Clinical trial NCT03295734
Conditions: Hypertension Aging Sedentary Lifestyle
Sponsor: University of Alabama at Birmingham
Start date: 2018-05-29; Completion date: 2024-09-19
Enrollment: 223 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this project is to conduct a randomized, controlled trial (RCT) to determine if choice of antihypertensive medication influences changes in functional status and other cardiovascular risk factors among older persons with hypertension when combined with physical exercise.

Detailed description:
The purpose of this project is to conduct a randomized, controlled trial (RCT) to determine if choice of antihypertensive medication influences changes in functional status and other cardiovascular risk factors among older persons with hypertension. Functional status, determined by measures of physical performance, is an important predictor of cardiovascular outcomes in older adults. Seniors with compromised function experience more CV events, have a higher risk of undergoing cardiac surgery and higher risk of CVD-related death than higher-functioning peers. Seniors with hypertension experience accelerated declines in function, and presently physical exercise is the primary strategy for preventing this decline. However, functional responses to exercise are highly variable and appear to be influenced by the type of antihypertensive medication(s) utilized to control blood pressure. Preliminary evidence suggests that, compared to other first-line antihypertensive agents, angiotensin converting enzyme (ACE) inhibitors enhance exercise-derived improvements in functional status among hypertensive seniors. This RCT will test this hypothesis. Sedentary men and women \> 60 years of age with functional limitations and hypertension will be recruited from two sites to participate in a longitudinal intervention study. Participants will be randomly assigned to one of three first-line antihypertensive agents: (1) the ACE inhibitor perindopril, (2) AT1 receptor antagonist losartan, or (3) the thiazide diuretic hydrochlorothiazide. Note: Participants with a documented history of hypersensitivity to ACE inhibitors will be randomized 1:1 to one of the two other study drugs. All participants will also participate in a structured aerobic exercise intervention. The primary aim is to determine if, compared to losartan and HCTZ, perindopril improves self-paced gait speed. The secondary aim is to determine the relative effect of perindopril on a) exercise capacity, b) body mass and composition, and c) circulating indices of cardiovascular risk. This study is expected to differentiate beneficial effects of three FDA-approved antihypertensive medications on an emerging cardiovascular risk factor in a clinically-relevant population. Thus the study has important implications for expeditiously influencing clinical practice guidelines in the prescription of antihypertensive drugs to millions of Americans.

Arms: arm 1: 4 mg qd titrated to 8 mg qd perindopril + aerobic exercise arm 2: 50 mg qd titrated to 100 mg qd losartan + aerobic exercise arm 3: 12.5 mg qd titrated to 25 mg qd HCTZ + aerobic exercise
Interventions: intervention 1: Aerobic exercise intervention 2: Perindopril intervention 3: Losartan intervention 4: HCTZ
Intervention descriptions: intervention 1: Twice weekly centered based aerobic exercise + 3/week home-based walking intervention 2: 4 mg qd titrated to 8 mg qd perindopril intervention 3: 50 mg qd titrated to 100 qd losartan intervention 4: 12.5 mg qd titrated to 25 qd HCTZ

Protocol documents:
Prot_SAP_001.pdf: 
 
Page 1 of 13 
 
Protocol 
9/14/2021 
NCT# 03295734 
Project Title 
ACES – Ace Inhibitors Combined with Exercise for hypertensive Seniors 
Abstract: 
The purpose of this project is to conduct a randomized, controlled trial (RCT) to determine if choice of 
antihypertensive medication influences changes in functional status and other cardiovascular risk factors 
among older persons with hypertension. Functional status, determined by measures of physical 
performance, is an important predictor of cardiovascular outcomes in older adults. Seniors with 
compromised function experience more CV events, have a higher risk of undergoing cardiac surgery and 
higher risk of CVD-related death than higher-functioning peers. Seniors with hypertension experience 
accelerated declines in function, and presently physical exercise is the primary strategy for preventing this 
decline. However, functional responses to exercise are highly variable and appear to be influenced by the 
type of antihypertensive medication(s) utilized to control blood pressure. Preliminary evidence suggests 
that, compared to other first-line antihypertensive agents, angiotensin converting enzyme (ACE) inhibitors 
enhance exercise-derived improvements in functional status among hypertensive seniors. This RCT will 
test this hypothesis. Sedentary men and women > 60 years of age with functional limitations and 
hypertension will be recruited from three sites to participate in a 32 week intervention study. Participants 
will be randomly assigned to one of three first-line antihypertensive agents: (1) the ACE inhibitor 
perindopril, (2) AT1 receptor antagonist losartan, or (3) the thiazide diuretic hydrochlorothiazide. All 
participants will also participate in a structured aerobic exercise intervention. The primary aim is to 
determine if, compared to losartan and HCTZ, perindopril improves self-paced gait speed. The secondary 
aim is to determine the relative effect of perindopril on a) exercise capacity, b) body mass and 
composition, and c) circulating indices of cardiovascular risk. In exploratory analyses, skeletal muscle 
biopsies will be collected to evaluate the influence of study drugs on indices of skeletal muscle 
angiogenesis. This study is expected to differentiate beneficial effects of three FDA-approved 
antihypertensive medications on an emerging cardiovascular risk factor in a clinically-relevant population. 
Thus the study has important implications for expeditiously influencing clinical practice guidelines in the 
prescription of antihypertensive drugs to millions of Americans. 
Background: 
Cardiovascular disease (CVD) is the leading cause of death in the United States, and persons over 60 
years of age account for over 80% of deaths attributable to CVD.1 CVD is also the second leading 
cause of disability among older adults,2an important contributor to the loss of independence and 
subsequent institutionalization. As a consequence, older adults account for nearly three-quarters of 
health care expenditures related to CVD.3 Importantly, these expenditures are expected to increase 
dramatically in coming years as the number of older adults is expected to double to approximately 80 
million in the next three decades.4 This aging of the American population predicts massive burden in 
terms of clinical and economic costs related to CVD.  Consequently, the identification of interventions 
capable of reducing CVD risk among older adults is an important goal with dramatic public health 
implications.  
The loss of functional abilities in advanced age is associated with not only the onset of disability and 
the loss of independence but also with increased rates of cardiovascular morbidity and mortality.5-
7Declines in self-paced walking speed, a recommended indicator of health and well-being among 
seniors,8,9 is also associated with incident stroke,10 adverse outcomes following cardiac surgery,11 as 
well as cardiovascular and all-cause mortality.6,7,12 Compared to normotensive counterparts, older 
persons with hypertension experience accelerated declines in walking speed 13,14 and increased rates 


 
Page 2 of 13 
 
of disability.15,16 We also observed this phenomenon in the Lifestyle Interventions and Independence for 
Elders Pilot (LIFE-P) study. Seniors with hypertension who were given a control intervention had slower 
long-distance walking speeds at baseline (p < 0.001) and experienced gait slowing that was not 
observed in normotensive persons.  
Currently, physical exercise is the standard intervention for improving physical function among older 
adults. Indeed, several studies have demonstrated the beneficial effects of exercise programs on the 
function of older adults.17-20 We also recently demonstrated the general efficacy of exercise training in 
improving the functional status of moderately-impaired seniors in LIFE-P.21 However despite the global 
benefit of the exercise program on the functional status of the study population, these benefits did not 
extend to a large proportion of individuals. Improvements in functional measures observed in response 
to exercise were driven largely by persons using ACE inhibitors22  – despite the fact that this group 
accounted for approximately one quarter of the study population. Indeed, persons not using ACE 
inhibitors displayed relatively poor functional adaptations to exercise. 
ACE inhibitors lower blood pressure by blocking the conversion of angiotensin I (ANG I) to 
angiotensin II (ANG II) and inhibiting the degradation of bradykinin, a potent vasodilatory substance. 
However, some therapeutic effects of ACE inhibitors may be mediated by mechanisms that are 
independent of blood pressure regulation. Proposed pleiotropic effects of ACE inhibitors include 
reducing reactive oxygen species production, anti-inflammatory properties, and reducing myocyte 
hypertrophy and fibrosis.23 In high risk patients enrolled in the Heart Outcomes Prevention Evaluation 
(HOPE) trial, most of the benefit of ramipril compared to placebo appeared to be unrelated to blood 
pressure lowering.24 Moreover, three trials in patients with hypertension and type 2 diabetes,25-27 
suggested that, for the prevention of cardiovascular events, ACE inhibitors were superior to other 
drugs, despite minimal differences in blood pressure levels. We also reported similar results in a meta-
analysis extended to all patients with hypertension.28  
 
In recent years, ACE inhibitors have been purported to attenuate declines in functional status 
among seniors.29,30 Epidemiologic evidence from the Women’s Health and Aging Study (WHAS) and 
the Systematic Assessment of Geriatric drug use via Epidemiology (SAGE) study indicated that, 
compared to non-users, seniors using ACE inhibitors displayed attenuated declines in walking speed 
and limitations in Activities of Daily Living (ADL).31,32 Despite this promising evidence, the benefits of 
ACE inhibitors on functional outcomes appear to be limited when utilized as an isolated treatment.22,33,34 
However, our preliminary evidence suggests that these benefits may be manifest when combined with 
exercise. We previously reported retrospective findings suggesting that older persons who took ACE 
inhibitors had greater exercise-derived improvements in functional status than non-users.22 As a result 
of these findings and other pre-clinical and epidemiological findings from our group,31,35-37 we developed 
our central hypothesis that – compared to other first line antihypertensive therapies – ACE inhibitors 
enhance functional responses to exercise among hypertensive seniors. We then conducted a pilot RCT 
to refine the study protocol and demonstrate the safety and feasibility of conducting the study 
interventions in the target population. The objective of this project is to conduct a fully-powered RCT to 
test our central hypothesis. 
Specific Aims: 
We propose to compare, when combined with chronic exercise, the effects of the ACE inhibitor 
perindopril to those of an AT1 receptor antagonist (losartan) and an alternative first-line 
antihypertensive that functions independent of the renin-angiotensin system (hydrochlorothiazide). We 
will recruit hypertensive seniors with functional limitations (N = 213) from two geographically distinct 
sites and follow them for 32 weeks. Participants (n = 71/group) will be randomly assigned to receive, in 
a triple-masked fashion, either perindopril (dose titrated to a maximum of 8 mg/day), losartan 
(maximum 100 mg/day) or HCTZ (maximum 25 mg/day). All participants will also engage in a 20-week 
structured exercise program (150 min/week of aerobic exercise) preceded and followed by 6-week 
observational periods. The specific aims are to:  


