.0 Background……………………………………………………………..4
3.0 Inclusion and Exclusion Criteria………………………………………..12
4.0 Study-Wide Number of Subjects………………………………………. 14
5.0 Study-Wide Recruitment Methods…………………………………….. 14
6.0 Multi-Site Research……………………………………………………. 14
7.0 Study Timelines………………………………………………………... 14
8.0 Study Endpoints………………………………………………………...14
9.0 Procedures Involved…………………………………………………….15
10.0 Data and Specimen Banking…………………………………………..24
11.0 Data and Specimen Management……………………………………...25
12.0 Provisions to Monitor the Data to Ensure the Safety of Subjects……..28
13.0 Withdrawal of Subjects………………………………………………..28
14.0 Risks to Subjects………………………………………………………29
15.0 Potential Benefits to Subjects………………………………………… 31
16.0 Vulnerable Populations………………………………………………. 32
17.0 Community-Based Participatory Research……………………………32
18.0 Sharing of Results with Subjects……………………………………... 32
19.0 Setting………………………………………………………………… 32
20.0 Resources Available…………………………………………………...32
21.0 Prior Approvals………………………………………………………..33
22.0 Recruitment Methods………………………………………………….33
23.0 Local Number of Subjects……………………………………………. 35
24.0 Confidentiality………………………………………………………... 35
25.0 Provisions to Protect the Privacy Interests of Subjects………………..35
26.0 Compensation for Research-Related Injury…………………………...35
27.0 Economic Burden to Subjects…………………………………………35
28.0 Consent Process………………………………………………………. 35
29.0 Process to Document Consent in Writing……………………………..36
30.0 Drugs or Devices………………………………………………………36
31.0
 
References…………………………………………………………….. 37
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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1.0 Objectives
1.1
Purpose, Objectives, Specific Aims
Our work and that of others shows that patients with lower extremity 
peripheral artery disease (PAD) have greater functional impairment, faster 
functional decline, and higher rates of mobility loss compared to people 
without PAD (1-7).  PAD-related ischemia-reperfusion of calf skeletal 
muscle during walking activity is associated with calf skeletal muscle fiber 
atrophy and impaired calf muscle mitochondria function (8-12).  These calf 
muscle abnormalities in people with PAD are associated with functional 
impairment and mobility disability (13-15).  Yet few medical therapies are 
available to improve functioning or prevent disability in PAD.   
Recent evidence suggests that the angiotensin receptor blocker (ARB) 
telmisartan may reverse the skeletal muscle dysfunction present in PAD (16-
19).  In normal mice, telmisartan increases Type I skeletal muscle fibers, 
improves mitochondrial function, and enhances exercise performance (16-
18).  Also in mice, ARBs reduce fibrosis and enhance satellite cell-
dependent muscle regeneration after muscle injury (20-23).  We hypothesize 
that these favorable effects of ARBs and telmisartan on skeletal muscle in 
mice may be particularly beneficial for the ischemia-reperfusion related calf 
muscle injury observed in patients with PAD.  In support of our hypothesis, 
a small pilot trial in humans showed that telmisartan improves treadmill 
walking performance in people with PAD (19).    
After a discussion with the Data Safety Monitoring Board on 10/31/19, it 
was determined that the sample size would be reduced from 240 participants 
to 112 participants and that the primary comparison will be comparing all 
participants randomized to telmisartan (with and without exercise) vs. all 
participants randomized to placebo (with and without exercise).  The 
specific aims and power calculation and statistical analysis plan were 
revised accordingly.  The reason for the change in sample size was due to 
difficulty with enrollment, because most people with peripheral artery 
disease were already taking either an ACE inhibitor or an angiotensin 
receptor blocker (ARB).    
This study will definitively establish whether telmisartan improves walking 
performance in people with PAD.  We will conduct a randomized clinical 
trial (2 x 2 factorial design) of 112 participants with PAD randomized to one 
of four arms:  Group A: telmisartan + supervised exercise therapy; Group B: 
telmisartan + a “no exercise” control group; Group C: placebo + supervised 
exercise therapy; and Group D: placebo + a “no exercise” control group.  
Our primary outcome is change in six-minute walk performance between 
baseline and 6-month follow-up.  Our secondary aims will measure change 
in treadmill walking performance, patient-reported walking performance 
(measured by the Walking Impairment Questionnaire (WIQ)), and quality of 
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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life (measured by the Short Form-36 Physical Functioning (SF-36 PF) 
score).  In exploratory aims, we will obtain calf muscle biopsies to delineate 
biologic pathways by which these therapies improve functioning.  
 
Primary Specific Aim.  Our primary specific aim for this study is as 
follows: We will determine whether telmisartan therapy with or without 
exercise improves six-minute walk distance at 6-month follow-up, compared 
to placebo with or without exercise.  Specifically, this aim consists of a two 
group comparison of all participants randomized to telmisartan vs. all 
participants randomized to placebo.  
Secondary specific aim #1. We will determine whether telmisartan 
combined with supervised treadmill exercise achieves greater improvement 
in six-minute walk distance at 6-month follow-up, compared to supervised 
exercise alone and compared to telmisartan alone, respectively.  
Secondary specific aim #2.  We will determine whether telmisartan alone 
improves six-minute walk distance at 6-month follow-up, compared to 
placebo.  
Secondary specific aim #3.  We will determine whether telmisartan with or 
without exercise improves maximal treadmill walking distance, the Walking 
Impairment Questionnaire, and the Short Form 36 physical functioning 
score compared to placebo with or without exercise Specifically, this aim 
consists of a two group comparison of all participants randomized to 
telmisartan vs. all groups randomized to placebo.
Tertiary specific aim 1. We will determine whether telmisartan therapy 
alone significantly improves maximal treadmill walking distance, the 
Walking Impairment Questionnaire (WIQ), and the Short Form 36 (SF-36) 
PF score at 6-month follow-up, compared to placebo alone.  
  
Tertiary specific aim 2:  We will determine whether telmisartan combined 
with supervised treadmill exercise achieves greater improvement in 
maximal treadmill walking distance, the Walking Impairment Questionnaire 
(WIQ), and the Short Form 36 (SF-36) PF score at 6-month follow-up, 
compared to supervised exercise alone and compared to telmisartan alone, 
respectively.  
Our first exploratory specific aim is to determine the effects of telmisartan 
(with and without exercise) on gastrocnemius muscle biopsy measures of 
quantity and activity of peroxisome proliferator activator receptor delta 
(PPARδ), PPAR-γ coactivator-1alpha (PGC-1α), adenosine monophosphate-
activated protein kinase (AMPK), relative gene expression of PPARδ, PGC-
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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1α, AMPK, FOXO3A, and SIRT-1, satellite cell number, and Type 1 muscle 
fiber composition at 6-month follow-up, compared to placebo (with and 
without exercise).  This aim will facilitate the identification of potential 
biologic pathways underlying improved walking performance in people with 
PAD. 
Our second exploratory specific aim is to determine the effects of 
telmisartan alone, exercise alone, and the combination of telmisartan plus 
exercise on gastrocnemius muscle biopsy measures of quantity and activity 
of peroxisome proliferator activator receptor delta (PPARδ), PPAR-γ 
coactivator-1alpha (PGC-1α), adenosine monophosphate-activated protein 
kinase (AMPK), relative gene expression of PPARδ, PGC-1α, AMPK, 
FOXO3A, and SIRT-1, satellite cell number, and Type 1 muscle fiber 
composition at 6-month follow-up, compared to placebo.  This aim will 
facilitate the identification of potential biologic pathways underlying 
improved walking performance in people with PAD. 
1.2
Hypotheses.
We hypothesize that:
1. PAD participants randomized to telmisartan with or without exercise (i.e. 
all participants randomized to telmisartan) will achieve greater improvement 
in six-minute walk distance at 6-month follow-up, compared to placebo with 
or without exercise (i.e. all participants randomized to placebo).
2. PAD participants randomized to the combination of telmisartan plus 
supervised treadmill exercise will achieve greater improvement in six-
minute walk distance at 6-month follow-up, compared to telmisartan alone 
and supervised exercise alone, respectively.
3. PAD participants randomized to telmisartan alone will achieve greater 
improvement in six-minute walk distance compared to placebo.
4. PAD participants randomized to telmisartan (with or without exercise) 
will achieve greater improvement in maximal treadmill walking distance, 
the WIQ, and the SF-36 PF score at 6-month follow-up, compared to 
participants randomized to placebo (with or without exercise).  Specifically, 
we hypothesize that all participants randomized to telmisartan will improve 
each outcome significantly more than all participants randomized to 
placebo.
5. PAD participants randomized to telmisartan alone will significantly 
improve maximal treadmill walking distance, the WIQ and the SF-36 PF 
score at 6- month follow-up, compared to placebo.
6. PAD participants randomized to the combination of telmisartan plus 
supervised treadmill exercise will achieve greater improvement in maximal 
treadmill walking distance, the WIQ, and the SF-36 PF score at 6-month 
follow-up, compared to telmisartan alone and as compared to supervised 
exercise alone, respectively.  
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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2.0
Background
2.1
Relevant prior experience and gaps in current knowledge
A.  Lower extremity peripheral artery disease (PAD) causes functional 
impairment, functional decline, and disability.   PAD affects eight 
million men and women in the U.S. and more than 200 million men and 
women worldwide (24,25).  PAD will be increasingly common as the 
population survives longer with chronic disease (26).  Our work and that of 
others demonstrate that people with PAD have greater functional 
impairment, more rapid functional decline, and faster mobility loss than 
those without PAD (1-7).  Recent evidence shows that chronic disability, 
such as that associated with PAD, accounts for more than half of U.S. health 
burden (26). Furthermore, therapeutic advances have not kept pace with the 
growing burden of disability from chronic disease (26).  
B.  Few therapies have been identified to improve functioning and 
prevent disability in PAD.  Only two medications, pentoxifylline and 
cilostazol, are FDA-approved for treating PAD-associated walking 
impairment.  Of these, recent data show that pentoxifylline is usually 
ineffective and benefits from cilostazol are modest (27-31).  New therapies 
are urgently needed to prevent disability in patients with PAD.  
