Clinical trial NCT04181606
Conditions: Aging
Keywords: Esmolol hydrochloride Exercise
Sponsor: David N. Proctor, PhD
Start date: 2022-02-02; Completion date: 2023-04-25
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will test the central hypothesis that postmenopausal women will demonstrate increased oxygen extraction in active leg muscle during leg cycling exercise while receiving an infusion of Esmolol, a fast-acting β1 selective antagonist, when compared to premenopausal women

Detailed description:
This study will test the central hypothesis that postmenopausal women will demonstrate increased oxygen extraction in active leg muscle during leg cycling exercise while receiving an infusion of Esmolol, a fast-acting β1 selective antagonist, when compared to premenopausal women. β1 selective antagonists (or "β1 blockers") are used to lower heart rate and improve O2 supply-to-demand balance in patients with coronary artery disease. By using esmolol to attenuate the central sympathetic response to exercise (increased heart rate and cardiac output) we can examine peripheral mechanisms of O2 delivery. The current project will evaluate how older postmenopausal women adjust active muscle O2 supply to an acute reduction in systemic O2 delivery during large muscle dynamic exercise when compared to younger premenopausal women.

Arms: arm 1: Drug: Esmolol Hydrochloride Dosage form: Intravenous Infusion Dosage/Frequency: 0.5 mg/(kg Fat Free Mass·min) for 3 min followed by a maintenance infusion of 0.25 mg/(kg Fat Free Mass·min) for remainder of trial, up to a maximum of 1 hour. arm 2: Saline infusion volume/rate matched to the calculated dose of esmolol.
Interventions: intervention 1: Esmolol infusion intervention 2: Saline infusion intervention 3: Pre exercise baseline intervention 4: Isometric handgrip exercise intervention 5: Semi-recumbent cycling
Intervention descriptions: intervention 1: The Esmolol loading dose will be 0.5 mg/kg fat free mass/min administered over the first 3 minutes, followed by a maintenance dose of 0.25 mg/kg fat free mass/min for the remainder of the protocol (maximum of 60 minutes). intervention 2: Saline will be rate/volume matched to the calculated esmolol dose. intervention 3: Subject rests quietly while drug infusion begins (3 min loading dose followed by 10 min of maintenance dose) until heart rate and blood pressure stabilize. intervention 4: The subject will grip at 40% of their maximum and maintain that grip for 90 seconds. Once at rest and once during heavy intensity cycling. intervention 5: Subjects will pedal for 2-4 minutes at a very light intensity (20W), followed immediately by 5 minutes at a moderate intensity (at a workload intended to elicit 85% of the oxygen consumption observed at the lactate threshold), and 5 minutes of cycling at a heavy intensity (at a workload estimated to elicit oxygen consumption half way between those observed at the lactate threshold and respiratory compensation point). Subjects will then continue cycling at the heavy intensity for 90 seconds while performing isometric handgrip exercise.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 33 (V.01/21/2019) 
                                                                                       
HRP-591 - Protocol for 
Human Subject Research
Protocol Title:
STUDY00010736:  Age Comparisons of Exercising Muscle O2 Supply in Healthy Adults:  Effects of Esmolol Infusion.
Principal Investigator:
Name: 
David N. Proctor, PhD 
Department: 
Kinesiology
Telephone: 
814-863-0724 (office) or 814-571-5234 (cell)
E-mail Address: 
dnp3@psu.edu
Version Date:
10/20/22
Clinicaltrials.gov Registration #:
N/A
Table of Contents
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1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Data and Safety Monitoring Plan
10.0
Risks
11.0
Potential Benefits to Subjects and Others
12.0
Sharing Results with Subjects
13.0
Subject Payment and/or Travel Reimbursements
14.0
Economic Burden to Subjects
15.0
Resources Available
16.0
Other Approvals
17.0
Multi-Site Study
18.0
Adverse Event Reporting
19.0
Study Monitoring, Auditing and Inspecting
20.0
Future Undetermined Research: Data and Specimen Banking
21.0
References
22.0
Confidentiality, Privacy and Data Management
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1.0
Objectives
1.1
Study Objectives
In this study, we will test the central hypothesis that postmenopausal women will demonstrate increased 
oxygen extraction in active leg muscle during leg cycling exercise while receiving an infusion of Esmolol, a fast-
acting β1 selective antagonist, when compared to premenopausal women. β1 selective antagonists (or “β1 
blockers”) are used to lower heart rate and improve O2 supply-to-demand balance in patients with coronary 
artery disease3. By using esmolol to attenuate the central sympathetic response to exercise (increased heart rate 
and cardiac output) we can examine peripheral mechanisms of O2 delivery. The current project will evaluate 
how older postmenopausal women adjust active muscle O2 supply to an acute reduction in systemic O2 delivery 
during large muscle dynamic exercise when compared to younger premenopausal women.
1.2 Primary Study Endpoints
The primary outcome variable is the difference in the change in skeletal muscle oxygenation (%SmO2) in the 
active leg muscle from baseline during recumbent cycling exercise between saline and esmolol (∆%∆SmO2). We 
predict that older women will have a greater ∆%∆SmO2 than premenopausal women during esmolol infusion.
1.3 Secondary Study Endpoints
Secondary outcome variables will include the effect of concurrent sympathetic stimulation via isometric 
handgrip exercise on active thigh and inactive forearm muscle ∆%∆SmO2. We will also include measurements of 
blood pressure, heart rate, cardiac output, and VO2. 