 
Page 3 of 13 
 
PRIMARY AIM. Determine if, compared to losartan and HCTZ, perindopril improves the primary 
outcome of short distance (4m) self-
paced gait speed, a key predictor of 
cardiovascular outcomes in seniors.10-
12,39-41    
SECONDARY AIM. Determine the 
relative effect of perindopril on the 
following secondary outcomes: (1) 
exercise capacity, defined by distance 
covered during a maximal 6-minute 
walk test, (2) body mass and 
composition, measured by DEXA, (3) 
clinical measures of cardiovascular 
risk, e.g. glucose, cholesterol, hsCRP, 
(4) systemic and vascular 
inflammation, e.g. TNF-α, IL-6, VCAM-
1, E-selectin, and (5) circulating indices 
of oxidative stress, e.g. oxLDL, MPO.  
EXPLORATORY AIM. Assess the 
effects of study drugs on exercise-induced changes in indices of skeletal muscle angiogenesis, 
including 1) the proportion of type I (oxidative) muscle fibers, 2) capillaries per muscle fiber, and 3) 
muscle content of mRNA and proteins related to angiogenesis.   
Research Plan: 
We propose to conduct a randomized, triple-masked trial to evaluate the efficacy of combining physical 
exercise with ACE inhibitor use as a strategy to improve functional status and other cardiovascular risk 
factors among older persons with hypertension. We will recruit 107 adults over 60 years of age with 
hypertension and randomly assign them to daily use of one of three first-line antihypertensive 
medications: 1) the ACE inhibitor Perindopril, 2) the ARB Losartan, or 3) the thiazide diuretic 
Hydrochlorothiazide (HCTZ). All participants will also engage in a 20 week structured exercise 
intervention. The total intervention period will be 32 weeks and separated into 3 phases: Pre-exercise 
observation (weeks 1-6), exercise intervention (weeks 7-26), and post-exercise follow-up (weeks 27-32).  
STUDY POPULATION.  
Inclusion criteria 
Exclusion criteria 
• 
Age 60 years and older  
• 
Hypertension – untreated (SBP ≥ 130 mm 
Hg or DBP ≥ 80 mm Hg) or treated  
• 
> 290 seconds needed to complete long-
distance corridor walk test, as an indicator of 
functional limitation and moderate to low 
aerobic fitness7  
• 
Sedentary lifestyle, defined as <150 min/wk 
of moderate physical activity as assessed by 
CHAMPS questionnaire42 
• 
Willingness to participate in all study 
procedures, including allowing study team to 
communicate with primary care physician 
regarding changes in antihypertensive 
treatment 
• 
Resistant hypertension, defined as BP > 140/90, despite the 
use of three or more anti-hypertensive drugs43 
• 
SBP > 180 mm Hg or DBP > 110 mm Hg 
• 
Chronic kidney disease 
• 
Serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women 
• 
Serum potassium exceeding the laboratory reference 
• 
Urinary protein > 1 on dipstick  
• 
Abnormal liver enzymes (AST, ALT, or alkaline phosphatase > 
2.5 times the upper limit of normal) 
• 
Severe cardiac disease, including NYHA Class III or IV 
congestive heart failure, clinically significant aortic stenosis, 
history of cardiac arrest, use of a cardiac defibrillator, or 
uncontrolled angina   
• 
Subjective or objective indicators (ECG) of ischemic heart 
disease (e.g., angina, ST segment depression) or serious 
arrhythmias at rest without follow-up evaluation Significant 
cognitive impairment, defined as a known diagnosis of 
dementia or a Mini-Cog™ score < 3;  
 
Scheme 1. Overview of Study Design. 


 
Page 4 of 13 
 
• 
History of hyponatremia with use of HCTZ 
• 
Simultaneous participation in another intervention trial 
• 
Known hypersensitivity to ACE inhibitors (exclusion only to 
ACEi arm; will be randomized among other two interventions) 
RECRUITMENT. We will develop a targeted recruitment approach based on previous experiences 
utilizing methods of recruitment that include direct mailings, newspaper classified and print ads, 
community luncheons and health fairs, as well as clinic referrals. Our group has been extremely 
successful in implementing this approach in past studies. 
SCREENING AND STUDY ENTRY. Participants deemed eligible based on an initial phone screening will be 
encouraged to consult with their physician and invited to an in-person screening visit. If all study entry 
criteria are met, participants will be scheduled to return to the clinic for baseline assessments. 
Randomized participants will be followed with clinic visits for a total follow-up duration of 32 weeks 
following randomization. In addition to the screening visit, participants are required to attend the clinic 
for 6 assessment visits which includes a final close-out visit 6 weeks following the completion of study 
interventions. The assessment schedule is provided below.   
PRIMARY AND SECONDARY OUTCOMES.  
Outcome 
Explanation 
Gait speed 
(Primary) 
Declining gait speed in late-life is associated with increased risk of numerous cardiovascular 
outcomes,7,10-12 and has been proposed as a novel cardiovascular screening outcome in 
older adults due to its high prognostic capacity, high reproducibility, and extraordinary cost-
effectiveness.44,45 We will assess gait speed by asking the participants to walk at their usual 
pace over a 4 m course.  
Exercise 
Capacity 
We will assess exercise capacity of participants using the six-minute (6-min) walk test, a safe 
and reliable test of aerobic endurance in older persons and those with cardiovascular 
conditions.46,47 This test has strong reproducibility, with intra-subject coefficients of variation 
averaging < 10%, and has a modest correlation with peak VO2.48 Participants will be asked to 
walk as far and fast as possible for 6-min on a 40 m track. Participants will be allowed to use 
their customary walking aids and to rest if required.  
Body 
Composition 
Body composition is a critical cardiovascular risk factor and a primary contributor to exercise 
capacity and overall functional status. We will assess body composition by measuring whole-
body fat percentage (BF%) as well as central adiposity (lumbar region) using dual x-ray 
absorptiometry.  
Circulating 
indices of 
cardiovascular 
risk 
In addition to measurement of clinical safety parameters, fasting blood samples (serum or 
plasma as appropriate) will be sent to Quest Diagnostics for clinical laboratory evaluation of 
blood lipids, glucose, and hemoglobin A(1c) levels. Samples will also be assayed for 
prominent markers of inflammation (e.g. TNF-α, IL-6, VCAM-1, E-selectin) and oxidative 
stress(e.g. oxidized LDL and myeloperoxidase).  Assays will be performed using previously-
utilized, commercially-available ELISA kits.  
EXPLORATORY OUTCOMES. Skeletal muscle biopsies will be collected at baseline and 26 weeks from a 
subset of participants. Participation in the biopsy will be voluntary, thus unwillingness to participate in 
the biopsy will not preclude them from participating in the trial. Biologics analyses of skeletal muscle 
samples will prioritize analyses related to angiogenesis given the finite amount of tissue obtained. 
Remaining tissue will be saved to evaluate other possible biologic mechanisms of interest including 
mitochondrial function, inflammation, and glucose metabolism. Skeletal muscle immunohistochemistry 
(i.e. fiber typing/capillarization) will be performed as published.49 Skeletal muscle content of mRNA and 
protein related to angiogenesis – including vascular endothelial growth factor (VEGF), VEGF receptor 
2, hypoxia inducible factor 1α,  and nitric oxide isoforms 1-3 – will be measured by Q-PCR and western 
blotting as published.49-51 
SUPPORTIVE OUTCOMES. In addition to the measures proposed in the aims, we will also evaluate a 
select group of supporting measures that will aid in the interpretation of study outcomes. These 
measures will include co-morbidity, diet, physical performance via the Short Physical Performance 
Battery (SPPB), and objective monitoring of daily physical activity via accelerometry. Co-morbidity will 


 
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be evaluated using the Charlson Index.52 Dietary habits will be evaluated using NIH Quick Food Scan 
Questionnaire Physical activity will be measured using a hip-worn physical activity monitor as published 
previously.54 Additionally, participants volunteering for the biopsy portion of the study will also be asked 
to complete a treadmill-based test of aerobic fitness to determine maximal ventilatory capacity. 
DATA COLLECTION SCHEDULE.  
Data collection summary by study visit  
Study Phase 
Pre-
randomization Pre-Exercise 
Exercise 
Post-
Exercise 
Visit description (FU=follow-up, CO= close-out) Scre
en Baseline 
Dose 
Titration 
FU 
FU 
FU 
CO 
Visit number 1 
2 
3 
4 
5 
6 
7 
Week number -2 
0 
2 
6 
16 
26 
32 
Informed consent, review inclusion/exclusion criteria 
x 
 
 
 
 
 
 
Personal interview, medical history, medication use 
x 
 
 
 
 
 
 
Office blood pressure (sitting + standing), vital signs 
x 
x 
x 
x 
x 
x 
x 
Anthropometry, ECG, Physical Exam 
x 
 
 
 
 
 
 
Functional measures for screening 
x 
 
 
 
 
 
 
Blood and urine for safety labs  
x 
 
x 
x 
x 
x 
 
Randomization 
 
x 
 
 
 
 
 
4 m walk, 6 minute walk, blood for study assays 
 
x 
 
x 
 
x 
x 
DEXA, Short Physical Performance Battery  
 
x 
 
 
 
x 
 
Dispense study medications 
 
x 
x 
 
x 
 
 
Collect home BP monitor data 
 
 
x 
x 
x 
x 
x 
Collect supportive outcome measures 
 
x 
 
x 
 
x 
x 
Assess adverse experiences 
 
 
x 
x 
x 
x 
x  
 
RANDOMIZATION. Study randomization will be performed by using a randomization scheme provided by 
the study biostatistician. The randomization scheme will be concealed to investigators and study staff 
until the completion of the study. 
PHARMACOLOGIC INTERVENTION. Eligible participants will be randomly assigned to one of the three study 
medications. Blood pressure will be controlled according to published hypertension guidelines.. 
Participants assigned to Perindopril will be given an initial dose of 4 mg/day for two weeks after which, 
pending approval of the study medical safety officer, the dose will be increased to 8 mg/day.  If the 4 
mg/day dose controls blood pressure to ≤120/≤80 or the low dose is not tolerated due to issues such as 
hypotension, cough, or hyperkalemia, the participant will be given the lower tolerated dose. The same 
scheme will be utilized for the Losartan group (dose titrated from 50 mg/day to 100 mg/day) and the 
HCTZ group (12.5 mg/day to 25 mg/day). ***Note: Participants with a prior history of adverse 
experiences to ACE inhibitors will be randomly assigned to either Losartan or HCTZ.*** 
The study clinician also has the discretion to immediately start the participant at the higher dose 
should it be warranted to safely manage the participant’s blood pressure. It is possible that participants 
may need > 1 drug to control blood pressure after receiving the full dose of study drug. In this case, 
amlodipine will be used for each group as it is a good combination agent and does not cause 
bradycardia. If needed, amlodipine can be given at 2.5, 5 or, 10 mg/day. The proportion of each study 
arm requiring amlodipine will be determined and evaluated in sensitivity analyses when interpreting 
study data. Participants requiring additional medications to control blood pressure will be removed from 
the study, though we envision this scenario as unlikely based on our entry criteria and experience in our 
pilot study. Because of the effects of HCTZ on potassium, it is also possible that some participants may 
require potassium supplementation in addition to the study medication. Serum potassium will be 
evaluated at study assessment visits and oral potassium chloride  will be prescribed for any serum 
potassium <3.5 mEq/L. Serum potassium will then be rechecked (in addition to regular study visits) 
every 2-3 weeks with potassium doses increased as needed until potassium is normalized. 