C.  Ischemia-reperfusion injury damages calf skeletal muscle in patients 
with PAD.  Patients with PAD experience calf muscle ischemia during 
walking activity, when metabolic demands exceed oxygen supply.  Patients 
with PAD experience calf muscle reperfusion during rest, when blood 
supply increases sufficiently to meet calf muscle oxygen requirements.  This 
phenomenon of ischemia-reperfusion generates reactive oxygen species 
(ROS), such as superoxide anion and hydrogen peroxide, that damage 
muscle fibers, impair mitochondrial function, and promote apoptosis (8-
12,32-34). For example, in a study of 34 participants with PAD and 21 
without PAD who underwent calf muscle biopsy, PAD participants had 
higher protein carbonyl content (695 grayscale units + 1.32 vs. 486 
grayscale units + 135) and higher 4-hydroxy-2-nonenal (HNE) levels (436 
grayscale units+ 119 vs. 261 grayscale units + 101, P<.001), indicating 
higher calf muscle levels of oxidative stress in the PAD participants.  Higher 
quantities of oxidative stress were associated with fewer myofibers in 
participants with PAD (8).  
D.  Further evidence of damaged calf skeletal muscle in patients with 
PAD.  People with PAD have smaller calf muscle mass, impaired calf 
muscle mitochondria function, and poorer leg strength compared to people 
without PAD (8,11-13,32-36).  Several examples follow.  First, in our 
Walking and Leg Circulation Study (WALCS) II cohort, we used computed 
tomography (CT) to image calf skeletal muscle in 439 people with PAD and 
265 without PAD (13).  Presence and severity of PAD were associated with 
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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smaller calf muscle area (ABI < 0.50: 5,193 mm2; ABI 0.50-0.90: 5,546 
mm2; ABI 0.91-1.30:  5,941 mm2, P<0.001) and higher calf muscle percent 
fat (ABI < 0.50: 12.8%; ABI 0.50-0.90: 11.4%; ABI 0.91-1.30: 9.2% 
P=0.02) even after adjusting for known and potential confounders including 
age, sex, comorbidities, and physical activity (13).  Second, among patients 
with PAD, electron microscopy of calf skeletal muscle shows pathologic 
changes in myofibrils, mitochondria, nuclei, and sarcolemma of calf muscle 
myofibers (11).  Third, calf muscle mitochondria from PAD patients have a 
quantitative mitochondria dysfunction, with reduced energy production 
(33,34).  One study used magnetic resonance spectroscopy to measure the 
efficiency with which mitochondrial oxidative phosphorylation restores 
levels of adenosine triphosphate (ATP) following ATP-depleting exercise in 
12 men with PAD and 14 without PAD who engaged in 90 seconds of 
submaximal plantarflexion exercise.  The PAD participants had significantly 
poorer phosphocreatine recovery (137 seconds + 41 vs. 44 seconds + 3, 
P=0.02) and poorer ATP recovery (60 seconds + 10 vs. 29 seconds + 2, 
P=0.02) following exercise than patients without PAD (33).  These results 
demonstrate a defect in calf muscle mitochondrial oxidative phosphorylation 
in PAD that is independent of differences in blood flow between people 
with and without PAD.  Fourth, in two separate studies, poorer 
mitochondrial function, measured by respirometry from muscle biopsy 
specimens (14) or magnetic resonance spectroscopy (34), was associated 
with poorer treadmill walking in people with PAD.  Fifth, more adverse calf 
muscle characteristics, measured by CT, are associated with higher rates of 
mobility loss at two-year follow-up among people with PAD (15).  Among 
370 PAD participants in our WALCS II cohort, those in the lowest tertile for 
calf muscle area at baseline and those in the highest (worst) tertile for calf 
muscle percent fat at baseline had the highest rates of mobility loss (Hazard 
Ratio (HR) = 3.29, 95% Confidence Interval (CI)-1.40-7.73) and HR =5.55, 
CI=1.82-16.7), adjusting for confounders at two-year follow-up (15).  In 
summary, people with PAD have adverse calf skeletal muscle 
characteristics, characterized by loss of muscle fibers and impaired 
mitochondrial function.  These skeletal muscle impairments are associated 
with walking impairment and mobility loss in people with PAD.
2.2
Relevant Preliminary Data.
The TELEX Trial builds on our prior work. Prior study has established that 
patients with PAD have significant functional impairment and faster 
functional decline and mobility loss than people without PAD (1-6). We 
have successfully completed large randomized trials of exercise in PAD 
patients (43,60). Our preliminary evidence supports our hypotheses and 
shows that PAD participants taking an ACE inhibitor or an ARB have more 
favorable mitochondrial function and respond more favorably to an exercise 
intervention than those not taking these medications. 
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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2.3
Scientific background and significance of research based on existing 
literature.
A. Telmisartan improves oxygen consumption and running endurance 
in mice by up-regulating peroxisome proliferator activated receptor 
delta (PPARδ) and increasing skeletal muscle levels of adenosine 
monophosphate-activated protein kinase (AMPK) (16,18).  In cell 
culture and animal studies, telmisartan up-regulates PPARδ and AMPK, 
suggesting a mechanism underlying beneficial effects of telmisartan on 
muscle contractile properties and energy production (16,18,36,37).  PPARδ, 
expressed in high concentrations in skeletal muscle, regulates the metabolic 
and contractile properties of myofibers (36,37).  Mice that overexpress 
PPARδ have greater oxidative Type I muscle fibers, improved oxygen 
consumption, enhanced whole-body insulin sensitivity, and greater walking 
endurance (36,37).  Type I muscle fibers are rich in mitochondria that 
provide a steady supply of ATP and are fatigue resistant.  AMPK is a major 
regulator of energy metabolism in skeletal muscle that directly up-regulates 
PGC-1α, increases mitochondrial biogenesis, and enhances mitochondrial 
function (37).  
Two studies from the Zhu laboratory showed that telmisartan fed mice had 
increased quantities of Type I muscle fibers, increased oxygen consumption, 
and improved running endurance compared to control mice (16,18).  In in 
vitro analyses of cultured myotubes, telmisartan increased PPAR-δ mRNA 
and protein expression by 105% and 102%, respectively, and increased 
AMPK expression by more than two-fold (16).  The resulting increased 
PPAR-δ quantity in gastrocnemius muscle was associated with increased 
AMPK phosphorylation, increased Type I muscle fiber quantity, improved 
insulin mediated glucose uptake, increased oxygen consumption, and 
improved running endurance (16,18).   None of these favorable effects of 
telmisartan occurred in mutant mice lacking PPARδ skeletal muscle 
receptors (16,18).  In summary, in normal mice, telmisartan improves 
oxygen consumption and increases running endurance and these favorable 
effects are mediated by higher levels of PPARδ and AMPK that act to 
increase abundance of Type I muscle fibers and improve mitochondrial 
function.  We hypothesize that telmisartan will improve walking 
performance in patients with PAD by increasing the abundance of Type I 
muscle fibers and by improving mitochondrial function.  We further 
hypothesize that these changes will be mediated by increased expression of 
PPARδ and AMPK in calf skeletal muscle.  
B.  Angiotensin receptor blockers (ARBs) increase skeletal muscle 
perfusion (38).  Angiotensin Type 1 (AR1) and Type 2 (AR2) receptors 
exist throughout the skeletal muscle microcirculatory system (39).  AR1 
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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activation promotes vasoconstriction and smooth muscle proliferation.  AR2 
activation promotes vasodilation in small vessels. Chai and colleagues 
studied the effect of losartan, an ARB, on skeletal muscle blood flow in 
mice (38).  Losartan increased muscle blood volume by more than three-fold 
and increased muscle interstitial oxygenation by two-fold.  These favorable 
effects of losartan were independent of femoral artery blood flow and were 
due to blocking the vasoconstrictive properties of AR1 and allowing the 
vasodilatory properties of AR2 to predominate (38).  The net result was an 
increase in skeletal muscle perfusion and oxygen delivery.  Telmisartan has 
more than a 3000-fold greater affinity for AR1 blockade, compared to AR2 
and has a much stronger affinity for AR1, compared to alternative ARBs 
(40).  To our knowledge, telmisartan is the only pharmacologic agent with 
properties that both increase skeletal muscle perfusion and intrinsically 
improves skeletal muscle quality.  Together, these properties make 
telmisartan an extremely promising therapy for PAD.  
C. A pilot study suggests that telmisartan improves treadmill walking 
performance and endothelial function in people with PAD.  Zankl and 
colleagues randomized 36 individuals with PAD to telmisartan vs. placebo 
for 12 months (19).  Participants randomized to telmisartan achieved greater 
gains in maximal treadmill walking distance compared to participants 
randomized to placebo (from 132 to 191 meters in the telmisartan group vs. 
from 100 to 103 meters in the placebo group, P<0.001) and greater increases 
in brachial artery flow-mediated dilation compared to placebo (from 0.06 to 
0.08 mm in the telmisartan group vs. from 0.05 to 0.04 mm in the placebo 
group, P<0.001).  This pilot study supports our hypothesis that telmisartan 
improves treadmill walking performance as compared to placebo.  However, 
the sample size was small.  To our knowledge no other trials have studied 
telmisartan in PAD patients. 
D.  Telmisartan may enhance benefits of supervised treadmill exercise 
in people with PAD.  Supervised treadmill exercise significantly improves 
treadmill walking and six-minute walk performance in people with PAD 
(42-44).  The mechanism by which supervised treadmill exercise improves 
functional performance in people with PAD is unclear (45).  However, 
several studies that obtained gastrocnemius muscle biopsies before and after 
a supervised exercise intervention in PAD patients have begun to delineate 
biologic pathways of improved walking performance in response to 
supervised exercise (46-49).  Collectively, these studies indicate that 
supervised treadmill exercise increases capillary density, but does not 
improve myofiber or mitochondrial function in PAD (46-49).  For example, 
Duscha and colleagues randomized 35 patients with PAD to supervised 
treadmill exercise vs. a less intensive home-based walking program for 12 
weeks (46).  PAD patients randomized to supervised exercise increased their 
calf muscle capillary density (from 216 capillaries/mm2 + 66 to 286 
capillaries/mm2 + 78, P<0.01), but participants randomized to the less 
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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intensive home-based exercise had no change in capillary density (from 238 
capillaries/mm2 + 78 to 235 capillaries/mm2 + 91).  Neither group had a 
meaningful change in quantity of calf skeletal muscle Type I fibers or levels 
of citrate synthase, a measure of mitochondrial function.  These data and 
others demonstrate that supervised treadmill exercise, conducted at the 
intensity recommended by clinical practice guidelines, increases calf muscle 
capillary density but does not improve calf muscle metabolism (46-49).  We 
propose that by combining telmisartan (an intervention that increases Type I 
muscle fibers and mitochondrial function) with supervised treadmill 
exercise (an intervention that increases calf muscle capillary density), the 
combination of telmisartan + supervised treadmill exercise will achieve 
greater benefit than either therapy alone (Figure 1).  