2.0
Background 
2.1
Scientific Background and Gaps
Understanding the mechanisms facilitating the acute adjustments in oxygen uptake (VO2) during large muscle 
exercise is biomedically important, as it is a major determinant of exercise tolerance17,18 and functional quality of 
life1 in both health and disease. The physiological adjustments that mediate increases in VO2 during exercise are 
highly integrated and involve increases in mean arterial pressure (MAP), systemic and exercising muscle blood 
flow, and arterial-venous O2 content (primarily via increased O2 extraction)9. The matching of O2 delivery-to-
utilization/demand during dynamic exercise, and the speed with which these processes occur at exercise onset 
(kinetics), reflects the integrated functioning of the autonomic, pulmonary, cardiovascular, and muscular 
metabolic systems which in turn determine the necessity for substrate-level (nonoxidative) energy supply and 
subsequent exercise tolerance/intolerance22.  
Interventions that alter the normal balance between sympathetic control, active muscle O2 supply, and extraction 
have the potential to advance our understanding of the mechanisms regulating kinetic and steady state VO2 
responses to exercise. Studies employing beta-adrenergic blockade, which acutely reduce heart rate, contractility, 
and systemic O2 delivery (refs), report compensatory increases in systemic4,6 and leg15,16 arterial-venous O2 content 
difference during submaximal cycling exercise in healthy younger humans.
Age- and sex-related differences in O2 utilization. It has been previously shown that older women demonstrate an 
attenuated ability to increase cardiac output and leg vascular conductance during moderate-intensity (50-60 
watts) cycling exercise resulting in reduced leg blood flow and O2 delivery19. However, unlike older men (who 
displayed no reduction in leg blood flow during exercise), older women did not demonstrate an increase in O2 
extraction compared to their younger counterparts21. It is unclear whether these differences represent a better-
preserved ability to deliver oxygen to active muscle or an impairment in oxygen extraction. By infusing esmolol 
during exercise, we will attempt to further reduce oxygen delivery to examine oxygen extraction in young vs older 
women. 
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Age-related reductions in Functional Sympatholysis. Previous studies, both from our lab19,21 and others8,23, indicate 
substantial age differences in the ability of metabolically active muscles to blunt sympathetic vasoconstriction 
(functional sympatholysis). The age-related attenuation of this response is particularly evident in older post-
menopausal women and could contribute, along with an accelerated stiffening of central arteries and altered 
baroreflex function, to the exaggerated systemic blood pressure responses observed in these women when they 
perform dynamic exercise. Isometric handgrip has been established as a reliable way to acutely augment systemic 
sympathetic outflow2,12 and NIRS has been used to assess the resultant functional sympatholysis response in 
various populations24 including in post-menopausal women5. The present study will assess how functional 
sympatholysis is affected by an acute esmolol-mediated reduction in cardiac output during dynamic cycling 
exercise and how this response may differ between younger and older women. 
2.2
Previous Data
Because of its rapid onset and offset, Esmolol is used commonly in anesthesia and critical care to treat tachycardia.  
Our dose-finding studies indicated that infusing of ~125 mg of Esmolol (range 90 to 162 mg) acutely blocks beta-
1 adrenergic receptors (β1ARs) in healthy young men and women14.  β1ARs remain blocked in these subjects if a 
maintenance infusion of Esmolol continues.  When the infusion ends, the β1ARs return to baseline within 45 
minutes. 
There are minimal published data using Esmolol in the context of exercise physiology experiments.  The Proctor 
lab recently utilized the rapidly acting β1 selective antagonist esmolol to transiently reduce exercise heart rate in 
a mixed (age and sex) sample of healthy adults20.  Larger reductions in near infrared spectroscopy (NIRS)-derived 
oxyhemoglobin/myoglobin O2 saturation (an index of O2 extraction) were observed within the exercising leg 
muscles (vastus lateralis and medial gastrocnemius) of these subjects during esmolol (vs. saline) infusion20.  These 
findings provide strong evidence of the dynamic coupling that exists between systemic O2 delivery and active 
muscle O2 extraction during submaximal exercise in humans. 
2.3
Study Rationale
The effects of infused Esmolol on the heart are rapid (observed within 5 min), quickly reversible (9 min half-life), 
and do not provoke lightheadedness, nausea, or significant hypotension in healthy adults14.  This is in contrast to 
non-selective (β1+β2) blockers such as Propranolol, which are not rapidly reversible.  The use of β1-selective 
blockade is also advantageous in these studies because it does not impact β2-mediated responses in skeletal 
muscle (as we have shown with Esmolol14) and does not appear to suppress skeletal muscle glycolysis or hasten 
exercising muscle fatigue in the way that non-selective blockade does11.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
1. Capable of giving informed consent
2. Premenopausal women ages 18-35 years OR post-menopausal women ages 55-70 years
3. Satisfactory medical history and physical exam, as determined by a CRC clinician
4. Not currently taking medications affecting heart rate or contractility
5. Fluent in written and spoken English
3.2
Exclusion Criteria
Participants who will not be studied are those who: 
1.
Are less than 19 years of age or more than 70 years of age
2.
Are pregnant or lactating
3.
Are prisoners or institutionalized individuals or unable to consent
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4.
Diagnosed renal failure (Creatinine >2.0 mg/dl)
5.
Diagnosed liver disease (ALT and AST 2 times normal)
6.
Diagnosed Reynaud’s disease
7.
Have uncontrolled diabetes
8.
Have uncontrolled hypertension
9.