 
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If participants are interested and their primary care physician recommend continuing the assigned 
randomized study medication, the physician’s office can choose to complete the study medication 
information request form faxed directly to the site institution investigational drug service (keeping the 
study investigative team masked to assignment). On this form, the investigational drug service will 
identify the study medication and dose assigned and send it directly back to the requesting primary 
care physician office after all participation in study visits have ended in an a HIPAA-compliant manner.  
The medication disclosure would not happen until after final data collection, and participants would be 
provided with additional study drug to continue for a short period until receiving medication filled from 
their physician. 
DRUG PREPARATION. Study drugs will be provided by the Research Pharmacy which provides 
medications specifically for pharmacologic research studies. Study drugs will be placed in standard 
prescription medication receptacles large enough to supply the drug until the next study visit. The 
receptacles will be labeled with vital study information such as the study name, study week number, 
date of preparation, and study team contact information. The study coordinator will communicate with 
the Research Pharmacy prior to each patient follow-up visit to assure uninterrupted provision of study 
drug. 
EXERCISE INTERVENTION. In addition to taking the study drug, all participants will engage in a 20 week 
structured exercise intervention. The intervention will include twice weekly, center-based, aerobic 
exercise as well as home-based walking. This intervention is designed to achieve a total of 150 minutes 
of aerobic activity per week, meeting clinical and public health guidelines for the general public,55 older 
persons,56-58 and those with hypertension.59  
Each center-based session will begin with a brief warm-up followed by moderate-intensity treadmill 
walking. Other forms of endurance activity (e.g., stationary cycling) may also be utilized. Participants 
will be introduced to the intervention exercises in a structured way such that they begin with lighter 
intensity and gradually increase during the first weeks of the intervention. According to ACSM/AHA 
guidelines,56 exercise intensity will be monitored using a subjective 0-10 scale for physical exertion 
(Borg CR10 scale).60 Participants will initially be instructed to exercise at a moderate intensity, 
equivalent to a 5-6 on the CR10 scale. During each exercise session, participants will also be asked to 
wear a heart rate monitor to measure mean pulse during their sessions. Pulse measurement will allow 
interventionists to help participants with gauging the accuracy of their subjective ratings and promote 
safety. After the initial two weeks of activity, participants will be asked to exercise at a target intensity of 
70-80% of predicted maximal heart rate (220 – age). Walking/Cycling distance and grade will also be 
monitored during each session and participants will be encouraged to increase the distance and grade 
exercised each session. For home-based activity, participants will be encouraged to perform walking at 
a moderate intensity throughout the duration of the study. They will also be asked to wear a 
commercially-available fitness monitor throughout the study period to monitor home-based activity.  
STATISTICAL ANALYSIS PLAN. The primary outcome for the study will be change in 4m gait speed from 
week 6 to 26 (the exercise period) in the trial. Prior to all analyses, the assumption of normality will be 
checked using histograms and normal probability plots. For gait speed, we will use linear mixed effects 
models with random intercept to account for the temporal correlation among the multiple observations 
for each subject. Follow-up model-based contrast tests will be applied to test the effect of perindopril 
compared to losartan and HCTZ. For all the secondary outcomes other than body mass and 
composition, we will fit similar linear mixed effects models as for the primary outcome. For the body 
mass and composition measures, we will use the analysis of covariance (ANCOVA) method. 
Exploratory outcomes will also be evaluated using  ANCOVA. Corrections for multiple comparisons will 
be utilized within (e.g., four serum inflammatory analytes) but not between (i.e., exercise capacity vs. 
body composition vs. serum analytes) secondary and exploratory outcomes. For all outcomes, the 
primary analysis will include data from all randomized participants, in line with intent-to-treat principles. 
A secondary analysis will be performed to evaluate changes during the full intervention period (weeks 
0–32). For each analysis, sensitivity analyses will be performed to evaluate the impacts of relevant 
potential confounders including age, sex, race, site, retention (i.e., drop-out), adherence (i.e., 
medication and exercise). Given that those with cough history cannot be randomized to ACE, additional 


 
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sensitivity analyses will be performed on just those without cough history to examine the robustness of 
the primary and secondary analyses based on all randomized patients. 
SAFETY MONITORING PLAN. Safety of participants is our primary concern. Prior to study entry, 
prospective participants will be advised to consult with their physician. Numerous safety procedures will 
be utilized to insure participant safety. These strategies have proven successful in minimizing adverse 
events in large-scale trials from our group of both exercise21 and antihypertensive drug use.61 First, 
many of the exclusion criteria are designed to exclude those at moderate to high risk. Participant 
education about safety begins with the consent process and continues throughout the study. Potential 
adverse events for study related activities and interventions are explained to each participant by trained 
study personnel during the informed consent process. Participants will be encouraged to notify study 
staff immediately if they have any adverse experiences that could be related to the study drug or their 
BP management. The dose titration and physician monitoring of BP and clinical chemistries are in place 
to minimize adverse responses to the study drugs. Abnormal symptoms or vital signs detected during 
intervention visits will be discussed with the study physician in real time, who will dictate the appropriate 
course of action. Study staff will also inform the participant’s primary care physician of the participant’s 
initial enrollment in the trial, as well as of all changes in medication prescription during their participation 
in the trial. Participants will be provided with a copy of the letter sent to their physician. They will also be 
provided with a wallet size card containing study details and contact information.  
In addition, subjects will be provided a home blood pressure monitor and encouraged to conduct 
daily blood pressure monitoring. We will provide participants with a home BP monitor that meets the 
standards of the British Society of Hypertension and the Association for the Advancement of the 
Medical Instrumentation.62 This device utilizes a triplicate mode of measurement and averages the 
values, to closely resemble clinical measurements. The device records and stores SBP, DBP, HR, and 
a date/time stamp which are downloadable via a computer interface. Participants will be instructed to 
take their home BP three times daily, on rising from bed, midday and before retiring. Participants will be 
instructed to report any SBP > 180 or < 90 mmHg or DBP > 100 or < 60 mmHg to the study coordinator 
immediately. Those with two or more such pressures will be scheduled immediately for a clinic visit, at 
which time it will be determined whether the patient is taking the home BP properly. Blood pressure will 
also be monitored at each assessment visit in the clinic.  Participants will be withdrawn from the study 
at the discretion of the study clinician for any DBP > 100 mmHg or SBP > 180 mmHg, and will be 
automatically removed from the study for any weekly average home BP above these thresholds.  The 
cardiologist may decide to exclude subjects with slightly lower BP levels than these cut points, but for 
whom there is any medically-relevant concern that would preclude continued participation. Withdrawn 
participants will be returned to their standard antihypertensive therapy under the supervision of their 
physician or referred for care.  
If study treatments according to the scheduled protocol do not manage hypertension safely, the 
study clinician has full discretion to manage the antihypertensive regimen to ensure safety. He can be 
un-blinded to study medication randomization at any time to ensure proper care. If abnormal BP 
readings or lab values are identified, he may alter antihypertensive regimen as appropriate by either 
altering the dose of study medication, adding other antihypertensive drugs or supplements (e.g. 
potassium) to the drug regimen, or withdrawing the participant from the study medication and returning 
to pre-study therapy. When unblinding is required, the PI or designee will contact the study pharmacy 
which will send the information regarding medication the participant is taking directly to the cardiologist 
who will take the appropriate medical steps. In cases where the study team learns about a serious 
adverse event or medical emergency, the study clinician will be immediately informed. Unblinding 
procedures will be the same as described above. In cases of emergency, non-study medical personnel 
treating the participant will also be provided with study drug and dosage information as necessary to 
ensure proper care. The participant's primary care physician will also be notified of the emergency 
event.  
Clinical chemistry indicators – e.g.  creatinine, sodium, potassium, and urinary albumin – will be 
also monitored at all study visits. The study clinician can elect to replace potassium at any value, with 
protocol mandated prescription of oral potassium chloride for any potassium <3.5 mEq/L. If adverse 


 
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serum potassium values are noted, serum potassium will be rechecked (in addition to regular study 
visits) every 2-3 weeks with potassium doses increased as needed until potassium is normalized. If 
other adverse clinical responses occur, e.g. hyperkalemia or hyponatremia, the dose of study drug will 
be adjusted appropriately by the study clinician. Serious and non-serious adverse experiences will be 
monitored at each study visit and as reported. Interventionists will also monitor adverse events as they 
are reported as well as any potential events that occur during performance of the exercise intervention.  
Center-based assessments and interventions will be conducted and supervised by trained staff who 
will monitor potential adverse experiences and symptoms. All assessors and interventionists receive 
CPR training and training on management of acute events including syncope, chest pain, acute 
dyspnea, focal neurological symptoms and abnormal vital signs. Portable defibrillators are available 
and all study staff have on-call access to the study physician and contact numbers for emergency 
services are. Institutional and community EMS services will be activated if needed. As indicated 
previously, participants will be taught the importance and proper method of warming-up prior to and 
cooling-down following structured activity sessions. If at any point during an exercise session, 
participants develop chest pain, shortness of breath, or dizziness, they will be instructed to rest and to 
contact the center and their physicians if these symptoms persist or recur with further exercise. Blood 
pressure and heart rate will be measured before and after the training session at each center. 
Physician clearance will be required prior to returning to exercise for participants experience any of the 
following during a previous exercise session: decrease in diastolic blood pressure ≥ 20 mm Hg during 
the activity, increase in systolic blood pressure to ≥ 200 mm Hg or in diastolic blood pressure ≥110 mm 
Hg in response to activity, increase in heart rate ≥ 90% of age predicted maximum, unusual or severe 
shortness of breath, chest pain or discomfort, palpitations, light headedness, dizziness or feeling about 
to faint, or a session had to be discontinued because of other medical symptoms, excluding 
musculoskeletal symptoms (e.g., knees, ankles, hips), reported by the participant.  
Any significant adverse events will be reported promptly to the IRB and to the Data Safety 
Monitoring Board (DSMB). Again, written informed consent will be obtained after explanation to 
subjects about all procedures and time commitments. The study interviewers will explain to prospective 
participants the purpose, methods and extent of the study. Potential participants will be asked to read 
the informed consent form and to ask questions. The form will be written in simple, easy-to-understand 
language. Staff members will also review all key aspects of the study verbally. Confidentiality of data 
will be maintained by using research identification numbers that uniquely identify each individual. Data 
will be used only in aggregate and no identifying characteristics of individuals will be published or 
presented. Finally, the study protocol has been registered at www.ClinicalTrials.gov (NCT# 03295734) 
and will be updated as required. 
Possible Discomforts and Risks: 
Potential risks are those associated with health information privacy, venipuncture, treatment with the 
antihypertensive agents, radiation from DEXA, and participation in exercise training and testing.  
 
Venipuncture can be associated with pain, bruising, hematoma formation, superficial phlebitis, and 
rarely cellulitis or fainting.  
 
Risks of antihypertensive drug therapy include the development of symptomatic orthostatic 
hypotension, postprandial hypotension, and syncope or falls.  Specific risks of perindopril include 
hyperkalemia, cough, headache, weakness, dizziness, diarrhea, stomach pain, and upset stomach. 
Serious, but infrequent, risks include swelling, difficulty swallowing, lightheadedness, fainting, fever, sore 
throat, and irregular heartbeats. Risks associated with losartan include dizziness, leg, knee, or back pain, 
muscle cramps or weakness, diarrhea, and heartburn. Serious but less frequent risks include swelling, 
difficulty breathing/swallowing, and chest pain. Risks associated with diuretics, including HCTZ, include 
electrolyte imbalances (most notably hypokalemia, but could include hyponatremia, hypomagnesemia, 
and hypochloremia), increases in fasting blood glucose, muscle weakness, dizziness, cramps, extreme 
thirst, stomach pain, nausea, vomiting, diarrhea, loss of appetite, headache, hair loss, and gout. More 
serious risks include sore throat with fever, unusual bleeding or bruising, severe skin rash, and difficulty 


 
Page 9 of 13 
 
breathing or swallowing. Notably, these drugs are FDA approved and widely utilized as therapies for 
hypertension among older adults. Significant attention will be paid to the monitoring of blood pressure, 
serum electrolytes and liver enzymes, and related adverse events to minimize risks associated with 
antihypertensive drug use.  
 