E.  Additional evidence to support combined therapy with telmisartan 
and supervised exercise.  Consistent with our hypothesis, a study of 
sedentary mice and a separate study of a muscular dystrophy mouse model 
each demonstrated that PPARδ agonist drugs act synergistically with 
exercise to improve running capacity (37,41).  In both studies, the 
synergistic effect of the PPARδ agonist drugs was mediated by PPARδ 
receptors and AMPK.  As described in section 2.3C, telmisartan is a PPARδ 
agonist drug that increases quantities of PPARδ and AMPK in skeletal 
muscle of normal mice.  Narkar and colleagues treated normal mice with the 
PPARδ agonist GW1516.  When administered alone, the PPARδ agonist 
GW1516 did not improve running endurance in mice.  However, when 
administered in conjunction with exercise, the PPARδ agonist GW1516 
significantly increased oxidative myofiber quantity and improved running 
endurance more than exercise alone.  This combined beneficial effect 
appeared to be due to an interaction of the PPARδ agonist GW1516 with 
exercise-induced increases in AMPK, which together favorably altered gene 
transcription to achieve increased oxidative myofibers and improved 
running endurance (37).  Consistent with this observation, a similar synergy 
was observed when the PPARδ agonist GW1516 was combined with 
AICAR, an oral agent that increases AMPK levels (37).  Because 
telmisartan is also a PPARδ agonist, this evidence supports our hypothesis 
that telmisartan combined with supervised exercise will achieve greater 
gains in walking endurance compared to telmisartan alone or supervised 
exercise alone, respectively.
F.  Telmisartan may promote skeletal muscle regeneration by 
increasing muscle satellite cells.   Prolonged or repeated skeletal muscle 
injury is associated with skeletal muscle fibrosis and impaired myofiber 
regeneration (21,50). PAD patients experience mitochondrial and myofiber 
injury from ischemia/reperfusion-induced oxidative stress in calf muscle 
during walking activity (8,12). Skeletal muscle injury is normally repaired 
through the activity of resident muscle stem cells, known as satellite cells 
(51).  Satellite cells reside beneath the basement membrane, closely 
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
TELEX Trial
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associated with the muscle fiber.  In response to muscle injury, they are 
activated, proliferate and fuse to either form new muscle fibers de novo or 
fuse with existing fibers to repair and replace lost fiber nuclei.  In addition to 
promoting muscle fiber regeneration, satellite cell activity facilitates 
endothelial cell function in a mouse model of ischemic injury (52).  Satellite 
cells increase in response to resistance training, likely in response to 
associated muscle damage induced by training, contributing to the 
hypertrophic response (53-55).  Satellite cells also increase in response to 
aerobic exercise (56), potentially contributing to both muscle fiber growth 
(57) and to muscle adaptation and remodeling, independent of myofiber 
hypertrophy in humans (58). The angiotensin receptor blocker (ARB) 
losartan increases muscle regeneration in damaged muscle (59).  We 
hypothesize that satellite cells are an important but unexplored target for 
improving muscle function in PAD patients and that similar to the ARB 
losartan, telmisartan, will increase satellite cells in damaged muscle.  This 
hypothesis will be evaluated in our Exploratory Aim.      
Theoretical Framework.  The underlying pathophysiology of PAD-related 
functional impairment consists of ischemia-reperfusion damage of calf 
skeletal muscle that reduces the quantity of calf muscle myofibers, impairs 
mitochondrial function, reduces walking endurance, and leads to mobility 
loss (Figure 1a).  Telmisartan targets these PAD-related skeletal muscle 
deficiencies with therapeutic actions that increase abundance of Type I calf 
muscle fibers, improve mitochondrial function, increase calf muscle 
perfusion, and promote calf muscle regeneration after injury (Figure 1b).  
Supervised exercise targets PAD-related skeletal muscle deficiencies by 
increasing calf muscle capillary density, increasing satellite cells, and 
promoting skeletal muscle regeneration (Figure 1b).  Based on this 
evidence, we hypothesize that telmisartan will improve the six-minute walk 
as compared to placebo and that the combination of telmisartan with 
supervised exercise will improve six-minute walk more than either therapy 
alone.       
Figure 1.  Theoretical Model for the TELEX Trial
Patients with lower 
extremity 
atherosclerosis 
(PAD) 
Impaired oxygen 
consumption
Reduced leg strength
Poor six minute walk 
performance
Increased rates of 
mobility loss
Reduced myofibers in calf muscle
Impaired  mitochondrial function
Muscle damage and degeneration
Ischemia 
reperfusion of calf 
skeletal muscle
Increased type I calf muscle fibers
Improved mitochondrial function
Increased bradykinin-mediated calf 
muscle perfusion
Improved muscle repair after injury
Increased calf muscle capillary density
Increased satellite cells and muscle 
regeneration
Improved six 
minute walk
Reduced 
mobility loss
Telmisartan
Supervised treadmill exercise
Improved oxygen 
consumption
Improved lower 
extremity muscle 
strength
Figure 1b.  Therapeutic Potential of Telmisartan combined with exercise
Figure 1a.  Underlying Pathophysiology of Peripheral Artery Disease
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PROTOCOL TITLE: Telmisartan Plus Exercise to Improve Functioning in PAD:  The 
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Innovation of the Research.
A. To our knowledge no prior studies have assessed whether the 
combination of telmisartan and supervised treadmill exercise improves 
walking performance more than either individual therapy (i.e. more 
than telmisartan alone or more than supervised exercise alone) in any 
population.  We hypothesize that by combining telmisartan therapy, which 
increases calf skeletal muscle Type I fibers and improves mitochondrial 
function in mice, with supervised exercise, which increases calf muscle 
capillary density and skeletal muscle regeneration in humans, the 
combination will be better than either individual therapy (16,18,46-49).  
Telmisartan is a PPARδ agonist (16,18).  In healthy mice, and in mice 
models of muscular dystrophy, other PPAR-δ agonists that are not clinically 
available act synergistically with exercise induced-increases in AMPK to 
increase oxidative myofiber quantity, improve mitochondrial function, and 
increase running endurance (37,41).  Together, these findings support our 
hypothesis that the combination of telmisartan plus supervised exercise will 
have substantially greater benefit than either individual therapy.  Yet no 
randomized trials in any human population have ever tested whether the 
combination of any ARB with exercise improves walking performance more 
than either treatment alone.  
B.  The TELEX Trial will measure changes in gastrocnemius muscle 
biopsy measures of satellite cell number, Type 1 muscle fiber 
composition, and quantity and activity of PPARδ, PGC-1α, AMPK, and 
relative gene expression of PPARδ, PGC-1α, AMPK, FOXO3A, and 
SIRT-1 in response to study interventions. Changes in these muscle 
outcomes in response to telmisartan, with or without exercise, have not been 
measured in any human population. This component of the TELEX Trial 
enables us to delineate biologic pathways by which the interventions may 
improve functioning in patients with PAD.  Identifying biologic 
mechanisms of these therapies will help identify new therapies, with similar 
biologic actions, that improve walking performance in people with PAD.  
This is a highly innovative feature of our proposal. 
C.  Summary of distinctive features of this trial, compared to prior 
work.  Only one previous study, a small pilot study, demonstrated that 
telmisartan increased treadmill walking performance and endothelial 
function in patients with PAD (19).  Our proposal has multiple unique 
features as compared to this small pilot study (19).  First, the primary 
outcome in the pilot study was treadmill walking performance (19).  In 
contrast, our primary outcome is the six-minute walk, a well-validated 
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outcome in people with PAD that better reflects mobility in the community 
than treadmill walking performance.  Second, the TELEX Trial will test 
whether the combination of telmisartan plus supervised treadmill exercise is 
superior to telmisartan alone and supervised treadmill exercise alone, 
respectively, for improving functional performance in PAD. As described 
above, preliminary evidence supports our hypothesis that telmisartan may be 
more efficacious when delivered with supervised treadmill exercise, but this 
question has never been addressed in any human study to our knowledge. 
Third, our proposed muscle biopsies will delineate myocellular pathways of 
improved walking performance in people with PAD.    
3.0
Inclusion and Exclusion Criteria  
3.1
Screening for eligibility 
 
Initial eligibility criteria will be assessed by telephone.  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. 
3.2
Inclusion and Exclusion Criteria.
Inclusion Criteria.  All participants will have PAD. PAD will be 
defined as follows. First, an ABI < 0.90 at the baseline study visit is 
an inclusion criterion for PAD.  ABI < 0.90 is a well-accepted 
standard for defining PAD (61-64).  Second, potential participants 
who have an ABI > 0.90 but ≤ 1.00 and experience a 20% or higher 
drop in ABI after heel-rise exercise will be eligible.  Third, potential 
participants with an ABI > 0.90 who have vascular lab evidence of 
PAD or angiographic evidence of PAD will be eligible. Finally, 
potential participants with a history of lower extremity 
revascularization who do not meet the criterion above and have an 
ABI > 0.90 with a 20% or higher drop in ABI after heel-rise exercise 
will be eligible.
Exclusion Criteria.  
1. Above or below knee amputation, critical limb ischemia, 
wheelchair confinement, inability to walk without a walker, or 
current foot ulcer. These are exclusion criteria because they prevent 
full participation in the intervention or imply an underlying 
impairment that is too severe to be improved with trial interventions. 
2. Walking is limited by a condition other than PAD. This is an 
exclusion because 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. This is an 
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exclusion because exercise may not be safe for these individuals. 
Potential participants may become eligible following an abnormal 
baseline treadmill stress test if they have evidence of an absence of 
coronary ischemia based on testing with their own physician.
4. Currently taking an angiotensin receptor blocker or an ACE 
inhibitor or use of these medications in the past three months. This is 
an exclusion because these individuals are already receiving a major 
component of the trial intervention.  
5. Currently taking aliskiren (Tekturna). This is an exclusion because 
telmisartan may not be safe to take concurrently with akiskiren.
6.  Blood pressure < 100/50 at baseline or potassium > 5.0 meq/L at 
baseline. 
7. Blood pressure < 100/50 after run-in or potassium > 5.5 meq/L at 
the end of run-in. 
8. Severe hepatic impairment defined by two or more liver function 
enzyme values greater than 2.5 the upper limit of normal. 
9. Acute decline in renal function on telmisartan, defined as a 30% 
or greater decline in eGFR following the two-week run-in as 
compared to baseline.  If the participant had a baseline eGFR 
performed by his/her physician within two months of the baseline 
eGFR for the TELEX trial, the participant’s physician’s eGFR may 
be considered the baseline measure, at the study principal 
investigator’s discretion. 