Have a left ventricular ejection fraction < 40%
10. Have a recent history of unstable angina or myocardial infarction (<6 months), unstable angina, or 
use of nitrate medications within past 2 weeks
10.  Severe lung disease (i.e., on supplemental oxygen or frequently use rescue inhalers)
11.  Diagnosed bleeding or clotting disorder or recent blood transfusion
12. Have asthma, history of thyroid issues or hyperkalemia
13. Known use of recreational drugs
14. Methylphenidate use
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Participation in this study will be discontinued if pre-screening requirements are not met, pregnancy, 
failure to follow pre-study instructions or main variables cannot be measured. If vital signs fall below or 
rise above acceptable levels or if the subject does not tolerate a procedure, the procedure will be stopped.  
The subject may withdraw from the study at any time.
3.3.2
Follow-up for withdrawn subjects
Subjects withdrawn from the study will not return for any more visits. The research nurses will contact 
subjects after withdrawal to ensure there are no further problems.
4.0
Recruitment Methods
4.1
Identification of subjects
Subjects will be identified from our own subject pool who meet the inclusion/exclusion criteria and 
previously agreed to be contacted.
Subjects will also be recruited from Penn State campus, State College community, and Centre County area 
by flyers and advertisements.  Flyers will contain basic information about the study, as well as contact 
information for study personnel in the Integrative Vascular Physiology Laboratory (201 Noll Lab).  Potential 
participants who show interest in the study by contacting study personnel will be sent an informed consent 
form over email with instructions to contact one of the study investigators if she has any questions or 
would like to schedule a visit to Noll Lab for the screening and familiarization visit.
In addition to flyers and advertisements, StudyFinder will be used for recruitment purposes.
4.2
Recruitment process
4.2.1
How potential subjects will be recruited.
Subjects will be recruited through the CRC and through study finder. Potential subjects, who are 
interested in participating, will be informed about the details of the study using the phone script.  
If they are interested in participating, then they will be informed that a series of pre-screening 
questions pertaining to their health, medical background and history (Patient Information sheet) 
will be asked over the phone and that by answering the questions, they will be giving their consent 
to allow us to use and retain that information. If subjects wish to participate in additional research 
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studies, they may indicate that they allow their information to be retained and used in the future 
by the research group to contact them about future studies.  If they indicate that they are not 
interested in future studies, their information will be destroyed at the end of this study or at any 
future time when they request destruction.  The information will not be disclosed to anyone 
outside of the CRC Research team
No race or ethnicity will be excluded from the study.
Recruitment materials
Invitation to participate/Permission to contact letter
Phone screening questions
StudyFinder
Study Flyers
4.2.2
Where potential subjects will be recruited.
Subjects will be identified from our own subject pool who meet the inclusion/exclusion criteria 
and previously agreed to be contacted.
Potential subjects will be recruited from State College, PA and the surrounding region (i.e., Centre 
County). 
4.2.3
When potential subjects will be recruited.
Recruitment of potential subjects will begin upon study approval.
4.2.4
Describe the eligibility screening process and indicate whether the screening process will occur 
before or after obtaining informed consent. Screening begins when the investigator obtains 
information about or from a prospective participant in order to determine their eligibility.  In 
some studies, these procedures may not take place unless HIPAA Authorization is obtained OR 
a waiver of HIPAA Authorization when applicable for the screening procedures is approved by 
the IRB.  
Members of the Integrative Vascular Physiology Laboratory will answer phone calls (office 
phone) or emails from potential participants. During these exchanges, prospective participants 
may ask any questions regarding the study and/or schedule a visit to complete informed 
consent and screening process.
After signing the IRB approved consent the subjects will participate in the screening visit a brief 
medical history, physical exam, resting EKG, and blood draw (CBC and CMP) will be performed to 
confirm each participant’s health status.  Women of childbearing potential will have a urine 
pregnancy test to confirm they are not pregnant. We will also have subjects fill out a physical 
activity history questionnaire. These questionnaires will not be used to determine study eligibility 
(inclusion or exclusion), but will be used to describe the study groups in future publications.  
5.0
Consent Process and Documentation 
5.1
Consent Process:
Check all applicable boxes below:
   Informed consent will be sought and documented with a written consent form 
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 Implied or verbal consent will be obtained – subjects will not sign a consent form (waiver of 
written documentation of consent) 
  Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). 
 Informed consent will not be obtained – request to completely waive the informed consent 
requirement.
5.2
Obtaining Informed Consent 
5.2.1
Timing and Location of Consent 
Prior to coming to the laboratory, subjects will be contacted using the Study Prep phone script. 
The participants will avoid alcohol and strenuous exercise for 24 hours prior to each study visit.  
Participants will also refrain from caffeine at least 12-24 hours and NSAIDS/cold prep medications 
24 hours prior to each study visit.  Participants will be asked to eat a small meal 2 to 3 hours before 
their scheduled appointment but dietary intake will not be rigorously controlled.  ALL participants 
will review their prescribed medications, with a CRC (Clinical Research Center) clinician.
Once the subject arrives at the CRC, they will be given sufficient time to read the consent, all 
procedures will be explained in layman’s terms and they will be given a copy of the signed consent 
form.
5.2.2
Coercion or Undue Influence during Consent 
The subject will be provided with ample opportunity to have questions answered before 
participating in the study. All procedures will be explained to them in layman’s terms and they 
will be given a copy of their signed consent form. Subjects will have the right to withdraw from 
the study at any time.
5.3
Waiver of Written Documentation of Consent 
N/A   Subjects will sign the IRB-approved consent form.
5.3.1
Indicate which of the following conditions applies to this research:
 The research presents no more that minimal risk of harm to subjects and involves no procedures 
for which written consent is normally required outside of the research context.
OR
  The only record linking the subject and the research would be the consent document and the 
principal risk would be potential harm resulting from a breach of confidentiality. Each subject 
will be asked whether the subject wants documentation linking the subject with the research, 
and the subject’s wishes will govern. 