The risk of radiation exposure from the 2 DEXA scans is very low. The radiation exposure from the 2 
scans is equal to about 6 millirems, which is comparable to about 4 to 6 days of natural background 
radiation to which people in the United States are exposed to during their lives.  The risk from this 
radiation exposure is considered to be low when compared to other every day risks. 
 
The primary risk associated with moderate-intensity exercise training is skeletal muscle soreness. 
There are also other risks that relate to soft tissue injury, falls and fractures, exacerbation of arthritis and 
other joint conditions, post-exercise hypotension, and cardiovascular events.  There is a risk that a 
participant may trip, stumble, or fall during the physical performance tests and experience shortness of 
breath, dizziness, palpitations, chest pain or discomfort, heartburn, light headedness, or feeling about to 
faint during the six min walk test. 
Possible Benefits: 
Importantly, the proposed project will have direct, tangible benefits for participants. These benefits include 
information about their health and assessments of their functional status. All study participants will be 
encouraged to communicate the results from the study to their primary care providers. Moreover, all 
participants – regardless of randomized group – will receive supervised exercise training and instruction 
about how to maintain exercise habits at home. We expect that these benefits will improve quality of life 
for all participants.   
Conflict of Interest: 
There are no conflicts of interest to report.  
  
 
Literature Cited 
1. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de 
Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, 
Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, 
Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, 
Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J, 
American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease 
and stroke statistics--2011 update: a report from the American Heart Association. Circulation 2011; 123 
(4): e18-e209. 
2. Yazdanyar A and Newman AB. The burden of cardiovascular disease in the elderly: morbidity, 
mortality, and costs. Clin.Geriatr.Med. 2009; 25 (4): 563,77, vii. 
3. Hodgson TA and Cohen AJ. Medical care expenditures for selected circulatory diseases: 
opportunities for reducing national health expenditures. Med.Care 1999; 37 (10): 994-1012. 
4. Federal Interagency Forum on Aging-Related Statistics. Statistical Data of Older Americans. 
2009; Accessed October 14, 2009 
5. Shaw LJ, Olson MB, Kip K, Kelsey SF, Johnson BD, Mark DB, Reis SE, Mankad S, Rogers WJ, 
Pohost GM, Arant CB, Wessel TR, Chaitman BR, Sopko G, Handberg E, Pepine CJ, Bairey Merz CN. 
The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored 
Women's Ischemia Syndrome Evaluation (WISE) Study. J.Am.Coll.Cardiol. 2006; 47 (3 Suppl): S36-43. 
6. Studenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M, Brach J, Chandler J, Cawthon 
P, Connor EB, Nevitt M, Visser M, Kritchevsky S, Badinelli S, Harris T, Newman AB, Cauley J, Ferrucci 
L, Guralnik J. Gait speed and survival in older adults. JAMA 2011; 305 (1): 50-8. 


 
Page 10 of 13 
 
7. Newman AB, Simonsick EM, Naydeck BL, Boudreau RM, Kritchevsky SB, Nevitt MC, Pahor M, 
Satterfield S, Brach JS, Studenski SA, Harris TB. Association of long-distance corridor walk 
performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 2006; 295 
(17): 2018-26. 
8. Abellan van Kan G, Rolland Y, Andrieu S, Bauer J, Beauchet O, Bonnefoy M, Cesari M, Donini 
LM, Gillette Guyonnet S, Inzitari M, Nourhashemi F, Onder G, Ritz P, Salva A, Visser M, Vellas B. Gait 
speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an 
International Academy on Nutrition and Aging (IANA) Task Force. J.Nutr.Health Aging 2009; 13 (10): 
881-9. 
9. Hall WJ. Update in geriatrics. Ann.Intern.Med. 2006; 145 (7): 538-43. 
10. McGinn AP, Kaplan RC, Verghese J, Rosenbaum DM, Psaty BM, Baird AE, Lynch JK, Wolf 
PA, Kooperberg C, Larson JC, Wassertheil-Smoller S. Walking speed and risk of incident ischemic 
stroke among postmenopausal women. Stroke 2008; 39 (4): 1233-9. 
11. Afilalo J, Eisenberg MJ, Morin JF, Bergman H, Monette J, Noiseux N, Perrault LP, Alexander 
KP, Langlois Y, Dendukuri N, Chamoun P, Kasparian G, Robichaud S, Gharacholou SM, Boivin JF. 
Gait speed as an incremental predictor of mortality and major morbidity in elderly patients undergoing 
cardiac surgery. J.Am.Coll.Cardiol. 2010; 56 (20): 1668-76. 
12. Dumurgier J, Elbaz A, Ducimetiere P, Tavernier B, Alperovitch A, Tzourio C. Slow walking 
speed and cardiovascular death in well functioning older adults: prospective cohort study. BMJ 2009; 
339b4460. 
13. Dumurgier J, Elbaz A, Dufouil C, Tavernier B, Tzourio C. Hypertension and lower walking 
speed in the elderly: the Three-City study. J.Hypertens. 2010; 28 (7): 1506-14. 
14. Rosano C, Longstreth WT,Jr, Boudreau R, Taylor CA, Du Y, Kuller LH, Newman AB. High 
Blood Pressure Accelerates Gait Slowing in Well-Functioning Older Adults over 18-Years of Follow-Up. 
J.Am.Geriatr.Soc. 2011; 59 (3): 390-7. 
15. Hajjar I, Lackland DT, Cupples LA, Lipsitz LA. Association between concurrent and remote 
blood pressure and disability in older adults. Hypertension 2007; 50 (6): 1026-32. 
16. Balzi D, Lauretani F, Barchielli A, Ferrucci L, Bandinelli S, Buiatti E, Milaneschi Y, Guralnik JM. 
Risk factors for disability in older persons over 3-year follow-up. Age Ageing 2010; 39 (1): 92-8. 
17. Ettinger WH,Jr, Burns R, Messier SP, Applegate W, Rejeski WJ, Morgan T, Shumaker S, Berry 
MJ, O'Toole M, Monu J, Craven T. A randomized trial comparing aerobic exercise and resistance 
exercise with a health education program in older adults with knee osteoarthritis. The Fitness Arthritis 
and Seniors Trial (FAST). JAMA 1997; 277 (1): 25-31. 
18. Nelson ME, Layne JE, Bernstein MJ, Nuernberger A, Castaneda C, Kaliton D, Hausdorff J, 
Judge JO, Buchner DM, Roubenoff R, Fiatarone Singh MA. The effects of multidimensional home-
based exercise on functional performance in elderly people. J.Gerontol.A Biol.Sci.Med.Sci. 2004; 59 
(2): 154-60. 
19. Brown M, Sinacore DR, Ehsani AA, Binder EF, Holloszy JO, Kohrt WM. Low-intensity exercise 
as a modifier of physical frailty in older adults. Arch.Phys.Med.Rehabil. 2000; 81 (7): 960-5. 
20. Dolansky MA and Moore SM. Effects of cardiac rehabilitation on the recovery outcomes of 
older adults after coronary artery bypass surgery. J.Cardiopulm.Rehabil. 2004; 24 (4): 236-44. 
21. LIFE Study Investigators, Pahor M, Blair SN, Espeland M, Fielding R, Gill TM, Guralnik JM, 
Hadley EC, King AC, Kritchevsky SB, Maraldi C, Miller ME, Newman AB, Rejeski WJ, Romashkan S, 
Studenski S. Effects of a physical activity intervention on measures of physical performance: Results of 
the lifestyle interventions and independence for Elders Pilot (LIFE-P) study. J.Gerontol.A 
Biol.Sci.Med.Sci. 2006; 61 (11): 1157-65. 
22. Buford TW, Manini TM, Hsu FC, Cesari M, Anton SD, Nayfield S, Stafford RS, Church TS, 
Pahor M, Carter CS. Angiotensin-converting enzyme inhibitor use by older adults is associated with 
greater functional responses to exercise. J.Am.Geriatr.Soc. 2012; 60 (7): 1244-52. 


 
Page 11 of 13 
 
23. Sica D. Are there pleiotropic effects of antihypertensive medications or is it all about the blood 
pressure in the patient with diabetes and hypertension? J.Clin.Hypertens.(Greenwich) 2011; 13 (4): 
301-4. 
24. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-
converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart 
Outcomes Prevention Evaluation Study Investigators. N.Engl.J.Med. 2000; 342 (3): 145-53. 
25. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F. Outcome results 
of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with 
hypertension and NIDDM. Diabetes Care 1998; 21 (4): 597-603. 
26. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of 
nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-
dependent diabetes and hypertension. N.Engl.J.Med. 1998; 338 (10): 645-52. 
27. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof 
B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE. Effect of angiotensin-converting-enzyme 
inhibition compared with conventional therapy on cardiovascular morbidity and mortality in 
hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353 (9153): 
611-6. 
28. Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Cavazzini C, Furberg CD. 
Health outcomes associated with calcium antagonists compared with other first-line antihypertensive 
therapies: a meta-analysis of randomised controlled trials. Lancet 2000; 356 (9246): 1949-54. 
29. Cranney A. Is there a new role for angiotensin-converting-enzyme inhibitors in elderly patients? 
CMAJ 2007; 177 (8): 891-2. 
30. Sumukadas D, Struthers AD, McMurdo ME. Sarcopenia--a potential target for Angiotensin-
converting enzyme inhibition? Gerontology 2006; 52 (4): 237-42. 
31. Onder G, Penninx BW, Balkrishnan R, Fried LP, Chaves PH, Williamson J, Carter C, Di Bari M, 
Guralnik JM, Pahor M. Relation between use of angiotensin-converting enzyme inhibitors and muscle 
strength and physical function in older women: an observational study. Lancet 2002; 359 (9310): 926-
30. 
32. Gambassi G, Lapane KL, Sgadari A, Carbonin P, Gatsonis C, Lipsitz LA, Mor V, Bernabei R. 
Effects of angiotensin-converting enzyme inhibitors and digoxin on health outcomes of very old patients 
with heart failure. SAGE Study Group. Systematic Assessment of Geriatric drug use via Epidemiology. 
Arch.Intern.Med. 2000; 160 (1): 53-60. 
33. Cesari M, Pedone C, Incalzi RA, Pahor M. ACE-inhibition and physical function: results from 
the Trial of Angiotensin-Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) 
study. J.Am.Med.Dir.Assoc. 2010; 11 (1): 26-32. 
34. Zi M, Carmichael N, Lye M. The effect of quinapril on functional status of elderly patients with 
diastolic heart failure. Cardiovasc.Drugs Ther. 2003; 17 (2): 133-9. 
35. Carter CS, Giovannini S, Seo DO, DuPree J, Morgan D, Chung HY, Lees H, Daniels M, 
Hubbard GB, Lee S, Ikeno Y, Foster TC, Buford TW, Marzetti E. Differential effects of enalapril and 
losartan on body composition and indices of muscle quality in aged male Fischer 344 x Brown Norway 
rats. Age (Dordr) 2011; 33 (2): 167-83. 
36. Carter CS, Marzetti E, Leeuwenburgh C, Manini T, Foster TC, Groban L, Scarpace PJ, Morgan 
D. Usefulness of preclinical models for assessing the efficacy of late-life interventions for sarcopenia. 
J.Gerontol.A Biol.Sci.Med.Sci. 2012; 67 (1): 17-27. 
37. Di Bari M, van de Poll-Franse LV, Onder G, Kritchevsky SB, Newman A, Harris TB, Williamson 
JD, Marchionni N, Pahor M, Health, Aging and Body Composition Study. Antihypertensive medications 
and differences in muscle mass in older persons: the Health, Aging and Body Composition Study. 
J.Am.Geriatr.Soc. 2004; 52 (6): 961-6. 