10.  Allergy to ARBs. 
11. Congestive heart failure with an ejection fraction <40.
12. Failure to successfully complete the 2-week study run-in, defined 
as failing to attend the health education and treadmill exercise run-in 
sessions and/or failing to take the study medication daily for 10 or 
more days in the two-week period (i.e. one pill per day for > 10 days 
out of the 14 day run-in period). 
13. Surgery including lower extremity revascularization, coronary 
revascularization with stenting, or orthopedic surgery during the past 
3 months or anticipated in the next 6 months or myocardial 
infarction or stroke in the past 3 months. 
14. Major medical illness including renal disease requiring dialysis, 
lung disease requiring oxygen, Parkinson’s disease, a life-threatening 
illness with life expectancy less than six months, or cancer requiring 
treatment in the previous two years. [NOTE: potential participants 
may still qualify if they have had treatment for an early stage cancer 
in the past two years and the prognosis is excellent.  Patients who 
only use oxygen at night may still qualify.] This is an exclusion 
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because these conditions may interfere with the ability to fully 
participate in and complete the study. 
15. MMSE score < 23 (65) or dementia.  This is an exclusion 
because it may interfere with the ability to fully participate in the 
study. However, investigator discretion may be used to allow some 
people 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.   
16. Currently walking regularly for exercise at a level similar to the 
study intervention. This is an exclusion because these individuals are 
already engaged in a significant component of the intervention.  
17. Participation in another clinical trial or cardiac rehabilitation or 
completion of a clinical trial or cardiac rehabilitation in the previous 
three months. [NOTE: after completing a stem cell or gene therapy 
intervention, participants will become eligible after the final study 
follow-up visit of the stem cell or gene therapy study so long as at 
least six months have passed since the final intervention 
administration. After completing an exercise intervention or a 
supplement or drug therapy (other than stem cell or gene therapy), 
participants will be eligible after the final study follow-up visit as 
long as at least three months have passed since the final intervention 
of the trial.] This is an exclusion because interference with ability to 
determine whether study interventions are responsible for improved 
outcomes.
18. Non-English speaking, a visual impairment that limits walking 
ability, or a hearing impairment that interferes with study 
participation. This is an exclusion criterion because these potential 
participants may not be able to participate fully in the intervention.
19. In addition to the above criteria, investigator discretion will be 
used to determine if the trial is unsafe or not a good fit for the 
potential participant.   
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
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6.0
Multi-Site Research
To accommodate the recruitment rate for this study, we will use additional 
sites, Ochsner Medical Center and Tulane University. Dr. Lydia Bazzano 
will serve as the site investigator for TELEX at Ochsner and Tulane. 
Participants will complete all study measures at Ochsner or Tulane’s site. 
However, muscle biopsies and long-term storage of blood may not be 
offered at Oschner or Tulane.  The Tulane IRB acknowledges Ochsner’s 
IRB decision based on a reliance agreement between each site’s IRB to 
facilitate single IRB review of multi-site research.
7.0
Study Timelines
Each participant’s part in this study will last approximately six 
months. We plan to enroll participants within five years of the study 
start date. The estimated date to complete primary analyses is 
between five and six years from the study start date.
8.0
Study Endpoints
The primary study endpoint is the six-month change in the six 
minute walk data.
Secondary study endpoints include a) six-month change in treadmill 
walking performance; b)six-month change in Walking Impairment 
Questionnaire; c) six-month change in health-related quality of life, 
measured with the Short-Form-36 Physical Functioning Score. 
Exploratory study endpoints are change in calf muscle biopsy 
measures, consisting of calf muscle biopsy-obtained satellite cell 
number, Type I muscle fiber composition, PPARδ, PGC-1α, AMPK 
quantity and activity, and relative gene expression of PPARδ, PGC-
1α, AMPK, FOXO3A, and SIRT-1. 
Additional exploratory outcomes are a) six-month change in usual-
paced four-meter walking velocity; b) six-month change in fast-
paced four meter walking velocity; c) six-month change in the short 
physical performance battery (SPPB) score.
All data will be collected at baseline and at the 6-month follow-up 
visit.
9.0
Procedures Involved
9.1
Study design.
STUDY OVERVIEW.  We will randomize a minimum of 112 and up to 
240 participants with PAD to one of four parallel study arms: Group A: 
telmisartan + supervised exercise; Group B: telmisartan + a “no exercise” 
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control group; Group C: placebo + supervised exercise; and Group D: 
placebo + a “no exercise” control group. Participants will undergo baseline 
testing, a two-week study run-in period, six months of their assigned study 
group, and six-month follow-up testing (Figure 2). 
Figure 2.  Overview of the Telmisartan Trial Design.
Telephone screening.
Initial eligibility criteria will be assessed by telephone via a telephone call 
script. The study will be described to the potential participant and the 
participant will be asked a series of eligibility questions to determine 
whether they qualify for a baseline study visit. If they qualify for a baseline 
visit, we will collect their name, address, telephone number(s), email 
address, date of birth, gender, race, and ethnicity.
Baseline testing.
Participants will be asked to come to Northwestern Memorial 
Hospital at baseline for the purposes of providing informed consent.  
In addition, at the baseline study visits, we will obtain the ankle 
brachial index (ABI) measurement, to ensure they are eligible for the 
study.  If the participant meets initial eligibility requirements, we 
may mail a letter to the participant’s physician to notify him or her 
of their patient’s involvement with the study, unless the participant 
does not have a physician or requests that we do not notify their 
physician. We will administer study questionnaires, such as the 
Walking Impairment Questionnaire and the Short-Form-36 Physical 
Functioning Score, to obtain information about their medical history.  
We will perform baseline physical functioning tests including the 
six-minute walk test, chair stands, balance testing, and the treadmill 
walking performance test.  We will take a blood sample, measure 
participants’ height and weight, and measure the blood pressure in 
their arm. In addition, participants will be asked to undergo a calf 
muscle biopsy at baseline. Participation in the calf muscle biopsy is 
optional.  Participants will be asked to have a physical examination 
prior to randomization. Baseline study visits will be performed over 
multiple days.
Details of baseline visit procedures are described in section 9.2.
Run-in period.  
Prior to randomization, all potential participants will be required to 
successfully complete a two week run-in period, during which they will take 
Baseline 
Testing
2 week 
run in
Randomize 
Eligible 
Participants
Group A: Telmisartan + Supervised Exercise Intervention
Group B: Telmisartan + No exercise 
Group C: Placebo + Supervised Exercise Intervention
Group D: Placebo + No exercise
6 Month follow-up
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20 mgs daily of telmisartan. Participants will also be required to attend one 
exercise session and one attention control session prior to randomization. 
Participants will return for a blood pressure check and measurement of 
potassium and renal function at the end of the run-in period.  Participants 
unable to tolerate telmisartan due to hypotension (i.e. blood pressure < 
100/50 on telmisartan) or hyperkalemia (potassium level > 5.5) or a 30% or 
greater decline in renal function compared to baseline, measured by eGFR, 
will be excluded for safety reasons. Participants who fail to take the study 
medication for 10 or more days in the two-week period (i.e. one pill per day 
for > 10 days out of the 14 day run-in period) will be excluded. Participants 
who report significant new or increased symptoms of lightheadedness or 
dizziness during run-in will also be excluded if the symptoms are thought to 
be related to the study medication. If a participant’s blood pressure is less 
than or equal to 100/50 at the end of the telmisartan run-in period, the blood 
pressure may be rechecked after 3 to 10 additional days of telmisartan at the 
discretion of the principal investigator.  For instance, if the participant had 
another medical condition that was thought to be contributing to the low 
blood pressure after run-in- OR if the blood pressure reading is very 
discordant from prior readings. If a participant’s baseline eGFR 
substantially differs from their prior recent eGFR values, and the 
discrepancy in the baseline value, compared to prior recent values, may 
contribute to a 30% or greater decline in eGFR after run-in, then at the 
investigator’s discretion, the baseline eGFR and run-in may be repeated.  
This protocol change was approved by the study’s Data Safety Monitoring 
Board during the week of September 14, 2020.  
Randomization.  Participants will be randomized to one of four arms using 
a SAS computer program.  Block randomization will be implemented to 
ensure balance between the four groups throughout recruitment.  Block sizes 
will be randomly selected from eight and twelve.  Randomization will be 
stratified according to whether or not the participant will have a muscle 
biopsy at baseline.  Randomization was stratified by site (added on 
1/27/2021 to reflect that when a new site was added, randomization was 
stratified by site).
Participants who are in the supervised exercise group will attend sessions 
three times weekly for six months, and participants that are in the “no 
exercise” group will attend one hour educational sessions once a week for 
six months. Participants randomized to telmisartan (Group A and Group B) 
will take 40 to 80 mgs of telmisartan per day.  Participants randomized to 
placebo (Groups C and D) will take placebo daily.  
Telmisartan/placebo and assessments.  Participants randomized to receive 
telmisartan will begin at a dose of 20 mgs or 40 mgs daily based on the 
results of post-run-in assessments. The dose will be increased as tolerated to 
80 mgs daily based on results of dose-increase visits and monthly 
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assessments post-randomization. Using results of these assessments, the 
pharmacy will receive a drug order specifying whether the dose should be 
changed in order to maintain blinding. The telmisartan dose may be reduced 
or discontinued and/or replaced with placebo pills. Participants randomized 
to receive placebo will also return for dose-increase visits and monthly 
assessments to maintain blinding. All participants will have their blood 
pressure checked at least monthly and their potassium levels checked at 2- 
and 5-month follow-up. Patients with a baseline eGFR < 30 will have their 
potassium level checked at the one-month follow-up visit as well.  
Participants will have blood pressure, potassium, and eGFR measurements 
approximately two weeks after telmisartan dose increases. All participants 
who are eligible for a dose increase based on their assessments will return 
for follow-up blood pressure and/or blood work whether they are on 
telmisartan or placebo in order to maintain blinding. Participants may be 
asked to return for additional measurements as needed for safety purposes. 
If a participant returns two weeks after a dose increase for a blood pressure 
and potassium measurement, and these blood pressure and potassium 
measurements are also within 30 days of an upcoming scheduled 2- or 5-
month follow-up visit, the 2- or 5-month visit is not also required (e.g. if a 
participant is eligible for a dose increase at the 1-month follow-up visit and 
returns at 1.5 months for a measurement of blood pressure, potassium, and 
eGFR, their blood pressure and potassium will not necessarily need to be 
checked again at the 2-month mark). In these instances, investigator 
discretion will be used to determine whether the additional 2- or 5-month 
follow-up visit measures are also needed.  