OR
  If the subjects or legally authorized representatives are members of a distinct cultural group or 
community in which signing forms is not the norm, that the research presents no more than 
minimal risk of harm to subjects and provided there is an appropriate alternative mechanism 
for documenting that informed consent was obtained.  
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5.3.2
Indicate what materials, if any, will be used to inform potential subjects about the research 
(e.g., a letter accompanying a questionnaire, verbal script, implied consent form, or summary 
explanation of the research)
Subjects will be contacted using the Study Prep phone script to obtain verbal consent to avoid 
alcohol and strenuous exercise for 24 hours prior to the experiments. This poses no more than 
minimal risk, so verbal consent is appropriate. Once the subject arrives in the Clinical Research 
Center (CRC), they will be given sufficient time to read the consent form and have all their 
questions answered, and to sign the written consent.
5.4
Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). 
5.4.1
Indicate the elements of informed consent to be omitted or altered.  - Not applicable
5.4.2
Indicate why the research could not practicably be carried out without the omission or 
alteration of consent elements. - Not applicable
5.4.3
Describe why the research involves no more than minimal risk to subjects. Not applicable
5.4.4
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.  Not applicable
5.4.5
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format. Not applicable
5.4.6
Debriefing   Not applicable
5.5
Informed consent will not be obtained – request to completely waive the informed consent 
requirement
5.5.1
Indicate why the research could not practicably be carried out without the waiver of consent- 
Not applicable
5.5.2
Describe why the research involves no more than minimal risk to subjects.
Not applicable
5.5.3
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects                                                                                                                                                         
Not Applicable
5.5.4
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.                                                                     
Not applicable
5.5.5
Additional pertinent information after participation. - Not applicable
5.6
Consent – Other Considerations  
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5.6.1
Non-English-Speaking Subjects - Not applicable
5.6.2
Cognitively Impaired Adults.  
5.6.2.1 Capability of Providing Consent - Not applicable
5.6.2.2
Adults Unable to Consent - Not applicable
5.6.2.3 Assent of Adults Unable to Consent - Not applicable
5.6.3
Subjects who are not yet adults (infants, children, teenagers) 
5.6.3.1 Parental Permission -  Not applicable
5.6.3.2 Assent of subjects who are not yet adults - Not applicable
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study.
Authorization will be obtained and documented as part of the consent process. 
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). 
Full waiver is requested for entire research study (e.g., medical record review studies). 
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). 
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1
Plan to protect PHI from improper use or disclosure
Not applicable
6.2.1.2
Plan to destroy identifiers or a justification for retaining identifiers 
Not applicable
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
Not applicable
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6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
Not applicable
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any other 
person or entity, except as required by law, for authorized oversight of the research study, or for other 
permitted uses and disclosures according to federal regulations. 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) per 
federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
Design:  single blind, randomized, placebo-controlled, crossover (each person receives both treatments)
Subjects:  young and older women (2 groups, n=13 completed subjects each)
Independent variable:  β1 selective blockade with Esmolol vs. saline
Dependent variables:  heart rate, cardiac output, arm BP, finger BP, VO2, forearm, forehead, thigh and 
calf NIRS
There will be one screening visit and two study visits (one non-infusion and one infusion). The 
procedures for each visit are outlined in the diagram below:
 
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This is a single-blind study because, although the subjects, data collectors, and data analysts will not be 
aware of the treatment order, the nurses monitoring the subjects will be aware of the label on the infusion 
bag (Esmolol or saline). The nurses will be assessing safety (i.e., HR, BP, and symptoms).  However, the 
nurses will not be involved in any data analysis.  
Esmolol hydrochloride (2500 mg in 250 ml normal saline) will be purchased from McKesson in pre-mixed 
bags.  The placebo will be a 250 ml, 500 ml, or 1000 ml bag of normal saline.  The volume and rate of 
infusion will be constant for both trials.  Once the infusion pump is programmed by the research nurse, 
an opaque bag will be placed over the fluid bag so that the participants and researchers remain blinded 
to the treatment order.  
7.2
Study Procedures
7.2.1
Visit 1 (screening visit) 
When research staff schedules the subject (over the phone), the subject will be told to avoid alcohol, over 
the counter cold prep and NSAIDs, and strenuous exercise for 24 hours, and to eat a small meal 2-3 hours 
prior to coming to the laboratory.  They will also be asked to refrain from items containing caffeine 12 
hours prior to this visit. All participants will review their medications, including beta-blockers, with one of 
the research nurses.  This information will be shared with the CRC clinician who will then recommend 
which medications can be taken prior to the patient’s scheduled second and third study visit, and which 
ones should be withheld until after each study visit.  
During the first visit, informed consent will be obtained.  Women of childbearing potential (pre-
menopausal) will take a urine pregnancy test to ensure they are not pregnant.  This will be done at all 3 
visits before conducting any of the study measurements.   The subject will then complete a medical history 
questionnaire (all subjects) and a physical activity history questionnaire.  The subject will also have their 
height and weight (without shoes) and waist circumference measured.  The subject will then undergo a 
physical exam and a resting EKG (conducted by medical personnel).  A venous blood draw will then be 
performed by a CRC nurse and sent for analysis (CBC and CMP; 7.5 ml total).  Lab values will be 
verified/signed off by a CRC clinician before infusion begins, and will be obtained no more than 6 weeks 
prior to the infusion.  During this first study visit, all subjects will also be asked to squeeze a handgrip 
device as hard as they can 3 times, with approximately 1 min recovery between each.  After a short 
recovery, the subject will then be asked to squeeze the handgrip device for approximately 1 minute at 
40% of their maximum effort.   Immediately after, we will ask the subject how they tolerated the 40% grip 
task (rating of perceived effort scale).  This procedure will familiarize the subject with the handgrip before 
they are asked to perform these tasks (for longer durations) during visits 2 and 3.  Analysis of the blood 
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tests, EKG and medical history/exam results, and the subject’s tolerance to the handgrip will collectively 
determine the final eligibility of the participant.