 
Page 12 of 13 
 
38. Buford TW, Anton SD, Bavry AA, Carter CS, Daniels MJ, Pahor M. Multi-modal intervention to 
reduce cardiovascular risk among hypertensive older adults: Design of a randomized clinical trial. 
Contemp.Clin.Trials 2015; 43237-42. 
39. Sergi G, Veronese N, Fontana L, De Rui M, Bolzetta F, Zambon S, Corti MC, Baggio G, 
Toffanello ED, Crepaldi G, Perissinotto E, Manzato E. Pre-frailty and risk of cardiovascular disease in 
elderly men and women: the Pro.V.A. study. J.Am.Coll.Cardiol. 2015; 65 (10): 976-83. 
40. Hamer M, Kivimaki M, Lahiri A, Yerramasu A, Deanfield JE, Marmot MG, Steptoe A. Walking 
speed and subclinical atherosclerosis in healthy older adults: the Whitehall II study. Heart 2010; 96 (5): 
380-4. 
41. Gutierrez-Misis A, Sanchez-Santos MT, Banegas JR, Castell MV, Gonzalez-Montalvo JI, Otero 
A. Walking speed and high blood pressure mortality risk in a Spanish elderly population. 
J.Hum.Hypertens. 2015; 29 (9): 566-72. 
42. Stewart AL, Mills KM, King AC, Haskell WL, Gillis D, Ritter PL. CHAMPS physical activity 
questionnaire for older adults: outcomes for interventions. Med.Sci.Sports Exerc. 2001; 33 (7): 1126-41. 
43. Rafey MA. Resistant hypertension in the elderly. Clin.Geriatr.Med. 2009; 25 (2): 289-301. 
44. Cleveland JC,Jr. Frailty, aging, and cardiac surgery outcomes: the stopwatch tells the story. 
J.Am.Coll.Cardiol. 2010; 56 (20): 1677-8. 
45. Lindman BR and Rich MW. Using Gait Speed to Refine Risk Assessment in Older Patients 
Undergoing Cardiac Surgery. JAMA Cardiol 2016; Published online May 11, 2016 
46. Enright PL, McBurnie MA, Bittner V, Tracy RP, McNamara R, Arnold A, Newman AB, 
Cardiovascular Health Study. The 6-min walk test: a quick measure of functional status in elderly 
adults. Chest 2003; 123 (2): 387-98. 
47. Fleg JL, Pina IL, Balady GJ, Chaitman BR, Fletcher B, Lavie C, Limacher MC, Stein RA, 
Williams M, Bazzarre T. Assessment of functional capacity in clinical and research applications: An 
advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical 
Cardiology, American Heart Association. Circulation 2000; 102 (13): 1591-7. 
48. Steele B. Timed walking tests of exercise capacity in chronic cardiopulmonary illness. 
J.Cardiopulm.Rehabil. 1996; 16 (1): 25-33. 
49. Buford TW, Macneil RG, Clough LG, Dirain M, Sandesara B, Pahor M, Manini TM, 
Leeuwenburgh C. Active muscle regeneration following eccentric contraction-induced injury is similar 
between healthy young and older adults. J.Appl.Physiol. 2013; 
50. Larkin KA, Macneil RG, Dirain M, Sandesara B, Manini TM, Buford TW. Blood Flow Restriction 
Enhances Post-Resistance Exercise Angiogenic Gene Expression. Med.Sci.Sports Exerc. 2012; 
51. Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LM, Aranda JM, 
Sandesara BD, Pahor M, Manini TM, Marzetti E, Leeuwenburgh C. The impact of aging on 
mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-
functioning elderly individuals. Aging Cell. 2012; 
52. Charlson ME, Sax FL, MacKenzie CR, Braham RL, Fields SD, Douglas RG,Jr. Morbidity during 
hospitalization: can we predict it? J.Chronic Dis. 1987; 40 (7): 705-12. 
53. Bunn JA, Buford TW, Serra MC, Kreider RB, Willoughby DS. Protein and Amino Acid 
Supplementation Does Not Alter Proteolytic Gene Expression following Immobilization. J.Nutr.Metab. 
2011; 2011539690. 
54. Fitzgerald JD, Johnson L, Hire DG, Ambrosius WT, Anton SD, Dodson JA, Marsh AP, 
McDermott MM, Nocera JR, Tudor-Locke C, White DK, Yank V, Pahor M, Manini TM, Buford TW, LIFE 
Study Research Group. Association of Objectively Measured Physical Activity With Cardiovascular Risk 
in Mobility-limited Older Adults. J.Am.Heart Assoc. 2015; 4 (2): 10.1161/JAHA.114.001288. 
55. U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for 
Americans. 2008; 


 
Page 13 of 13 
 
56. American College of Sports Medicine, Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, 
Minson CT, Nigg CR, Salem GJ, Skinner JS. American College of Sports Medicine position stand. 
Exercise and physical activity for older adults. Med.Sci.Sports Exerc. 2009; 41 (7): 1510-30. 
57. Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, Macera CA, Castaneda-
Sceppa C. Physical activity and public health in older adults: recommendation from the American 
College of Sports Medicine and the American Heart Association. Med.Sci.Sports Exerc. 2007; 39 (8): 
1435-45. 
58. Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, Macera CA, Castaneda-
Sceppa C, American College of Sports Medicine, American Heart Association. Physical activity and 
public health in older adults: recommendation from the American College of Sports Medicine and the 
American Heart Association. Circulation 2007; 116 (9): 1094-105. 
59. Pescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray CA, American College of 
Sports Medicine. American College of Sports Medicine position stand. Exercise and hypertension. 
Med.Sci.Sports Exerc. 2004; 36 (3): 533-53. 
60. Borg G. Perceived Exertion and Pain Scales. 1988; 
61. Cesari M, Kritchevsky SB, Atkinson HH, Penninx BW, Di Bari M, Tracy RP, Pahor M. 
Angiotensin-converting enzyme inhibition and novel cardiovascular risk biomarkers: results from the 
Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) 
study. Am.Heart J. 2009; 157 (2): 334.e1,334.e8. 
62. O'Brien E, Waeber B, Parati G, Staessen J, Myers MG. Blood pressure measuring devices: 
recommendations of the European Society of Hypertension. BMJ 2001; 322 (7285): 531-6. 
63. American Thoracic Society and American College of Chest Physicians. ATS/ACCP Statement 
on cardiopulmonary exercise testing. Am.J.Respir.Crit.Care Med. 2003; 167 (2): 211-77.  

ICF_002.pdf: 
ACES - ACE Inhibitors Combined With Exercise for Seniors With Hypertension (ACES) 
 
7/25/24 
 
NCT03295734 


Page 1 of 23
Version Date: 11/14/2022
CONSENT FORM
Title of Research:
ACES – Ace Inhibitors Combined with Exercise for
Hypertensive Seniors
UAB IRB Protocol #:
IRB-300000637
Principal Investigator:
Thomas Buford, PhD.
Sponsor:
National Institutes of Health
General Information
You are being asked to take part in a research study. This research study 
is voluntary, meaning you do not have to take part in it. The procedures, 
risks, and benefits are fully described further in the consent form.
Purpose
The purpose of this study is to see if regular exercise when combined with 
one of three commonly used high blood pressure medications can improve 
the physical abilities of older adults to perform their daily life activities and 
lowers their risk for heart disease.
Duration & Visits
You will come to the Center for 7 assessment visits over a 32 week period. 
For the exercise intervention, you will come to the Center 2x/week for 20 
weeks total (weeks 6 -26).
UAB IRB
Approved
26-Jul-2023
until
25-Jul-2024


Page 2 of 23
Version Date: 11/14/2022
Overview of 
Procedures
If you decide to take part in this study, a computer will assign you by 
chance to one of three blood pressure medications. This is called 
randomization. You will either be assigned to perindopril, losartan or 
HCTZ. Participants are asked to track their physical activity habits, take 
their blood pressure medication daily, and test their blood pressure three 
times daily on a study provided home blood pressure monitor.
During assessment visits, participants perform physical performance tests, 
questionnaires outlined in detail below.
You will also be asked to check your blood pressure at home using the 
blood pressure monitor provided to you three times each day and 
report any abnormal values to study staff as soon as possible.
The exercise intervention involves treadmill walking, stationary biking, and 
rowing followed by a balance and stretching routine.
For home-based activity, you will be encouraged to perform walking at a 
moderate intensity throughout the duration of the study. You will also be 
asked to wear the hip worn physical activity monitor provided to you 
throughout the study period to monitor home-based activity.
Risks
The most common side effects of the study medications include 
excessive drops in blood pressure that can lead to dizziness, fainting, 
headache, drowsiness or falls. Other symptoms may include cough, 
weakness, sore throat, upset stomach, swollen ankles, hands or feet, 
flushing, confusion, breathing problems, weakness or heaviness of legs, 
or localized photo sensitivity rash could occur when exposed
to UV light and rarely a systemic rash. With fasting, you may experience 
hunger, headache, and low energy. The risk of blood draw include 
discomfort from the needle stick and possible bruising. You may have 
some pain and soreness associated with the exercise training, and there 
is the risk of radiation exposure associated with the DXA scans.
Benefits
Potential benefits of this study to you include learning information about 
your health and overall physical function. Information gained from 
participation in this study may help to provide doctors with new 
information for prescribing medications to treat older adults for high 
blood pressure.
Alternatives
The alternatives is to not participate in the study.
Purpose of the Research
The purpose of this research study is to see if regular exercise when combined with one of three