Medication will be administered in a double-blinded fashion.  Northwestern 
Memorial Hospital’s (NMH) Investigational Pharmacy will receive 
randomization assignments from the study’s data management team and 
prepare identical appearing 30 day supplies of medication (telmisartan vs. 
placebo) for participants.  Participants will receive a new 30 day supply of 
medication each month.  
Six-month follow-up testing. After six months of participation in the study, 
participants will be asked to return for follow-up testing. All measures and 
tests that were conducted at baseline will be repeated. 
In the event that a participant is unable to return after six months of 
participation and follow-up testing is delayed, the participant may be given 
additional study pills to ensure that they are still on the study pills at the 
time of follow-up testing. In this instance, the participant may take study 
pills for more than six months. Study pills will not be provided for more 
than an additional three months. Investigator discretion will be used to 
determine if additional monthly assessments of blood pressure and/or blood 
tests are necessary prior to the completion of the study follow-up visits. 
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Some or all study measures may be repeated at baseline or follow-up for 
data quality (for example if a treadmill test must be stopped due to 
extremely high blood pressure before the patient completed the test- this is 
just one potential example). 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 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, Dr. Lloyd-Jones, or other 
qualified personnel.
Supervised treadmill exercise program.  Based on recommendations from 
clinical practice guidelines and evidence from clinical trial data, our 
supervised treadmill exercise intervention is a high-intensity exercise 
regimen (43,44,70).  Supervised exercise will be delivered three times 
weekly for six months.  In week one, participants will be asked to exercise 
on the treadmill for 15 minutes per session (excluding rest periods).  
Exercise duration will be increased by five minutes per session each week 
until 50 minutes of exercise per session is achieved (42,43,70).  At this 
point, exercise intensity will be increased by alternately increasing treadmill 
speed and treadmill grade.  Exercise intensity will be selected to ensure that 
participants experience ischemic leg symptoms within five minutes after 
onset of exercise.  Participants will be asked to continue walking until they 
achieve leg symptom severity of “4 or 5” on a visual analog pain scale 
ranging from 1 to 5 (43,70).  In the subset of participants without leg 
symptoms (i.e. those with asymptomatic PAD), participants will be asked to 
exercise to achieve a Borg Rating of Perceived Exertion (RPE) score of 12-
14 (71-75). Participants may be asked to participate in up to three focus 
groups to discuss their experience in the study.  We will ask consecutive 
patients who finished with the TELEX study if they would be willing to 
participate in a focus group, starting with the most recent finishers and 
working backwards. Participants would be asked to sign a separate focus 
group consent prior to participating. The purpose of the focus groups is to 
learn more about their experience with the study.  The investigative team is 
specifically interested in barriers to participation in supervised treadmill 
exercise for people with PAD, because the investigative team is developing 
an exercise program for people with PAD that maximizes efficacy and is 
also acceptable and accessible for people with PAD.
Attention Control Group.  Participants who are randomized to the non-
exercising group will attend weekly one-hour educational sessions at 
Northwestern University for six months.  These educational sessions are on 
topics of interest to the typical PAD patient and are led by physicians and 
other health care workers.  Topics include pneumonia, nutritional 
supplements, and hypertension.  Sessions do not include information about 
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exercise.   We have substantial experience with these weekly educational 
lectures in our previously conducted randomized trials (43,60,75). The 
attention control group may include participants who are taking part in other 
studies of PAD participants conducted by Dr. McDermott, including 
participants at other recruitment sites who may videoconference into the 
lecture (for instance, participants enrolled in one of Dr. McDermott’s PAD 
studies at Tulane University or University of Chicago or University of 
Minnesota may participate in the lecture via videoconference).  
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. 
9.2
Research procedures.
Data collection overview.  Table 3 shows the outcome measures planned at 
baseline and follow-up.
Table 3.  Data Collection Plan
Outcomes (prioritized)
Study Measure
Baseline
6-month follow-up
Primary outcome 
Change in six minute walk
X
X
Change in treadmill walking performance
X
X
Change in Walking Impairment 
Questionnaire
X
X
Secondary outcomes
Change in health-related quality of life1 
X
X
Exploratory outcome
Change in calf muscle biopsy measures2
X
X
1Health related quality of life will be measured with the Short-Form-36 Physical 
Functioning Score.  2Calf muscle biopsy measures consist of calf muscle biopsy-obtained 
satellite cell number, Type I muscle fiber composition, PPARδ, PGC-1α, AMPK quantity 
and activity, and relative gene expression of PPARδ, PGC-1α, AMPK, FOXO3A, and 
SIRT-1.
Ankle Brachial Index (ABI).  We have extensive experience measuring the 
ABI (4-9,50-52). After the participant rests supine for five minutes, the right 
brachial, dorsalis pedis (DP), posterior tibial (PT) and left DP, PT, and 
brachial artery pressures are measured using a hand-held Doppler probe. 
Pressures are measured twice. The ABI is calculated for each leg by 
dividing the average of the DP and PT pressures by the average brachial 
pressure.  If a participant qualifies for a heel-rise ABI based on their initial 
ABI, they will be asked to perform 50 heel-rises at a rate of one per second 
followed by additional measurements of the right and left brachial, DP, and 
PT pressures.
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Questionnaire Administration.  Participants will be administered study 
questionnaires by a trained and certified health interviewer. Health Related 
Quality of Life will be assessed with the SF-36 Physical Functioning score 
(80).  Patient perceived walking ability will be assessed with the Walking 
Impairment Questionnaire (WIQ) (78,81,82). Both are well-validated 
measures that improve in response to effective interventions (43,60,78,80-
82). 
At either baseline or the six-month follow-up visit, the Supervised Exercise 
Questionnaire will be administered either verbally by a coordinator or the 
participant will fill out a written version of the questionnaire. Typically the 
questionnaire will be administered by a coordinator; however, in some 
instances (e.g. if a participant is waiting for a research room to become 
available for testing) it may be self-administered.  
Six-minute walk.  Participants will be asked to walk back and forth along a 
100-foot hallway for six minutes.  They will be instructed that the purpose 
of the six-minute walk test is to measure the distance they can walk in six-
minutes.  A script will be read to describe the study procedure.  Participants 
will be asked whether they feel the test is safe to try and whether they have 
any questions. 
Treadmill testing.  The Gardner graded treadmill exercise test is the 
standard, accepted treadmill protocol for measuring change in maximal 
treadmill walking time in response to interventions among PAD participants 
(70,76-78).  In the Gardner exercise protocol, speed is maintained at 2.0 
miles per hour (mph) and treadmill grade increases by 2.0% every two 
minutes (76,77).  If patients cannot walk at 2.0 mph, treadmill speed is 
started at 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 two minutes.  
Blood collection and long-term storage. At baseline and six-month follow-
up study visits, participants will have up to approximately 45 mls of blood 
drawn for processing and long-term storage at -70 degrees Celsius. 
Approximately 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.  A subset of participants will be invited to have an 
additional 9 ml tube of blood collected for measurement of the P16 marker, 
a measure of cell senescence. For participants who agree to the optional 
element, blood will be obtained in blood tubes supplied by Sapere Bio, 
labeled with study ID number, and sent to Sapere Bio (400 Park Offices Dr, 
Research Triangle Park, NC 27709) for measurement of senescent cells. 
Sapere Bio will either destroy or return to Northwestern the remaining blood 
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after measuring senescent cells.  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.
Participants will have additional blood drawn (approximately 5 mls) at 
baseline, the end of the two-week run-in, and after randomization for safety 
measurements as detailed above. Participants with potassium levels greater 
than 5.0 at baseline may return for an additional blood draw to see if their 
potassium level meets the eligibility criterion at a later date. Additional 
blood samples may be ordered at the discretion of the principal investigator 
or safety officer. 
Calf muscle biopsies.  Muscle biopsies will be performed by co-
investigator Robert Sufit MD, a board-certified neurologist with > 30 years 
of experience performing muscle biopsies.  Dr. Sufit completed all biopsies 
for our pilot study.  The muscle biopsy will be obtained in the medial head 
of the gastrocnemius muscle in the leg with lowest ankle brachial index, 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 (83).  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 prepared for freezing at -70 degrees Celsius. 
Approximately 100 to 150 mgs of fat may be removed from the 
subcutaneous fat may be removed from below the fascial line during the 
muscle biopsy. In patients with more fat tissue, up to approximately 250 
mgs of fat will be removed from the subcutaneous fat and from below the 
fascial line, respectively, at the discretion of the physician performing the 
muscle biopsy. The fascia and wound are closed with absorbable and 
subcuticular sutures, respectively. Participants are asked to return for a 
wound check approximately one week later.  At 6-month follow-up, we will 
repeat the biopsy using identical techniques.
In addition, in a subset of participants, we will obtain a muscle biopsy on 
both the left and right legs, respectively. These bilateral biopsies could be 
obtained at baseline, 6-month follow-up, or at both baseline and follow-up. 
The first biopsy will be performed using our current procedures. The second 
biopsy will be performed on the opposite leg approximately seven to thirty 
days later. 
The incision at follow-up is made adjacent to the baseline incision.  In the 
open biopsy, muscle tissue is directly visualized, ensuring an optimal 
muscle sample and providing substantial advantages over blind needle 
biopsy.  Specimens will be stored and analyzed at Northwestern, the 
University of Florida, and/or the University of Kentucky.  Other measures 
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related to skeletal muscle quality and function may also be performed at 
Northwestern or at laboratories outside of Northwestern.
Measures of muscle protein and gene expression will be performed by 
Dr. Leeuwenburgh’s laboratory at University of Florida.   Dr. 
Leeuwenburgh’s laboratory performed measures of PGC-1α, citrate 
synthase, and cox enzyme in our pilot muscle biopsy study.  Methods are 
well standardized and validated with excellent test re-test reliability in the 
University of Florida laboratory (84). We will determine protein and gene 
expression of select markers of metabolism and mitochondrial biogenesis.  
Protein expression of PPARδ, PGC-1α, and AMPK (phosphorylated and 
total) in whole tissue homogenate will be performed using Western Blot 
techniques as described previously (85).  Gene expression of PPARδ, PGC-
1α, AMPK, FOXO3, and SIRT-1 will be analyzed using quantitative real 
time PCR (qRT-PCR) as described previously (86,87).  These measures of 
gene expression will allow us to more fully delineate biologic pathways of 
improved functioning in PAD.  FOXO3 and SIRT-1 for example are 
downstream targets of AMPK.  Other measures related to skeletal muscle 
quality and function may also be performed.