(Figure from Iannetta et al., 2020)10
Then the subject will then lay on an exam bed for placement of EKG pads and a doppler ultrasound device 
will be used to determine skinfold thickness of the thigh. The NIRS sensors will then be placed (one on the 
forearm, one on the forehead and two on the leg). The subject will then be assisted onto the recumbent 
bike. The subject will be asked to squeeze a handgrip device as hard as they can with their hand.  The 
maximum force they can exert (highest of 2 to 3 efforts) will be used to determine how hard they will 
squeeze this device later in the study (40% of this maximum value).  A silicone face mask will be placed 
over the subject’s nose and mouth to monitor their oxygen consumption and breathing frequency, and 
blood pressure devices will be placed over their arm (SunTech Tango) and finger (Finometer). After all 
instrumentation is in place, baseline measurements of heart rate, cardiac output, oxygen consumption, 
blood pressure, and NIRS will begin.
The subject will then be asked to complete three exercise bouts on a recumbent bike.  The first bout will 
consist of very light pedaling for 2 minutes (warm-up) followed by approximately 6 minutes of pedaling 
at what should be a moderate effort for the subject.  After a few minutes of rest and/or light pedaling 
(recovery), the subject will be asked to perform a second bout of exercise, which will consist of a very 
gradual increase in workload (“ramp”) until the subject can no longer maintain the required pedal speed 
or needs to stop due to fatigue.  This second bout will likely last between 6 and 12 minutes.  After a few 
minutes of light pedaling, the face mask will be removed and the subject will recover in a comfortable 
chair.  After 30 minutes of recovery, the subject will be assisted back on the bike and the facemask will be 
reattached. The subject will then pedal for 2 minutes at a very light workload, followed immediately by 
up to 12 minutes of pedaling at a moderately heavy workload.  After a brief cool-down of light pedaling, 
the facemask and other sensors (e.g., EKG, NIRS, etc) will be removed.  At several points throughout this 
visit (minimum of 3, maximum of 6) a small drop of blood from your fingertip will be used to measure the 
subject’s blood lactate level.  The measurements obtained during this first study visit will determine the 
exercise workloads that will be individually assigned during study visits 2 and 3.
Women who are currently taking hormone therapy of any kind (oral contraceptives, estrogen 
replacement, etc) will not be excluded from participation in this study.  However, given the well-
documented effects of female sex hormones on resting blood pressure and exercise metabolic responses 
we will ask 1) pre-menopausal women to indicate their current menstrual status and oral contraceptive 
use and 2) post-menopausal women to self-report their history and duration of sex hormone 
replacement13.  This information will be collected at the time of their medical history/physical exam.
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2 min
5 min
5 min
1-2 min
Eligible participants will be asked to return for two experimental visits (non-infusion and infusion) at least 
48 hours apart.
7.2.2
Visit 2 (non-infusion)
As with the screening visit, the subject will be told to avoid alcohol, over the counter cold prep and NSAIDs, 
and strenuous exercise for 24 hours, and to eat a small meal 2-3 hours prior to coming to the laboratory.  
They will also be asked to refrain from items containing caffeine 12 hours prior to this visit. Women of 
childbearing potential (pre-menopausal) will take a urine pregnancy test to ensure they are not pregnant.
The subject will then lay supine as a Dual-Energy X-ray Absorptiometry (DEXA) scan is performed to 
determine fat free mass. Then the subject will then lay on an exam bed for placement of EKG pads as well 
as NIRS devices (one on the forearm, one on the forehead, and two on the leg) and measurement of vital 
signs. 
The subject will then be assisted onto the recumbent bike. The Subject will be asked to squeeze a handgrip 
device as hard as they can with their hand.  The maximum force they can exert (highest of 2 to 3 efforts) 
will be used to determine how hard they will squeeze this device later in the study (40% of this maximum 
value).  A silicone face mask will be placed over the subject’s nose and mouth to monitor their oxygen 
consumption and breathing frequency, and blood pressure devices will be placed over their arm (SunTech 
Tango) and finger (Finometer). After all instrumentation is in place, baseline measurements of heart rate, 
cardiac output, oxygen consumption, blood pressure, and NIRS will begin.
All measurements (HR, BP, cardiac output, oxygen consumption and NIRS) continue to be collected 
throughout the exercise protocol (some continuously, others intermittently).   Once these measurements 
have stabilized, the subject will be asked to squeeze the handgrip device (constant tension) at 40% of the 
force they developed during the maximum grip testing for 1-2 minutes. Once all measurements have 
returned to baseline, the subjects will then begin the cycling exercise protocol, (see figure above). Subjects 
will be asked to pedal for 2 minutes at a very light intensity, followed immediately by 5 minutes at a light 
intensity, and 5 minutes of cycling at a moderate intensity. Finally, the subject will continue cycling at the 
same moderate intensity for 1-2 minutes while simultaneously squeezing a handgrip device at 40% of 
their maximal effort. The subject will then rest for 45 mins, after which they will repeat the exercise 
protocol. Immediately following the second exercise bout, cuffs will be placed on the upper arm and on 
the upper thigh of the limbs with the NIRS probes attached. The cuffs will then be inflated to ~250 mmHg 
until the limbs have been completely deoxygenated (~5 minutes as determined by NIRS).