Page 3 of 23
Version Date: 11/14/2022
commonly used high blood pressure medications can improve the physical abilities of older adults to 
perform their daily life activities and lowers their risk for heart disease.
You are being asked to be in this research study because you are over 60 years of age, have high blood 
pressure and also have some trouble performing your day to day activities.
The National Institute of Health has provided financial support to conduct this study.
There will be about 213 people enrolled in the full study. 107 people will be enrolled at the University 
of Colorado and Translational Research Institute for Metabolism and Diabetes, and 107 people will 
be enrolled here at the University of Alabama at Birmingham (UAB). However, should recruitment be 
slow at any site, recruitment targets will be adjusted to allow the other sites to perform additional 
recruitment.
How long will you be in the study?
You will be in this study for about 32-36 weeks. However you can withdraw at any time.
Explanation of Procedures
No procedures in this study will be part of your normal clinical care. Tests done only for research 
purposes will not be evaluated or used to diagnose or treat any of your medical problems. These tests 
may need to be repeated if required for your medical care in the future.
A telephone screening indicated that you may be eligible to participate in the study. The first study 
visit (Screening visit) will further determine if you are eligible to participate. Should you be eligible, 
you will be asked to participate in a structured physical activity (exercise) program for 20 weeks and 
take daily medication to control your blood pressure. There will also be 6 weeks before and after the
exercise program to look at the effects of the medication alone. You will also be asked to return to the 
clinic for several additional assessment visits to monitor your safety and measure study results.
Visits for the study and the physical activity program will take place at the Orthopedic Specialties 
Building, 133, University of Alabama at Birmingham. 1313 13th Street South, Birmingham, AL 35205 
(UAB Center for Exercise Medicine). Due to COVID-19 some of the research procedures such as the 
written consent process, the assessment visits and its questionnaires, the exercise intervention and, 
the research procedures location may be adjusted and/or conducted remotely, if necessary.
Blood and urine samples will be collected during the study in order to help us to determine your 
eligibility and safety to participate and continue in the study and also to determine the effects of the


Page 4 of 23
Version Date: 11/14/2022
study medication. You will be asked to fast (not eat anything for at least 8-12 hours) before blood and 
urine sample collection. After we collect your blood and urine samples we will provide you a snack to 
eat before you continue with your other visit procedures.
SCREENING VISIT (STUDY VISIT # 1):
The screening visit will take 2 to 3 hours of your time. Details of study procedures that will be done 
during this visit are listed below. The order of these procedures may vary based on the schedules 
of study staff.
Written Consent: Before any tests or procedures are done, you will be asked to give written consent 
to participate in this research study. The study team member will explain in detail what is involved in 
the study and answers any questions that you may have. If you decide to participate we will ask you 
to sign this consent form. If necessary, the study team member will email/mail the written consent 
form and schedule a meeting with you via telephone/ video to explain the details of the study and 
answer any questions you may have. If you decide to participate we will ask you to sign this consent 
form and bring it with you in the screening visit. After your consent, the following would be done:
Questionnaires: You will be asked to answer questionnaire for personal information, medical history 
and medication use.
Office blood pressure (sitting + standing): You will be asked to stand and sit while having your blood 
pressure tested.
Other vital signs: We will record your pulse.
Collection of fasting blood and urine samples: We will collect approximately 2 tablespoons of blood 
from a small vein in your arm and your urine sample.
Anthropometry: We will measure your height, weight, body mass index (BMI).
Electrocardiogram (ECG): An ECG will be performed for safety purposes and will be read by the study 
clinician after completion of the screening visit. ECG procedure involves having sticky pads placed on 
your chest to measure your electrical heart rhythm. If for some reason you are ineligible based on this 
test, you will be called to inform prior to scheduling a baseline visit and advise you if any follow up 
evaluation is recommended.
Physical exam: Our study clinician will also give you a short physical exam to determine if it is safe for 
you to participant in the study.


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Tests of physical performance: You will be asked to complete tests of your physical ability that 
include: Walking at your fastest pace a distance of about ¼ of a mile (400 meters) which is roughly 
equal to the length of around 4 and half football fields
The study clinician team will look at the tests performed during the screening visit and determine if 
you are eligible and it is safe for you to participate in the study. The study team member will call you 
to let you know if you are eligible or not to participate in this research and to schedule your next visit 
if you are eligible.
BASELINE VISIT AND RANDOMIZATION (STUDY VISIT # 2):
This visit is expected to take 2 to 3 hours of your time and will include:
•
Measurement of pulse and blood pressure
•
Collection of fasting blood sample
•
Tests of physical performance, including:
Walking as fast and far as you can for 6 minutes
Walking at your usual pace for a distance of 13 feet two (2) separate times
Standing from a seated position without using your arms five (5) times as fast as 
you can.
Holding your balance while standing in three (3) different positions.
Complete the Quick Food Scan and health-related quality of life questionnaires
WOMAC pain sub-scale
Waist circumference
•
Measurement of body composition (DXA Scan): Body composition will be measured with a 
test known as a DXA scan. DXA scans, like x-rays, are painless, and involve exposure to very 
small amounts of radiation. The scan takes less than 10 min, you will be asked to lie on your 
back while the special x-ray machine is scanning your body. You will be given a report of 
your scan (not to be used for diagnostic purposes), if you wish. Women who have had 
hysterectomy (uterus removal surgery), removal of both ovaries, who are postmenopausal, 
or no possibility of pregnancy, will not need a pregnancy test.
•
Additionally, you will also be given the following to take home a blood pressure (BP) 
monitor with instructions for its use, a hip worn Fitbit physical activity monitor, to wear 
and instructions for its use.
After the completion of baseline assessments, you will be randomly assigned (like flipping a coin) to receive 
either one of three study medications to continue treating your blood pressure


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Perindopril 
Losartan
Hydrochlorothiazide (HCTZ)
You will be given the study medications to take home until your next study assessment visit.
These medications are all standard, FDA-approved medications for the treatment of blood pressure. 
During the time of your participation in the study, you will be told how to stop the use of your current 
blood pressure medication(s) and instead take the medication given to you for the study. You must 
carefully follow all instructions of taking your blood pressure medication given to you by the study team.
These study medications will be put into similar looking capsules by the study pharmacy so that neither 
you nor the investigators will know which medication you are taking. However, if any medical or other 
reason arises during the study to know exactly what medication you are taking, this information can be 
obtained from the study pharmacy by the study investigators or other physicians treating you.
You will also be asked to check your blood pressure at home using the blood pressure monitor provided 
to you three times each day and report any abnormal values to study staff as soon as possible. This 
monitor automatically records each blood pressure reading. You will be given instructions on how to use 
the monitor and you will also be asked to bring this monitor to each assessment visit so that study staff 
can download the stored blood pressure readings. We will ask you to return this monitor at the end of 
your study participation.
Please report immediately to the study team if you blood pressure reading is lower than 90/60 mm Hg 
or higher than 180/100 mm Hg. If you have such readings twice, you will be asked to come for an 
additional study visit and will be seen by the study provider.
It may be possible that the study physician indicates that you need nutritional supplement or another 
medication prescribed along with your assigned blood pressure medication to safely control your blood 
pressure. If this is this case, this supplement (Potassium Chloride 20 – 40 mg) or medication (Amlodipine 
2.5, 5, or 10mg) will be provided to you by the study team.
It is also possible, that based on the study provider’s advice, you will be taken out from the study for your 
safety. Your treatment will be changed back to the medications that you were taking before joining the 
study and you will be referred to your Primary Care Physician (PCP) to manage your high blood pressure. 
You must carefully follow all instructions given to you by the study team when returning back to your 
previous treatment of high blood pressure.


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STUDY INTERVENTION:
Study interventions will be divided into 3 phases:
A.
6 week pre-exercise observational phase
B.
20 week structured exercise phase
C.
6 week post-exercise observational phase or close-out visit
[A] 6 WEEK PRE-EXERCISE OBSERVATIONAL PHASE:
In this phase, you will be started with a low dose of the medication for two weeks after which, if your 
study provider agrees, the dose will be increased. If the higher dose is not tolerated then you will be 
given the lower tolerated dose. For example if you are assigned to receive perindopril, you will be 
given an initial dose of 4 mg/day for two weeks after which, following approval of the study provider 
the dose will be increased to 8 mg/day. Similarly the dose increase for Losartan would be from 
50mg/day to a maximum of 100 mg/day and for HCTZ would be from 12.5mg/day to a maximum of 25 
mg/day.
Study staff will check your blood pressure during the study and any necessary adjustments to the 
medication will be made by the study clinician. Your PCP will be told about your enrollment in the 
study as well as of any medication changes by phone or fax.
Two study assessment visits will be done during this phase:
TWO WEEKS AFTER STARTING THE DRUGS (STUDY VISIT # 3):
This visit will take 45 minutes to 1 hour of your time and will include:
•
Fasting blood draw and urine collection
•
Measurement of vitals (body weight, pulse, blood pressure (sitting + standing)
•
Collection of home BP monitor data and Fitbit data
•
Questions about any bad experiences since starting the drug
•
Providing you with study medications
COMPLETION OF 6 WEEK PRE-EXERCISE OBSERVATIONAL PHASE (STUDY VISIT # 4):
This visit will take 1 to 2 hours of your time and will include:
•
Measurement of vitals (body weight, pulse, blood pressure (sitting + standing)
•
Collection of fasting blood and urine sample


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•
Completion of physical performance tests which includes 4 meter walk test and a 6-minute walk 
test,
•
Collection of home BP monitor data and Fitbit data
•
Quick Food Scan questionnaire
•
Positive and Negative Affect Scale (PANAS) and the Brief Pain Inventory (BPI)
•
Questions about any bad experiences since starting the drug
[B] STRUCTURED EXERCISE PHASE:
During this phase in addition to taking the study drug, you will also take part in a 20 week structured 
exercise intervention. The intervention will include twice weekly, center-based, aerobic exercise as 
well as home-based walking. This intervention is designed to achieve a total of 150 minutes of aerobic 
activity per week.
Each center-based session will begin with a brief warm-up followed by moderate-intensity aerobic 
exercise including treadmill, stationary bicycle, and rowing machine exercises. . You will be introduced 
to the intervention exercises in a structured way such that you begin with lighter intensity and 
gradually increase during the first weeks of the intervention. You will also be asked to perform light 
stretching and/or balance exercises as a part of warm-up and cool-down for the session. The center- 
based exercise intervention may be re-adjusted due to extended interruptions due to COVID-19, if 
necessary.
During each exercise session, you will also be asked to wear a heart rate monitor to measure mean 
pulse during your exercise sessions. This will help to maintain moderate-intensity exercise and help to 
guide in advancing you through the protocol. Walking/cycling distance and grade will also be 
monitored during each session and you will be encouraged to increase the distance and grade each 
exercised session.
For home-based activity, you will be encouraged to perform walking at a moderate intensity 
throughout the duration of the study. You will also be asked to wear the hip worn physical 
activity monitor provided to you throughout the study period to monitor home-based activity. 
You will also be asked to return this monitor by the conclusion of this study.
Two study assessment visits will be done during this phase:


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TEN WEEKS AFTER STARTING EXERCISE (STUDY VISIT # 5):
This visit is expected to take 1 hour of your time and will include:
•
Measurement of vitals (body weight, pulse, blood pressure (sitting + standing)
•
Collection of fasting blood and urine samples.
•
Collection of home BP monitor data and Fitbit data
•
Questions about any bad experiences since starting the drug
•
Providing you with study medications, collect leftover medication
COMPLETION OF EXERCISE PHASE AT 20 WEEKS (STUDY VISIT # 6):
This visit is expected to take 1 to 2 hours of your time and will include:
•
Measurement of vitals (body weight, pulse, blood pressure (sitting + standing)
•
Collection of fasting blood and urine samples.
•
Completion of physical performance tests completed at baseline.
•
DXA scan for body composition, waist circumference measurement
•
Collection of home BP monitor data
•
Collection of physical activity monitor data
•
Quick Food Scan questionnaire
•
Positive and Negative Affect Scale (PANAS) and the Brief Pain Inventory (BPI)
•
Questions about any bad experiences since starting the drug
[C] 6-WEEK POST-EXERCISE OBSERVATIONAL PHASE/CLOSE-OUT VISIT (STUDY VISIT #7):
This visit is expected to take 2 to 3 hours of your time and will include:
•
Measurement of vitals (body weight, pulse, blood pressure (sitting + standing)
•
Collection of fasting blood samples.
•
Completion of physical performance tests which includes a 4 meter walk test and a 6-minute 
walk test.
•
Collection of home BP monitor data
•
Collection of physical activity monitor data
•
Quick Food Scan and health- related quality of life questionnaires
•
Collection of leftover study medication
•
Questions about any adverse experiences since staring the drug and exercise