Measures of muscle fiber type and satellite cells with be performed by 
Dr. Peterson’s laboratory at University of Kentucky. Muscle 
morphology will be characterized on 7-μm thick fresh frozen serial muscle 
sections.  Sections will be stained with hematoxylin & eosin to examine 
muscle morphology and determine if overt muscle 
degeneration/regeneration or cellular infiltration is observed. Fibrosis will 
be quantified by picrosirious red staining of collagen and lectin binding to 
proteoglycans in the extracellular matrix using rodamine-conjugated wheat 
germ agglutinin (96). Fiber typing will be performed with monoclonal 
antibodies against myosin heavy chain (MyHC) isoforms.  Digital images 
are captured of the entire cross-section on a ZeissAxioImager MI 
microscope equipped with excitation/emission and dichroic filter sets for 
detection of DAPI/Hoechst, Coumarin, TRITC (Rhodamine), FITC 
(Fluorescein), Cy3.5 (Texas Red) and Cy5.  Fiber type distribution and 
cross-sectional area are quantified using automated software recently 
developed in the Peterson lab (89,90).  Quantification of satellite cells using 
immunohistochemistry with the Pax7 mouse monoclonal antibody (88), 
together with DAPI staining, will measure changes in response to the 
interventions.  
Other measures related to skeletal muscle quality and function and related to 
fat measures of inflammation and senescence may also be performed at 
Northwestern, the University of Florida, and/or the University of Kentucky, 
Mayo Clinic or at other institutions as designated by the Principal 
Investigator.
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Medications.  Participants and their physicians will be asked not to change 
their medications during the study if possible.  Participants will be asked to 
bring all of their medications to baseline and follow-up visits and to monthly 
blood pressure check visits.  We will systematically record names and doses 
of medications and inquire about medication changes at each of these visits.  
If we find differences in the use of specific medications between study 
groups (such as statins or cilostazol), we will adjust for these differences.  
Other measures.  Body mass index (BMI) will be assessed at baseline and 
follow-up by objectively measuring height and weight.  Patient report will 
be used to document comorbidities.  A four-meter walk test will be 
administered at usual and fastest pace at the baseline and follow-up visits.  
Participants will be asked to perform the usual paced four-meter walk at 
usual pace and the “fast paced” four meter walk at their fastest pace.  Each 
of these short walks will be performed twice.  Participants will be asked to 
complete a series of standing balance exercises and chair stands. Participants 
will undergo a physical exam by a physician and will have the blood 
pressure in their arm checked. Participants may be asked to return for a 
second blood pressure measurement at the discretion of the investigator (e.g. 
if the sitting blood pressure is not consistent with their typical blood 
pressure or if changes in medical condition or treatment may have 
spuriously altered the blood pressure value).
9.3
Overview of protection against risks.  
Adequacy of protection against risks and methods to minimize potential 
risks.  Dr. McDermott and the study safety officers are responsible for 
overseeing results of monthly blood pressure checks and regularly scheduled 
potassium levels and measures of renal function and will follow up with the 
participant and/or their physician as necessary.   
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 baseline.  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 cellular telephone number are 
provided to participants.  
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Minimizing risks related to exercise.  According to current clinical 
practice guidelines (70), 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 or Dr. Lloyd-Jones 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.  
Minimizing risk related to telmisartan.  Telmisartan is an FDA approved 
medication.  Side effects include sinus discomfort and congestion, back 
pain, and diarrhea. Other side effects include hypotension, kidney problems, 
and hyperkalemia. The study drug is in a class of drugs known to lower red 
blood cell count, potentially causing anemia which may potentially lead to 
worsening of leg pain, fatigue, and shortness of breath. The drug labeling 
indicates that a greater than 2 g/dL decrease in hemoglobin was observed in 
0.8% telmisartan patients compared with 0.3% placebo patients. However, 
no patients have needed to stop telmisartan because of anemia. Rarely, 
serious allergic reactions may happen. Side effects of telmisartan will be 
carefully monitored.  To maximize safety, we will measure blood pressure, 
liver enzymes, eGFR and potassium level at baseline.  Individuals with a 
baseline blood pressure < 100/50, those with baseline hepatic function 
abnormalities defined as two or more liver function enzyme values greater 
than 2.5 times the normal value, and those with a baseline potassium > 5.0 
will be excluded.  Remaining potential participants who successfully 
complete baseline testing (except the muscle biopsy, which will be 
performed after successful completion of the run-in) will be asked to 
complete a two-week run-in, during which they will be asked to take 
telmisartan 20 mgs daily.  Participants will return at the end of the two-week 
run-in for a repeat blood pressure check and measurement of potassium and 
eGFR.  Individuals with a blood pressure < 100/50 or a potassium level > 
5.5 at the end of the two-week run-in will be excluded.  Individuals with a 
30% or greater decline in eGFR following two-week run-in as compared to 
baseline will also be excluded.  If the participant had a baseline eGFR 
performed by his/her physician within two months of the baseline eGFR for 
the TELEX trial, the participant’s physician’s eGFR may be considered the 
baseline measure, at the study principal investigator’s discretion.  Finally, 
after randomization, all participants will be assessed monthly for pill counts, 
blood pressure monitoring, and administration of an adverse event form and 
will have their study medication adjusted appropriately. In addition, 
potassium levels will be measured at month two and at month five of the 
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study.  Participants with a baseline GFR of < 30 will also have their 
potassium level measured at the one-month follow-up visit.  Study 
medications will be appropriately adjusted depending on potassium level. 
Participants who have a potassium level of 5.0 or greater at any time in the 
study will receive a handout on how to avoid potassium-rich foods. 
Participants will return for blood pressure, potassium, and eGFR 
measurements following increases in dose. If a participant returns two 
weeks after a dose increase for a blood pressure and potassium 
measurement, and these blood pressure and potassium measurements are 
also within 30 days of an upcoming scheduled 2- or 5-month follow-up visit, 
the 2- or 5-month visit is not also required. In addition, participants will be 
provided with a list of side effects of telmisartan and will be provided with 
Dr. McDermott’s home and cellular telephone numbers, in case the 
participant develops side effects or has questions.  It is important to point 
out that in prior randomized trials of telmisartan therapy for prevention of 
cardiovascular events, telmisartan was well tolerated (19,66-68).  For 
example, in the pilot trial of telmisartan in 36 PAD participants, there were 
no adverse events (19).
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 muscle biopsy 
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.  
Many PAD participants take anti-platelet therapy to prevent cardiac and 
cerebrovascular events.  If potential participants are taking anti-platelet 
therapy, they may be asked to hold their anti-platelet therapy during the 
seven days leading up to each muscle biopsy procedure. Participants who 
undergo bilateral biopsies may be asked to hold their anti-platelet therapy 
for approximately 14 days. At follow-up, if the participant has had a 
coronary revascularization with stenting in the previous three months, the 
participant will not be asked to hold their anti-platelet therapy. Permission 
from the participant’s physician will be obtained before asking the 
participant to hold their anti-platelet therapy.  If the participant’s physician 
does not provide permission for the patient to stop the anti-platelet therapy, 
then the participant will either be excluded from the muscle biopsy portion 
of the study or the biopsy will be performed while the participant is taking 
anti-platelet therapy.  Participants who are taking warfarin or other anti-
coagulant therapy will be excluded from the muscle biopsy portion of the 
study. 
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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 or a senior study coordinator re-certifies coordinators 
approximately every six months to ensure continued adherence to study 
protocol.  Those who are not adhering to protocol undergo additional 
training followed by re-certification.    
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 
notifying 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 will have the opportunity to call a voicemail 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 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 
individual identifiers.
10.0
Data and Specimen Banking
10.1 Storage of specimens.
Muscle specimens and 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.
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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 muscle specimens and the blood samples that are stored will be labeled 
with this unique identifier and the date and time of the blood collection. 
10.3 Procedures to release data or specimens.
Only Dr. McDermott has control over release of study data or specimens.  
Any investigators seeking to analyze blood or muscle 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 or muscle specimens for analysis, 
other than those tests specifically named in this application.
11.0
Data and Specimen Management
11.1 Data management.
We will use REDCAP for data entry, via NUCATS.
11.2 Power Estimates/Calculations.  
On October 31, 2019 investigators along with the DSMB and the study 
sponsor, NHLBI, agreed to change the primary aim to a single comparison 
of telmisartan (with and without supervised exercise) vs. placebo (with and 
without supervised exercise) due to difficulty recruiting participants for the 
trial who were not already taking an ACE inhibitor or an angiotensin 
receptor blocker.  Although the investigators will still aim to recruit as many 
participants as possible (up to the originally proposed sample size), this 
change in primary aim provides statistical power for a sample size of 112 
participants.  Power calculations still take into account an anticipated 10% 
drop-out rate at 6-month follow-up, i.e., we expect to have approximately 25 
participants per group (i.e. 100 overall) completing the 6-month follow-up. 
PAD participants will be randomized to one of four study groups:  
Group A: telmisartan + supervised exercise therapy; 
Group B: telmisartan + a “no exercise” control group; 
Group C: placebo + supervised exercise therapy; and 
Group D: placebo + a “no exercise” control group. 
For our revised Primary Aim, we will determine whether Group A+B 
improves six-minute walk performance at 6-month follow-up, compared to 
Group C+D, stratified by the exercise status.  50 PAD participants in each 
group provides 80% power to detect a minimum difference of 0.566 
standard deviations (SD) between Groups A+B and C+D in changes of six-
minute walk performance, using a two-sided two-sample t-test with a 
significance level of 0.05. As a sensitivity analysis, the following table 
summarizes the power for testing the primary aim with different total 
numbers of enrolled participants. 
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#total patients
112
116
120
128
Power for detecting 0.566 SD
80%
82%
83%
85%
In our SILC and GOALS trials (43,60), the observed differences in change 
of six-minute walk performance at 6-month follow-up between the 
intervention and control groups were 0.70 SD and 0.78 SD, respectively. In 
our SILC and GOALS trials, these observed differences represented a 
difference in six-minute walk change of 40 meters between the intervention 
and control groups (43,60), a clinically meaningful difference (79). Thus, 
we have adequate power for detecting similar or slightly smaller difference 
in the Primary Aim.
For Secondary Aim 1, we will determine whether Group A achieves greater 
improvement in six-minute walk at 6-month follow-up, compared to Group 
B and Group C, respectively. 25 participants in each group provides 70% 
power to detect a minimum difference of 0.72 SD between Groups A and B 
and between Groups A and C, respectively, in change of six-minute walk 
performance, using a two-sided two-sample t-test with a significance level 
of 0.05.   For our Secondary Aim 2, we will determine whether Group B 
improves maximal treadmill walking, the WIQ, and the SF-36 PF score at 6-
month follow-up, compared to Group D. The 25 PAD participants in each 
group also provide 70% power to detect a minimum difference of 0.72 SD. 