At least three lactate measurements will be collected during each trial (6 total); one during rest, one after 
4 mins of light intensity exercise, and one after 4 mins of moderate intensity exercise.
  
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2 min
5 min
5 min
1-2 min
After the recovery period, most instrumentation will be removed (except for the blood pressure cuffs and 
EKG).  The subject will then sit up slowly as we monitor their BP and HR, and offer them juice and crackers.  
Once the subject’s BP and HR have returned to baseline levels, we will remove the remaining monitoring 
equipment and the subject may leave.
7.2.3
Visit 3 (Infusion)
The order of infusion will be randomized and “blinded” such that neither the subject nor the investigators 
will know what the infusion order is (only the nurses will know the order, for safety reasons).  
As with the screening visit, the subject will be told to avoid alcohol, over the counter cold prep and NSAIDs, 
and strenuous exercise for 24 hours, and to eat a small meal 2-3 hours prior to coming to the laboratory.  
They will also be asked to refrain from items containing caffeine 12 hours prior to this visit. Women of 
childbearing potential (pre-menopausal) will take a urine pregnancy test to ensure they are not pregnant.
Then the subject will then lay on an exam bed for placement of EKG pads as well as NIRS devices (one on 
the forearm, one on the forehead, and two on the leg) and measurement of vital signs. A nurse will then 
insert a catheter into a vein of the subject’s arm (visit 3 only).  This catheter will enable us to infuse the 
drug (Esmolol or saline).
The subject will then be assisted onto the recumbent bike. The subject will be asked to squeeze a handgrip 
device as hard as they can with their hand.  The maximum force they can exert (highest of 2 to 3 efforts) 
will be used to determine how hard they will squeeze this device later in the study (40% of this maximum 
value).  A silicone face mask will be placed over the subject’s nose and mouth to monitor their oxygen 
consumption and breathing frequency, and blood pressure devices will be placed over their arm (SunTech 
Tango) and finger (Finometer). After all instrumentation is in place, baseline measurements of heart rate, 
cardiac output, oxygen consumption, blood pressure, and NIRS will begin. After all instrumentation is in 
place baseline measurements of heart rate, cardiac output, oxygen consumption, blood pressure, and 
NIRS will begin.
A CRC clinician will join the research team immediately before it is time to start the infusion. The CRC 
clinician will be able to review the EKG results at that time if there are any concerns.  The subject will then 
receive an infusion of Esmolol or saline. The Esmolol loading dose will be 0.5 mg/kg fat free mass/min 
administered over the first 3 minutes (loading dose), followed by a maintenance dose of 0.25 mg/kg fat 
free mass/min for the remainder of the protocol (maximum of 60 minutes).
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All measurements (HR, BP, cardiac output, oxygen consumption and NIRS) will be continue to be collected 
throughout the exercise protocol (some continuously, others intermittently).   Once these measurements 
have stabilized (i.e., approximately 10 minutes into the maintenance infusion), the subject will be asked 
to squeeze the handgrip device (constant tension) at 40% of the force they developed during the 
maximum grip testing for 1-2 minutes. Once all measurements have returned to baseline, the subjects 
will then begin the cycling exercise protocol. Subjects will be asked to pedal for 2 minutes at a very light 
intensity, followed immediately by 5 minutes at a light intensity, and 5 minutes of cycling at a moderate 
intensity. Finally, the subject will continue cycling at the same moderate intensity for 1 to 2 minutes while 
simultaneously squeezing a handgrip device at 40% of their maximal effort. The subject will then rest for 
45 mins, after which they will repeat the exercise protocol. Immediately following the second exercise 
bout, cuffs will be placed on the upper arm and on the upper thigh of the limbs with the NIRS probes 
attached. The cuffs will then be inflated to ~250 mmHg until the limbs have been completely 
deoxygenated (~5 minutes as determined by NIRS).
  
After the recovery period, most instrumentation will be removed (except for the blood pressure cuffs and 
EKG).  The subject will then sit up slowly as we monitor their BP and HR, and offer them juice and crackers.  
Once the subject’s BP and HR have returned to baseline levels, we will remove the remaining monitoring 
equipment and the subject may leave.   There is no need to send subjects home with a heart rate monitor 
after the study because the effects of Esmolol are very short (9-minute half-life).
Listed below are all the parameters that will be measured.  The risks of each procedure are listed in Section 
11.0.
1.
Oxygen consumption (VO2): Pulmonary oxygen consumption will be measured using a COSMED Quark breath-
by-breath system. A silicone mask will be placed over the subject’s nose and mouth to measure breather 
frequency and volume in addition to the expired gas content.
2.
Cardiac Output and Heart Rate: Cardiac output and heart rate will be measured non-invasively using a 
PhysioFlow Enduro device. 6 EKG pads will be placed on the subject (2 on the neck, 2 on the chest, and 2 on 
the back). This device will determine heart rate using EKG and will use bioimpedance to estimate cardiac 
output throughout the experiment.
3.
Blood pressure: Blood pressure and heart rate will be measured non-invasively via an automatic 
sphygmomanometer (SunTech Tango) and with a photoplethysmographic device (Finometer, FMS, 
Netherlands). To optimize the accuracy of beat-by-beat data collected by the Finometer, care will be taken to 
stabilize the device on the hand at heart level, and the device will be turned off between protocols to prevent 
finger edema, which may interfere with the ability to measure finger blood pressure.  Baseline BP will be 
measured by the SunTech Tango and the Finometer will be adjusted to match that pressure to provide an 
accurate baseline pressure reading. The SunTech Tango device will not be used during the handgrip exercises 
because it cannot measure blood pressure under those conditions.
4.