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Risks and Discomforts
Risk of Randomization:
You will be assigned to a group by chance, which may prove to be less effective or to have more side 
effects than the other study group or alternatives.
Risk from study medications:
Risks include excessive drops in blood pressure that can lead to dizziness, fainting, headache, 
drowsiness or falls. Other symptoms may include cough, weakness, sore throat, upset stomach, 
swollen ankles, hands or feet, flushing, confusion, breathing problems, weakness or heaviness of legs, 
or localized photo sensitivity rash could occur when exposed to UV light and rarely a systemic rash.
These risks are similar to that which you would be exposed to during your normal use of blood 
pressure medications. Changing your blood pressure medication could also result in an increase or 
excessive drops in your blood pressure. Increases or excessive drops in your blood pressure may 
increase your risk of cardiovascular events such as stroke or heart attack.
The study team will closely monitor your blood pressure and laboratory blood tests to minimize the 
risks associated with the switching of your blood pressure medication and use of study medications 
that are possibly different from what you were taking before.
Risk of fasting:
The risks of short-term fasting include hunger, headaches, low energy, heartburn, bloating and 
constipation.
Risk of blood draw:
The risks of drawing blood from a vein include discomfort at the site of puncture; possible bruising 
and swelling around the puncture site; rarely an infection; and, uncommonly, faintness from the 
procedure.
Risk from Physical activity:
There may be some pain or soreness at the start of the study from increasing your physical activity. 
The possibilities include, but are not limited to, some muscle and joint stiffness. This stiffness 
generally subsides in 1 or 2 days, and is not considered to be serious. You might suffer an exercise- 
related injury such as a strain, sprain, or other injury to your muscles or joints. Other possible harmful 
physical responses include abnormal blood pressure, fainting, abnormal heart beats, and, in rare 
instances, heart attack, stroke, and death. Every effort is made to minimize these risks by reviewing 
information about your health before the activities begin. We will minimize the risks by showing you 
how to properly do the exercises in a safe manner and performing warm-up and cool-down exercises.


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We will also monitor heart rate and blood pressure before and after your exercise sessions. You will 
also be encouraged to report and discuss any discomforts with members of the study staff.
There is also a risk of losing your balance and falling associated with the physical performance-based 
testing (e.g., walking and rising from a chair). A fall places you at risk of a bone fracture. We will 
minimize this risk by: (1) safely escorting you to chairs located along the walking course should you 
become unsteady; (2) following you at a close distance; and, (3) being at your side should you need 
assistance.
Risk from DXA Scan:
There is a low risk of radiation exposure from the two DXA scans. The radiation exposure from the 
two scans is equal to about 8 days of natural background radiation. A DXA scan is an x-ray scan that 
uses a very low level of radiation to measure your [bone density | fat content]. You will be asked to 
lie still on a table for about a minute while the scanner takes data. In this study you will be exposed 
to a very low level of radiation during the 2 DXA scans. Each DXA scan is equivalent to about 4 days 
of natural background radiation. Background radiation is radiation normally received from sources 
such as cosmic rays and natural radioactivity in building materials and the ground.
Loss of privacy:
There is a risk of loss of your confidentiality in research. We will, however, make every effort to 
protect your confidential information to minimize this risk.
Benefits
Potential benefits of this study to you include learning information about your health and overall 
physical function. Also, you will have the chance to have supervised exercise training and instruction 
about how to maintain physical activity habits at home. Participation in these activities has the 
potential to improve your health and quality of life.
Information gained from participation in this study may help to provide doctors with new information 
for prescribing medications to treat older adults for high blood pressure. The study may also provide 
scientists and physicians with new knowledge about how to prevent physical disability among older 
adults with high blood pressure.
Alternatives
The alternative is to not participate in this study. If you do not join, your care at UAB will not be 
affected.


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Confidentiality
Information obtained about you for this study will be kept confidential to the extent allowed by law. 
However, research information that identifies you may be shared with people or organizations for 
quality assurance or data analysis, or with those responsible for ensuring compliance with laws and 
regulations related to research. They include:
•
The UAB Institutional Review Board (IRB). An IRB is a group that reviews the study to protect the 
rights and welfare of research you.
•
National Institutes of Health (NIH)
•
The Office for Human Research Protections (OHRP)
The information from the research may be published for scientific purposes; however, your identity 
will not be given out.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include 
a summary of the results. You can search this website at any time.
Confidentiality and Authorization to Use and Disclose Information for Research Purposes
Federal regulations give you certain rights related to your health information. These include the right 
to know who will be able to get the information and why they may be able to get it. The study clinician 
must get your authorization (permission) to use or give out any health information that might identify 
you.
What protected health information may be used and/or given to others?
All medical information, including but not limited to information and/or records of any diagnosis or 
treatment of disease or condition, which may include sexually transmitted diseases (e.g., HIV, etc.) 
or communicable diseases, drug/alcohol dependency, etc.; all personal identifiers, including but not 
limited to your name, social security number, medical record number, date of birth, dates of service, 
etc.; any past, present, and future history, examinations, laboratory results, imaging studies and 
reports and treatments of any kind, including but not limited to drug/alcohol treatment, 
psychiatric/psychological treatment; financial/billing information, including but not limited to copies 
of your medical bills; any other information related to or collected for use in the research study, 
regardless of whether the information was collected for research or non-research (e.g., treatment) 
purposes; records about any study drug you received or about study devices used; and consent forms


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from past studies that might be in your medical record.
Who may use and give out information about you?
Information about your health may be used and given to others by the study clinician and staff. They 
might see the research information during and after the study.
Who might get this information?
All Individuals/entities listed in the informed consent document(s), including but not limited to, the 
physicians, nurses and staff and others performing services related to the research (whether at UAB 
or elsewhere). Your information may also be given to the sponsor of this research. “Sponsor” includes 
any persons or companies that are working for or with the sponsor, or are owned by the sponsor, or 
are providing support to the sponsor (e.g., contract research organization).
Information about you and your health which might identify you may be given to:
•
the Office for Human Research Protections(OHRP)
•
the U.S. Food and Drug Administration(FDA)
•
Department of Health and Human Services (DHHS) agencies
•
Governmental agencies in other countries
•
Governmental agencies to whom certain diseases (reportable diseases) must be reported 
the University of Alabama at Birmingham - the physicians, nurses and staff working on the 
research study (whether at UAB or elsewhere); other operating units of UAB, UAB Hospital, 
UAB Highlands Hospital, University of Alabama Health Services Foundation, Children’s of 
Alabama, Eye Foundation Hospital, and the Jefferson County Department of Health, as 
necessary for their operations; the UAB IRB and its staff
•
the billing offices of UAB and UAB Health Systems affiliates and/or Children’s of Alabama and 
its billing agents
Why will this information be used and/or given to others?
Information about you and your health that might identify you may be given to others to carry out 
the research study. The sponsor will analyze and evaluate the results of the study. In addition, people 
from the sponsor and its consultants will be visiting the research site. They will follow how the study 
is done, and they will be reviewing your information for this purpose.
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. The 
researchers with this Certificate may not disclose or use information, documents, or biospecimens 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
action, suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, unless 
you have consented for this use. Information, documents, or biospecimens protected by this 
Certificate cannot be disclosed to anyone else who is not connected with the research except, if there


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is a federal, state, or local law that requires disclosure (such as to report child abuse or communicable 
diseases but not for federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, see below); if you have consented to the disclosure, including for your medical 
treatment; or if it is used for other scientific research, as allowed by federal regulations protecting 
research subjects.
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or
program evaluation by the NIH which is funding this project. You should understand that a 
Certificate of Confidentiality does not prevent you from voluntarily releasing information 
about yourself or your involvement in this research. If you want your research information 
released to an insurer, medical care provider, or any other person not connected with the 
research, you must provide consent to allow the researchers to release it.
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you 
have consented to in this informed consent document.
What if I decide not to give permission to use and give out my health information?
By signing this consent form, you are giving permission to use and give out the health 
information listed above for the purposes described above. If you refuse to give permission, 
you will not be able to be in this research.
May I review or copy the information obtained from me or created about me?
You have the right to review and copy your health information. However, if you decide to be 
in this study and sign this permission form, you will not be allowed to look at or copy your 
information until after the research is completed.
May I withdraw or revoke (cancel) my permission?
Yes, but this permission will not stop automatically. The use of your personal health 
information will continue until you cancel your permission.
You may withdraw or take away your permission to use and disclose your health information 
at any time. You do this by sending written notice to the study doctor. If you withdraw your 
permission, you will not be able to continue being in this study.
When you withdraw your permission, no new health information which might identify you will 
be gathered after that date. Information that has already been gathered may still be used and 
given to others. This would be done if it were necessary for the research to be reliable.
Is my health information protected after it has been given to others?


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If you give permission to give your identifiable health information to a person or business, 
the information may no longer be protected. There is a risk that your information will be 
released to others. Including others, outside of UAB, without your permission.
Voluntary Participation and Withdrawal
Whether or not you take part in this study is your choice. There will be no penalty if you decide 
not to be in the study. If you decide not to be in the study, you will not lose any benefits you 
are otherwise owed by UAB.
You are free to withdraw from this research study at any time. Your choice to leave the study 
will not affect your relationship with this institution. However, you should return to see the 
study provider for safety reasons so you can be taken off the study drug and referred for 
follow-up care. Contact the study staff at 205-996-3005 if you want to withdraw from the 
study.
You may be removed from the study without your consent if the sponsor ends the study, if the 
study provider decides it is not in the best interest of your health, if new information suggests 
that taking part in the research study may not be in your best interests or if you are not 
following the study rules.
If you are a UAB student or employee, taking part in this research is not a part of your UAB 
class work or duties. You can refuse to enroll, or withdraw after enrolling at any time before 
the study is over, with no effect on your class standing, grades, or job at UAB. You will not be 
offered or receive any special consideration if you take part in this research.
Cost of Participation
There will be no cost to you for taking part in this study. All supplements, exams, and physical 
activity sessions related to this study will be given to you at no cost during the 8-month study 
period.
All other medical services provided to you that are not directly related to the study will be 
billed to you or your insurance company. You will be responsible for paying any deductible, 
co-insurance, and/or co-payments for these services, and any non-covered or out-of- 
network services. Some insurance companies may not cover costs associated with research 
studies. Please contact your insurance company for additional information.