For our Secondary Aim 3, we will determine whether Groups A+B 
combined improves maximal treadmill walking distance, the WIQ, and the 
SF-36 functioning score, compared to Group C+D combined, stratified by 
exercise status.  50 PAD participants in each group provides 80% power to 
detect a minimum difference of 0.566 SD between Groups A+B and C+D 
using a two-sided two-sample t-test with a significance level of 0.05.  Thus, 
we have adequate power to detect effect sizes similar to the effect size in 6-
minute walk distance in SILC and GOALS for all three Secondary Aims.  
For Tertiary Specific Aim 1, we will determine whether Group B achieves 
greater improvement in maximal treadmill walking distance, the WIQ, and 
the SF-36 functioning score, compared to Group D. For Tertiary Specific 
Aim 2, we will determine whether Group A achieves greater improvement 
in maximal treadmill walking distance, the WIQ, and the SF-36 functioning 
score, compared to Group B and Group C, respectively. 25 participants in 
each group provides 60% power to detect a minimum difference of 0.64 SD 
between Groups A and B and between Groups A and C, respectively, using 
a two-sided two-sample t-test with a significance level of 0.05.  
In our SILC trial (43), the observed differences in change of maximal 
treadmill walking distance, WIQ distance score, and SF-36 functioning 
score were 0.60 SD, 0.59 SD, and 0.61 SD, respectively. Thus, we should 
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have reasonable power to detect similar effect sizes for outcomes in our 
Tertiary Aims.
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 
the assigned group.  For the Primary Aim, we will use analysis of 
covariance (ANCOVA) to compare changes in six-minute walk 
performance at 6-month follow-up between Group A+B combined and 
Group C+D combined, adjusting for study site (Northwestern or Tulane) 
and randomization to exercise status. For our Secondary Aim 1 and our 
Secondary Aim 2, we will use two sample two-tailed t-tests to compare 
changes in six-minute walk at 6-month follow-up between Groups A and B, 
between Groups A and C, and between Groups B and D, all stratified by 
study site. For our Secondary Aim 3, we will use ANCOVA to compare 
changes in maximal treadmill walking distance, the WIQ, and the SF-36 
physical functioning score between Groups A + B vs. Groups C + D, 
adjusting for  study site and randomization to exercise.  For our Tertiary 
Specific Aim 1, we will use t-tests to compare maximal treadmill walking 
distance, the WIQ, and the SF-36 functioning score, between Groups B and 
D stratified by study site.  For our Tertiary Specific Aim 2, we will use t-
tests to compare maximal treadmill walking distance, the WIQ, and the SF-
36 physical functioning score, between Groups A and B, and between 
Groups A and C, respectively, also stratified by study site. For our 
Exploratory Aims, we will use ANCOVA to compare changes in 
gastrocnemius muscle biopsy measures of each muscle measure between 
Groups A+B vs. C+D adjusting for study site and randomization to exercise.   
We will also compare Groups A, B, and C, respectively vs. Group D using 
two sample t-test stratified by study site. When the distribution of changes in 
the primary, secondary, and exploratory outcomes of interest is “very non-
Gaussian”, we will either apply appropriate transformation before 
conducting t-tests or perform Wilcoxon rank-sum test for the comparisons. 
Prior to analyses, we will also check the potential imbalance of socio-
demographic factors and prognostic factors (such as age, sex, race, baseline 
outcome measure, ABI, BMI, smoking status, comorbidities, and relevant 
medication use) between the two groups using t-tests for continuous factors 
and chi-square test for discrete factors. If there is any indication of major 
imbalance in these factors or baseline variables are associated with the 
change in outcome of interest, we will perform ANCOVA to further  adjust 
for the relevant baseline factors as potential confounders, in addition to 
randomization to exercise status and site, for two-group comparison.  
Similar analysis will be performed for exploratory aims.  In the analysis for 
the secondary, tertiary and exploratory aims, we will not adjust for multiple 
testing. However, we will report all the results regardless of their 
significance to present an overall picture of the treatment effect of 
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telmisartan.  In additional exploratory analyses, adjustment for multiple 
comparisons may be performed.  
Analyses regarding missing data:  If missing data due to participant 
dropout is missing completely at random, then the aforementioned 
analyses based on available data provide valid statistical inferences. 
When missing data due to dropout is not missing completely at 
random, we will perform several sensitivity analyses. Specifically, 
we will employ the multiple imputation approach to account for 
missing data at 6-month follow-up under the assumption of missing 
at random (91). We will perform additional sensitivity analyses to 
guard against the possibility of missing not at random using extreme 
value imputation, selection models and shared-parameter models 
(92).
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 Quality Control.  
Health interviewers will be trained by a senior coordinator and 
certified by Dr. McDermott in each data collection element, using a 
detailed checklist.  Health interviewers are rigorously evaluated for 
adherence to protocol, delineated in our manuals, prior to beginning 
data collection.  They are re-certified approximately every six 
months by a project manager or Dr. McDermott.  When deficiencies 
are identified, interviewers undergo additional training and re-
assessment. Ten percent of participants are randomly identified for 
quality control.  This subset has their ABI measured twice by 
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independent examiners and may have a split sample of muscle tissue 
(i.e. two samples from the same participant) sent for analyses.  The 
second muscle sample is designated an arbitrary identification 
number to which the technician is blinded.  Thus, quality control is 
monitored continuously.  Dr. McDermott meets with the exercise 
physiologist(s) to review individual participant’s progress.   
Blinding for data collection.  The health interviewer collecting 
outcome data will be blinded to the study group assignment.  
Participants are instructed not to reveal their group assignment.  If a 
participant reveals their group assignment, data collection is 
immediately stopped and another certified health interviewer is 
paged or contacted by telephone to continue the visit.  
Missing Data.  Missing data may occur when some participants are 
lost to follow-up.  First, we will make every effort to ensure that 
participants return for 6-month follow-up. We will use proxies to 
help us locate participants we are unable to reach and we will mail 
letters to participants who do not respond to our telephone contacts.  
We will encourage participants who do not adhere to their assigned 
groups to return for six-month follow-up. We will provide 
transportation and monetary incentives. Thus, we anticipate that 
most participants will complete six-month follow-up data collection.  
Second, we will record the reason for dropout for each participant. If 
dropout is completely at random, then the aforementioned analyses 
based on available data provide valid statistical inferences. When 
dropout is not completely at random, we will perform several 
sensitivity analyses. Specifically, we will employ the multiple 
imputation approach to account for missing data at 6-month follow-
up under the assumption of missing at random (91). We will perform 
additional sensitivity analyses to guard against the possibility of 
missing not at random using extreme value imputation, selection 
models and shared-parameter models (92).
12.0
Provisions to Monitor the Data to Ensure the Safety of Subjects
A Data Safety Monitoring Board (DSMB), approved by the National 
Heart Lung and Blood Institute, will monitor safety throughout the 
study.  Please see separate Data Safety Monitoring Board (DSMB) 
charter.  The DSMB charter will be a living document that can be 
modified during the study.  The DSMB met to review the study 
protocol and data collection forms prior to the start of the study.  The 
DSMB will receive notice of serious adverse events within seven 
days of the principal investigator learning of a serious adverse event.  
The DSMB will be notified of deaths within 24 hours of the 
principal investigator learning of deaths.  The DSMB will meet in 
person or by telephone approximately every six months to review 
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safety data.  However, additional meetings may be called by the 
DSMB at any time. 
Safety data will be systematically collected at monthly study visits 
using data collection forms.  In addition, serious adverse events that 
occur between monthly events and are communicated to the study 
team will be reported directly to the DSMB by Dr. McDermott using 
a case report form.  In addition to notifying the DSMB, the study 
statisticians and the study safety officer will be notified of serious 
adverse events.
During their meetings every six months, the DSMB will review data 
on recruitment, adverse events, serious adverse events, and 
adherence rates (to study drug and to the exercise intervention and 
health education sessions).    
The DSMB is comprised of two clinicians, including two vascular 
medicine experts, and a statistician.  Any statistical analyses of data 
on harms (or efficacy) will be analyzed by the statistical DSMB 
member. The DSMB has the ability to stop the study at any time if 
there are concerns about safety.
13.0
Withdrawal of Subjects
13.1 Anticipated circumstances under which subjects will be withdrawn 
from the research without their consent, including stopping 
participation for safety reasons.  We anticipate that subject 
withdrawal from the research without their consent will be 
infrequent.  However, a potential example is if a participant develops 
new chest pain during the study and the Principal Investigator and/or 
the medical safety officer feel it is not safe for the participant to 
continue exercising until the chest pain is evaluated by the 
participant’s physician.  In this circumstance, the participant would 
be advised to follow-up with their physician for chest pain 
evaluation.  If the participant refuses to follow-up with their 
physician, it may be necessary for them to be withdrawn without 
their consent. 
13.2 Procedures when subjects withdraw from the research. Subjects may 
withdraw from the research at any time. If they decide to leave the research, 
they should contact the principal 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
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Risks associated with the exercise program.  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 during supervised exercise, Dr. McDermott 
or the trial’s medical safety officer will be notified immediately.  Dr. 
McDermott or the medical safety officer 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).  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.  
Chest pain during exercise may result in additional cardiac work-up and 
may lead to procedures to improve coronary blood flow.  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 (70).  These exercise stress tests will be performed as 
part of our protocol and interpreted by board-certified cardiologist and co-
investigator Dr. Lloyd-Jones.  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.  If the 
baseline exercise stress test is equivocal or abnormal, the participant must 
demonstrate evidence of a recent (within the past six months) normal 
coronary perfusion test or coronary angiogram in order to be eligible for 
participation.  The latter tests would be ordered by the participant’s 
physician at their discretion.  
Exercise may sbe associated with muscle fatigue or soreness.  These 
symptoms typically resolve with rest. Exercise may increase the risk of 
falling.  However, the exercise physiologist who will supervise exercise 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.   