Venous catheter:  An IV will be placed in a peripheral vein to infuse Esmolol and saline, and to withdraw blood  
for CBC (complete blood count) and CMP (Chem-7).  The total volume of blood obtained will not exceed 50 
ml.  Blood will be sent to HMC Clinical Laboratory for processing.
5.
Skinfold thickness: Doppler ultrasound will be used to measure the fat thickness at the sites of the NIRS 
sensors (forearm and calf). 
6.
Physical activity questionnaire:  Healthy subjects will complete a physical activity history questionnaire, which 
is a pen and paper assessment of their estimated amount of leisure time physical activity 
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7.
Near infrared spectroscopy (NIRS): We will place a wireless portable near infrared spectroscopy (NIRS) device 
on the forearm (non-handgrip arm), as well as on the forehead, the vastus lateralis (thigh) and the 
gastrocnemius (calf) muscle of one leg. These devices are essentially small plastic boxes that measure skeletal 
muscle oxygenation noninvasively. The system measures the hemoglobin saturation of the investigated tissue, 
called the 'tissue saturation index' (TSI). In addition to TSI, the system also measures oxygenation changes in 
terms of oxy-hemoglobin, deoxy-hemoglobin, and total hemoglobin, which is an indication of the blood 
volume in the tissue. At the end of study visits 2 & 3, a cuff will be placed on the upper arm and upper thigh 
of the limbs with NIRS attached. The cuff will be inflated to a suprasystolic pressure (~250 mmHg) to occlude 
blood flow to fully deoxygenate the limb. This allows for calibration of the NIRS data.
8.
Isometric handgrip exercise:  Subjects will perform a maximal voluntary handgrip using a handgrip 
dynamometer (highest of 2 to 3 maximum efforts).  A percent maximum is calculated and set on a visual 
display so the subject grips at the appropriate intensity.  Subjects will be asked to grip at 40% of their maximum 
and to maintain that grip for 90 seconds.
9.
DEXA: Subjects will lay supine on a flat, open x-ray table and will be asked to remain very still during the scan. 
This will provide us with the subject’s fat free mass, which will be used to determine esmolol dosing.
10. Blood Lactate: Before each sample is collected, the finger will be cleaned with an alcohol wipe and allowed 
time to dry. The blood sampling procedure will involve a single-use fingerstick device, on the 3rd and 4th fingers 
of the hand. The first drop will be wiped with gauze and the second drop will collected on the test strip of the 
lactate analyzer.
7.3
Duration of Participation
The first visit could take up to 3 hours.  Visit 2 will take up to 3.5 hours. Visit 3 will take up to 4.5 hours.
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
Esmolol hydrochloride will be handled following the Institution’s Standard Operating Procedures for Clinical 
Research Section III, PM 306.  Esmolol will be tracked using an accountability record, and dispensed by a 
physician, pharmacist, PA, or CRNP.  The receipt, storage, dispensing and return/destruction will follow the 
Institution’s Standard Operating Procedures for Clinical Research.

Description
Esmolol hydrochloride (2500 mg in 250 ml normal saline) will be purchased from McKesson in pre-mixed 
bags.  The placebo will be a 250 ml, 500 ml, or 1000 ml bag of normal saline.

Treatment Regimen
The route of administration of Esmolol in our study is the same as in clinical care (IV pump).  The loading 
dose will be 0.5 mg/kg fat free mass/min administered over the first 3 minutes, followed by a maintenance 
dose of 0.25 mg/kg fat free mass/min for the remainder of the protocol (maximum of 60 minutes).

Method for Assigning Subject to Treatment Groups
This study uses a crossover design so all subjects will complete both treatments in random order. Subjects 
will be randomized to one of two treatment sequences using an equal allocation ratio of 1:1.  The two 
treatment sequences to which subjects will be randomized are 1) Esmolol infusion first and saline infusion 
second and 2) saline infusion first and Esmolol infusion second. The CRC nurses will generate the 
randomization that will use variable size, random permuted blocks with block size 2 and 4. CRC staff will 
maintain the randomization list until data collection has been completed to keep the research staff 
blinded.
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
Subject Compliance Monitoring
Not applicable.

Blinding of the Test Article
This study is single blind because the subjects, data collectors, and data analysts will not be aware of the 
treatment. For safety reasons, the CRC nurse will not be blinded.  Additionally, once the Esmolol/saline 
infusion pump is programmed by the research nurse, an opaque bag will be placed over the fluid bag so 
that the participant and all investigators in the room remain blinded to the treatment order.  

Receiving, Storage, Dispensing and Return 
7.4.1
Receipt of Test Article 
Esmolol hydrochloride will be purchased from McKesson.
7.4.2
Storage
Esmolol is stored at room temperature in a locked cabinet that is temperature-monitored in the 
CRC.  A special thermometer that records high and low temperatures will monitor the 
temperature in the storage area.  The thermometer is checked on a regular basis by staff in the 
lab.  The CRC is locked when unoccupied.
7.4.3
Preparation and Dispensing
A CRC physician or CRNP will calculate the required esmolol dose, configure the IV pump settings 
and monitor the subject during infusion. A CRC nurse will perform a double check of the calculated 
esmolol dose and IV pump settings prior to infusion. The amount of Esmolol used for each 
study/participant will be recorded on the study protocol flow sheet.
7.4.4
Return or Destruction of the Test Article
Any Esmolol bags (empty or partially used) remaining after completion of a study visit will be 
disposed on site.
7.4.5
 Prior and Concomitant Therapy
A list of prior and current medications will be obtained during the screening visit as part of the 
medical history. Subjects will be asked to withhold all over-the-counter medications (e.g. motrin, 
cold medicine) for 24 hours prior to each study and during the study procedures.  ALL participants 
will review their prescribed medications, including beta-blockers, with one of the research nurses.  