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Payment for Participation in Research
You can be compensated up to $450 total if all study visits are completed.
A gift card in the amount of $10 will be given at the completion of the screening visit.
If you are eligible and choose to participate, the gift card will be reloaded with a total of $40 
upon completion of each additional study assessment visit. If you complete all 6 study 
assessment visits you can receive up to a total of $240.
After completing the exercise training period, you can receive up to a total of $200. In order 
to receive the full $200 you must complete all exercise training visits. This would make each 
exercise training visit $5 each and is paid in one lump sum upon completion.
Payment for Research-Related Injuries
UAB has not provided for any payment if you are harmed as a result of taking part in this 
study. If such harm occurs, treatment will be provided. However, this treatment will not be 
provided free of charge.
Significant New Findings
You will be told by the study provider or the study staff if new information becomes available 
that might affect your choice to stay in the study.
Optional Research
Please note: This section of the consent form is about optional research that is being done 
with people who are taking part in this study. These procedures will be used to provide 
more information on how your body adapted to the exercise + study medication. Please 
take as much time as you need to decide. You may ask any questions that you may have 
and discuss this with the study team (your study provider and his/her staff). You may take 
part in this optional research if you want to. You can still be a part of this study even if you 
say no to take part in any of the optional research.
Optional Research #1
These are additional procedures that ask you to complete two additional visits. During each of 
these two visits, you will be asked to complete a strenuous exercise test on a treadmill and 
provide a sample of muscle tissue collected via a procedure known as a biopsy and perform


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the skeletal muscle function test. These additional visits for the exercise test, muscle biopsy, 
and skeletal muscle function test will occur after visit #2 at week 0 and visit #6 at week 26.
Explanation of Procedures
Muscle biopsy
A small piece about the size of a pencil eraser or “quarter of an inch” of muscle and/or fat 
tissue will be taken from your thigh. The muscle tissue will be taken from your vastus lateralis 
muscle which is located on the outside of your thigh and will be taken about one hand above 
your knee. A one inch by one inch area of hair may need to be shaved. We will inject an 
anesthetic (lidocaine) to numb the area. A small cut is made and a needle is inserted to pinch a 
piece of muscle for lab tests. The cut will be closed with a stitch and you will be told how to 
care for the area. This procedure will take about 30 minutes of your time.
Treadmill test
During this test you will be fitted with a mask that will collect inhaled and exhaled gases from 
your breath. The mask is placed over your nose and mouth and if you want we can show you 
the mask before you give informed consent. Then you will have sticky pads placed on your 
chest and asked to walk on a treadmill. You may hold onto the safety rails during the entire 
test.
First you will walk at a slow pace as a warm-up. After the warm-up phase, we will increase 
the elevation of the treadmill that may feel like walking up a hill which would make walking 
a little hard for you. We will ask you to walk as long as you can until you are too tired to 
continue.
The test will take around 10-20 minutes depending on how long you can walk on the 
treadmill. We will closely monitor your heart, breathing and blood pressure after the test so 
we make sure your values return to normal. If for any reason your heart rhythm becomes 
abnormal we will stop the test and ask you to take advice from your primary care physician.
Skeletal Muscle Function test
You will be asked to push your leg against a machine which pushes against you to measure the 
strength of your leg muscles.
Risks and Discomforts
Muscle Biopsy:
With the muscle biopsy procedure, there is a risk of bleeding, bruising, soreness, pain,


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infection, and scarring of the skin. Bleeding could rarely result in development of a 
hematoma (deep tissue collection of blood). Pain and soreness usually resolves within 24-48 
hours post-procedure. Numbness of the skin near the biopsy site may occur and is usually 
temporary, but this numbness may persist indefinitely.
Risk of anesthetic lidocaine:
You will be asked about any known lidocaine allergy to determine eligibility for the sub- 
study. Common side effects include numbness and tingling in the fingers and toes, 
swelling at the site of administration.
Treadmill Test:
There are risks associated with the exercise capacity testing on the treadmill. In general, 
treadmill testing is a relatively safe procedure. Anytime that you increase your heart rate there 
is a risk of heart complications. We will do screening tests to help protect you and we will 
monitor your heart during the test. However, there are no tests that can completely clear you 
from possible heart complications. If there is a complication, trained personnel monitoring the 
test will have the appropriate equipment and supplies to care for you.
During the test you may experience some sweating and breathing discomfort due the 
strenuous nature of the test. There is a risk of potentially tripping on the treadmill; however 
hand rails are in place to help to prevent falls. Plus, the glue that holds the pads to your chest 
may cause some mild irritation that will clear up in a day or two.
Skeletal Muscle Function test:
Risks from the skeletal muscle function test include muscle tightness, soreness or stiffness, 
fatigue, and possibly results in a strained muscle. This test will require physical exertion.
Voluntary Participation and Withdrawal
You can change your mind at any time about providing these muscle biopsy samples and 
allowing them to be used for this research.
You can request destruction of your samples by making a request to the study provider by 
calling study staff at 205-996-3005 and the sponsor will remove and destroy your samples. 
However, any data already generated from the samples will be kept to preserve the value of 
the research.
If you withdraw or are taken out of the main study at the discretion of the investigator or 
sponsor for safety, behavioral, or administrative reasons, any samples you have provided will


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continue to be stored and used by the sponsor unless you tell the study provider you would 
like them to be destroyed.
If you are a UAB student or employee, taking part in this research is not a part of your UAB 
class work or duties. You can refuse to enroll, or withdraw after enrolling at any time before 
the study is over, with no effect on your class standing, grades, or job at UAB. You will not be 
offered or receive any special consideration if you take part in this research.
Cost of Participation
There will be no charge to you for collection of the optional biopsy samples used for this 
research.
Payment for Participation in Research
You will be paid a total of $300 in a gift card for completing all components at both visits 
(i.e. 2 treadmill tests, 2 biopsies, and 2 skeletal muscle function tests). You must complete 
all six of these procedures to receive compensation for this optional research. Initial your 
choice below:
I agree to have my muscle biopsy samples collected and to take the treadmill test for this 
study.
  I do not agree to have my muscle biopsy samples collected and to not take the treadmill 
test for this study
Optional Research #2
These are additional procedures that ask you to complete at three study visits. At the end of 
these visits you will be provided a three-day diet record, a plastic container to supply a 24-hour 
urine collection and plastic container to supply a fecal sample. You will be asked to record 
everything you eat for the three days leading up to sample collection. Additionally, you will be
asked to drink a sugar solution and to take the containers home and provide the 24-hour urine 
collection and a fecal sample. At the end of your 24-hour urine collection, we ask that you bring 
the containers with your collection to us as soon as possible. Once the fecal sample is collected, 
we ask that you bring your sample and diet record to us within one hour. We also ask that for 
the 2nd and 3rd collections you eat the same as you did for the first. The three-day diet recall,


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24-hour urine collection, and fecal sample collection will occur after visit #4 at week 6, visit #6 
at week 26, and visit #7 at week 32.
Explanation of Procedures
24-hour urine collection
You will be provided with containers to store your 24-hour urine collection, a smaller urine cup, 
and a cooler with ice packs to take home. You will be asked to collect all urine produced over 
the 24-hour time span specified using the smaller urine cup for collection and transfer to the 
containers. You will be asked to store the containers on ice packs in the cooler provided, or in a 
refrigerator. Once the 24 hours is over, you will be asked to bring the collection containers into 
the laboratory as soon as possible.
Fecal sample
You will be provided a three-day diet record prior to each sample collection. You will be asked 
to record what you eat for the three days leading up to the first sample collection. For the two 
subsequent samples you will be asked to consume the same items you did for the first 
collection. For each collection you will be provided with a cooler, ice packs, a plastic container, 
and a holder that fits over a toilet seat, to take home. Once sample collection is complete, you 
will be asked to immediately store the sample on ice packs in the cooler provided and bring the 
sample and diet record into the laboratory within 1 hour to ensure minimal degradation.
Risks and Discomforts
24-hour urine collection
Risks from the 24-hour urine collection are contamination of skin, clothing, and food with urine. 
The urine collection supplies are designed so urine can be collected with minimal discomfort.
To help prevent risk, please was your hands after collecting your sample.
Fecal sample
Risks from the fecal sample collection are contamination of skin, clothing, and food with feces. 
Contamination with food could lead to food borne illness. The stool collection kit is designed so 
that the samples can be collected without touching the stools, however, there is a small chance 
this may occur. To help prevent risk please wash your hands after collecting your sample.
Voluntary Participation and Withdrawal
You can change your mind at any time about providing the 24-hour urine collection and fecal


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samples and allowing them to be used for this research.
You can request destruction of your samples by making a request to the study provider by calling 
study staff at 205-996-3005 and the sponsor will remove and destroy your samples. However, 
any data already generated from the samples will be kept to preserve the value of the research.
If you withdraw or are taken out of the main study at the discretion of the investigator or 
sponsor for safety, behavioral, or administrative reasons, any samples you have provided will 
continue to be stored and used by the sponsor unless you tell the study provider you would like 
them to be destroyed.
If you are a UAB student or employee, taking part in this research is not a part of your UAB class 
work or duties. You can refuse to enroll, or withdraw after enrolling at any time before the 
study is over, with no effect on your class standing, grades, or job at UAB. You will not be 
offered or receive any special consideration if you take part in this research.
Cost of Participation
There will be no charge to you for collection of the optional fecal and urine samples used for 
this research.
Payment for Participation in Research
You will be paid a total of $225 in a gift card for completing all components of the fecal and 
urine sample collection (i.e. 3 fecal samples and 3 24-hour urine collections). You must 
complete all sample collections to receive compensation for this optional research.
Initial your choice below:
   I agree to have my urine and fecal samples collected
I do not agree to have my urine and fecal samples
collected


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Storage of Specimens for Future Use
As part of this study, we would like to store some of the blood and optional muscle biopsy 
specimens, and fecal samples collected from you for future research related to exercise and/or 
aging.
The future research may be conducted by the study provider or by other researchers that 
obtain IRB approval for their research. The specimens will be labeled with a code that only the 
study provider can link back to you. Results of any future research will not be given to you or 
your doctor. The specimens obtained from you in this research may help in the development 
of a future commercial product. There are no plans to provide financial compensation to you 
should this occur. You do not have to agree to allow your specimens to be stored in order to 
be part of this study.
You may request at any time that your specimens be removed from storage and not be used 
for future research. If you decide you want your specimens removed, you may contact the 
study provider. Once the request is received, and if your specimens have not already been 
used for other research, they will be destroyed. If you do not make such a request, your 
specimens will be stored indefinitely or until used.
I agree to allow my specimens to be kept and used for future research on exercise and /or 
aging.
I do not agree to allow my specimens to be kept and used for future research on exercise 
and /or aging.
Questions
If you have any questions, concerns, or complaints about the research, you may contact study 
staff at 205-996-3005. If the concern is related to a research-related injury including available 
treatments, please contact the study clinician at 205-996-0832. The study clinician oversees 
medical safety.
If you have questions about your rights as a research participant, or concerns or complaints 
about the research, you may contact the UAB Office of the IRB (OIRB) at (205) 934-3789 or toll 
free at 1-855- 860-3789. Regular hours for the OIRB are 8:00 a.m. to 5:00 p.m. CT, Monday 
through Friday.


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Legal Rights
You are not waiving any of your legal rights by signing this consent form.
Signatures
Your signature below indicates that you have read (or been read) the information provided 
above and agrees to participate in this study. You will receive a copy of this signed consent 
form.
Signature of Participant
Date
Signature of Person Obtaining Consent
Date