Risks associated with Telmisartan.  Telmisartan is FDA approved for 
treating hypertension.  Side effects are infrequent and rarely require 
discontinuation of telmisartan (67-69).  Side effects include sinus discomfort 
and congestion, back pain, and diarrhea. Other side effects include 
hypotension, kidney problems, and hyperkalemia.  The study drug is in a 
class of drugs known to lower red blood cell count, potentially causing 
anemia which may potentially lead to worsening of leg pain, fatigue, and 
shortness of breath. The drug labeling indicates that a greater than 2 g/dL 
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decrease in hemoglobin was observed in 0.8% telmisartan patients 
compared with 0.3% placebo patients. However, no patients have needed to 
stop telmisartan because of anemia. Rarely, serious allergic reactions may 
happen. Side effects of telmisartan will be carefully monitored using 
monthly questionnaires administered to all participants.  Potassium level and 
blood pressure will be measured after the two-week run-in period in which 
participants will receive telmisartan.  Those with a potassium level > 5.5 and 
those with a blood pressure < 100/50 after run-in will be excluded from the 
study.  After randomization, blood pressure will be measured monthly in all 
participants.  Potassium levels will be monitored at 2- and 5-month visits 
during the study.  Potassium level will be monitored at the 1-month visit for 
participants with a baseline eGRF < 30. Participants will be provided with a 
list of telmisartan side effects and will be provided with Dr. McDermott’s 
home and cellular telephone, in case the participant develops side effects or 
has questions. Telmisartan may be discontinued at any time during the study 
based on investigator discretion.
Risks associated with the muscle biopsy.  Risks associated with the 
muscle biopsy include discomfort during the muscle biopsy procedure, 
scarring from the muscle biopsy skin incision, bleeding (including a 
hematoma), and infection.  Potential participants who are asked to hold their 
anti-platelet 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 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 receive verbal instructions.  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 asking participants to hold their anti-
platelet medication for the seven days prior to the procedure.  If the potential 
participant’s primary care physician does not provide permission for holding 
anti-platelet therapy, the potential participant will either not be eligible for 
muscle biopsy portion of the study or the biopsy will be performed while the 
participant is taking anti-platelet therapy.  
Six-minute walk test, four-meter walks, balance, and chair stands.  The 
physical functioning tests may be associated with muscle fatigue or 
soreness.  These symptoms typically resolve with rest.  These tests may be 
associated with falling or coronary ischemia or dyspnea due to heart failure 
or lung disease.   Rarely, falling 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 physical functioning 
tests is less than 1 in 5,000.   
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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.
Risks associated with questionnaire administration.  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.  
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. Participants undergoing a blood draw may experience 
lightheadedness, dizziness, or fainting.
15.0
Potential Benefits to Subjects
If our hypotheses are correct, millions of people with PAD will benefit from 
telmisartan therapy, thereby improving functioning and preventing mobility 
loss.  This is important because PAD is associated with significant disability 
(1-7), yet few effective therapeutic options are available to improve mobility 
or prevent disability in people with PAD.  Furthermore, our exploratory aim 
will delineate biologic pathways by which these interventions may improve 
functioning in patients with PAD.  Identifying biologic mechanisms of these 
therapies will help identify new therapies, with similar biologic actions, that 
improve walking performance in people with PAD.
Participants who are randomized to supervised treadmill exercise will 
receive an intervention at no cost to them that has been shown to improve 
walking performance in people with PAD.  Other participants will receive 
no direct benefits.
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 be asked 
whether they would like ABI and stress test results mailed to their 
physician. They will not be provided with other study results routinely, 
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However participants will be notified of abnormal stress test results, 
abnormal blood pressure results, and about dangerously elevated levels of 
potassium and significant declines in kidney function at the two-week 
follow-up visit.
19.0 Setting
Baseline and follow-up data collection will take place at Northwestern 
Memorial Hospital in the Galter Pavilion (675 N. St. Clair) on floors 11 or 
18 or at 680 N. Lake Shore Drive on the 14th floor.  Attention control 
sessions will take place at 750 N. Lake Shore Drive. Supervised treadmill 
exercise sessions will take place at LA Fitness (355 E. Grand or 55 E. 
Randolph).
20.0 Resources Available
Collaborating sites.  Dr. Christiaan Leeuwenburgh (University of Florida) 
is an internationally recognized expert in skeletal muscle biology and 
mitochondrial function.  Dr. Leeuwenburgh’s laboratory will measure 
protein expression of PPARδ, PGC-1α, and AMPK (phosphorylated and 
total) using standard Western Blot techniques.  Gene expression of PPARδ, 
PGC-1α, AMPK, FOXO3, and SIRT-1 will be analyzed using quantitative 
real time PCR (qRT-PCR) following standard protocols.  
In addition, Dr. Charlotte Peterson (University of Kentucky) is 
internationally recognized for her work focusing on elucidation of cellular 
and molecular mechanisms controlling skeletal muscle structure and 
function.  Dr. Peterson’s laboratory will measure changes in calf skeletal 
muscle Type I fiber composition and satellite cell number in response to the 
study interventions in frozen human muscle biopsies shipped to the 
University of Kentucky from Northwestern University.  
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 individuals with PAD who 
have participated previously in research conducted by Dr. McDermott 
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and/or who have expressed an interest in participating in future studies 
conducted by Dr. McDermott.
In addition, some PAD participants may be identified from among 
consecutive patients diagnosed with PAD in the non-invasive vascular 
laboratory at Northwestern Medical Group (NMG). Dr. Mark Eskandari is 
medical director of the non-invasive vascular laboratory at NMG and will 
assist with identifying potential participants from the non-invasive vascular 
laboratory. As director of the vascular laboratory at NMG, 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 
NMG to Dr. McDermott using an encrypted file. Dr. Leibovitz is the 
Director of Clinical Information Systems at Northwestern Medicine. 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 electronic message (EPIC or e-mail), to ask for 
permission to contact their patient about the study. If a reply is not received 
within three weeks, up to five letters are mailed from Dr. McDermott about 
the research study. We have substantial experience with our 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 and individuals at high risk for 
peripheral artery disease from Northwestern’s Enterprise Data Warehouse 
(EDW). EDW 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.
Similar methods will be used as those described above, in which the 
patient’s physician will be contacted via fax, telephone, page, or electronic 
message (EPIC or email) to ask for permission to contact their patient about 
the study. If a reply is not received within three weeks, up to five letters are 
mailed from Dr. McDermott about the research study.  
We may also contact by telephone (after three weeks) those who do not 
respond to the first mailing within three weeks. 
In the recruitment letters, recipients are asked to call us if they are interested 
in participation or if they do not want to be contacted further. Potential 
participants who do not call us within three weeks of the first mailed 
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recruitment letter may be telephoned by study staff and invited to 
participate.
In addition, we will use newspaper advertising and radio advertising to 
identify potential participants for this study. We will also use brochures, 
flyers, or posters that we will post in relevant office practices and public 
areas. We will also advertise on public transportation vehicles or trains.
We will obtain a list of patients who may be in an eligible age range for the 
study and live in the Chicago area from a mass mailing company. Using 
this, we will send postcards to those individuals on the list. The postcards 
will instruct people to call a study number if they are interested. 
Participants who have participated in previous studies and indicated interest 
in future studies will be contacted. Participants who we screen for ongoing 
studies who may have PAD but are ineligible for that study and interested 
participating in a study may be screened for this study.
We will also use the PCOR-NET for recruitment.  PCOR-NET is a PCORI-
funded network of institutions in the Chicago area. The purpose of the 
PCOR-NET is to assist investigators with recruitment for clinical trials.  
PCOR-NET has its own IRB (University of Illinois at Chicago).  PCOR-
NET uses ICD-9 codes and the electronic health record to identify potential 
participants who have PAD.  These patients with PAD receive a recruitment 
letter that describes the TELEX trial and invites the PAD patients to 
participate.
We will mail letters to Jesse Brown VA Medical Center patients with known 
PAD. A research coordinator with WOC status at JBVAMC will send letters 
to JBVAMC patients with PAD and make follow-up calls from JBVAMC. 
Participants recruited through these methods will sign a VA consent 
document and will undergo some study testing on-site at the VA. Study tests 
include questionnaires and functional performance measures.
We will use the University of Chicago for recruitment. The University of 
Chicago will obtain IRB approval at their site to identify potential 
participants who have PAD. Those patients will PAD will be mailed 
recruitment letters that describes the trial and invites the patient to 
participate. A University of Chicago coordinator will screen potential 
participants over the telephone and schedule participants for baseline visits 
at Northwestern.
22.2     Payment
Participants will receive up to $225 for taking part in this research study. 
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Participants will receive $25 for completing six-month follow-up testing 
and $100 per muscle biopsy.
Participants will be given assistance and/or reimbursement for expenses 
related to travel such as parking, bus/train fare, taxi fare, and mileage, if 
requested. A receipt will be required for taxi fare reimbursement. 
Participants will be provided up to $90 per visit for travel reimbursement. 
If they require the use of our taxi service, we will estimate the fare on 
www.taxifarefinder.com. A one-way fare estimate must be less than or 
equal to $45.00 (i.e. round trip of $90) in order for the study to provide 
taxi service.
23.0 Local Number of Subjects
We will identify and randomize 112 eligible PAD participants.
24.0 Confidentiality
NA
25.0 Provisions to Protect the Privacy Interests of 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.
Questionnaires and all research procedures will be conducted in an 
enclosed space by a trained and certified research assistant.  Dr. 
McDermott personally certifies research assistants in data collection 
to help ensure that participants are treated with the highest level of 
professionalism.  
26.0 Compensation for 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. 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. A research assistant will explain the study to 
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potential participants by telephone prior to their first study visit. 
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 at the initial baseline study visit in a private 
area on Northwestern’s medical campus. 
Potential participants will be provided plenty of time to read the 
consent form. The research assistant will answer questions and Dr. 
McDermott or another study investigator at Northwestern is also 
available to answer any questions that participants may have about 
the research. If the participant would like more time to discuss the 
research study with their physician or family member before signing 
the consent document, they will be allowed to do so and the study 
visit will be rescheduled for a later date. 
Potential participants who do not speak English, subjects who are 
not yet adults, cognitively impaired adults, and adults unable to 
provide written consent will not be eligible for study 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
Northwestern Memorial Hospital (NMH) Pharmacy will receive 
randomization assignments from the study’s data management team 
and prepare identical appearing 30 day supplies of medication 
(telmisartan vs. placebo) for participants.  Participants will receive 
each 30 day supply at their monthly visits.   
The Food and Drug Administration concluded that the TELEX trial 
meets all of the requirements for exemption from IND regulations. A 
copy of this exemption letter has been uploaded to the eIRB.
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symptoms in peripheral arterial disease: associated clinical characteristics and functional 
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2.  McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, Chan C, 
Martin GJ, Schneider J, Pearce WH, Taylor LM, Clark E.  The ankle brachial index is 
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JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler 
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25.  Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott 
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27.  Girolami B, Bernardi E, Prins MH, Ten Cate JW, Hettiarachchi R, Prandoni P, 
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28.  Stevens JW, Simpson E, Harnan S, Squires H, Meng Y, Thomas S, Michaels J, 
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