This information will be shared with the CRC clinician who will then recommend which 
medications can be taken prior to the patient’s scheduled study visit, and which ones should be 
withheld until after the study.  All medications consumed by the participants will be written on 
the flow sheet.
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
We plan to enroll no more than 40 subjects (20 subjects per group) in this study.  We plan to complete data 
collection on 13 young women (age 21-35) and 13 older postmenopausal women (age 55-70).
8.2
Sample size determination
∆%∆SmO2 (difference between %∆SmO2 during saline and esmolol trials) in response to moderate-intensity 
cycling exercise is our primary outcome. We do not have any pilot data pertaining to Esmolol infusion and exercise 
in postmenopausal women.  However, using data from our recent publication, older adults (65.0 + 2.6 years, n=3) 
displayed a greater ∆%∆SmO2 compared to their young (25.4 + 1.9 years, n=5) counterparts (22.0 + 4.0 % vs 16.2 
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+ 4.0 %)20. Considering this prior data, we will consider the difference between the pre-to-post Esmolol change 
and the pre-to-post placebo change (i.e., delta delta) of 5.8% to be clinically relevant20. Furthermore, we assume 
the variability (i.e., standard deviation) will be 4.78%, the standard deviation seen from this previous data20. We 
also assume there will be no carryover effect. Given these assumptions, a sample size of 11 subjects per group 
will provide 80% power to detect a difference in the change in %∆SmO2 between Esmolol and placebo, assuming 
a standard deviation of 4.78%, using a two-sided test having a significance level of 0.05.  To account for differences 
in subject population and exercise protocol between that study and this protocol, we plan to complete data 
collection on 13 subjects per group to ensure sufficient power. However, we expect a small number of individuals 
may not complete the study.  Therefore, we plan to enroll up to 20 subjects per group for a total of no more than 
40 subjects so that 13 subjects per group may complete the study.  
8.3
Statistical methods
Changes in outcomes will be calculated per patient prior to analyses. The data will be analyzed using repeated 
measures ANOVA, to account for the crossover design, with appropriate contrasts constructed to test hypotheses 
of interest (e.g., premenopausal vs postmenopausal). Additionally, where applicable, ANOVA will be used to assess 
differences between the groups for continuous outcomes (e.g., ∆%∆SmO2). As this is a relatively small-scale 
exploratory study, no corrections for multiple hypothesis testing will be employed.
9.0
Data and Safety Monitoring Plan
9.1  Periodic evaluation of data
Dr. Proctor will discuss the study with the research team at regularly scheduled lab meetings.  If necessary, he will 
conduct additional special meetings with relevant personnel if there is an immediate, specific issue that must be 
addressed (e.g. untoward events). It should also be noted that safety is constantly monitored in our laboratory 
because our studies involve beat-by-beat monitoring of physiological variables. Any concerns are immediately 
reviewed by the PI. Adverse events are not anticipated, but any occurring will be documented and reported 
according to HSPO policies and procedures. The PI will be solely responsible for data collection and verification, 
and review of cumulative adverse events.
9.2  Data that are reviewed
Relevant data safety and management procedures, interim data evaluation, untoward events (rare in this 
research), new developments in related research, problems with workflow, and quality control issues will be 
discussed. 
9.3  Method of collection of safety information
Lab members keep lab notebooks into which they note relevant safety issues and data that they identify for 
discussion. In the case of untoward events, those lab members present during the event are included in a 
debriefing and notes of the meeting are taken. The participant involved in an untoward event is interviewed in 
person or via telephone concerning the event and the responses are included into the notes for that event. 
9.4  Frequency of data collection
Data collection and note taking starts when the subject arrives at the laboratory for their study visit and continues 
until the subject leaves the laboratory. Safety is constantly monitored during every laboratory visit and is 
documented in the subject’s chart.
9.5  Individuals reviewing the data
The PI and research team will review the data on a regular basis.  The Data and Safety Monitoring Board (DSMB), 
composed of 3 independent investigators, will meet as required.  The PI is not a member of the DSMB but will be 
present at the meetings.  The DSMB Chair is Dr. Gilchrist.
9.6  Frequency of review of cumulative data
Subject data are analyzed by Dr. Proctor’s graduate student within two weeks of each study visit. Summary data 
are reviewed at least once per month to ensure the protocol and measurements are appropriate. Safety is 
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constantly monitored during the trials and any concerns are brought to the attention of the PI immediately. We 
do not wait for a cumulative review to assess safety.
9.7  Statistical tests 
Subject data are analyzed by the PI within one week of the experimental visit. Summary data are reviewed at least 
once per month to ensure the protocol and measurements are appropriate. Safety is constantly monitored during 
the trials and any concerns are brought to the attention of the PI immediately. We do not wait for a cumulative 
review to assess safety.
9.8  Suspension of research
In the case of an adverse event, research is suspended while evaluation, reporting, and rectification proceeds. 
Research is restored when the IRB and the DSMB determine that a rectification of the problem is satisfactory.
10.0
Risks
1.
Confidentiality: There is a risk of loss of confidentiality if medical information or identity are obtained by 
someone other than the investigators, but precautions will be taken to prevent this from happening.
2.
Pregnancy: It is important that a fetus not be exposed to any unnecessary risks; therefore, pregnant women will 
not be studied. A pregnancy test will be administered at the beginning of the study visit to all women of 
childbearing potential to ensure they are not pregnant.
3.
Blood pressure, heart rate: Minimal risk of skin irritation from EKG patches.
4.
PhysioFlow: 
5.
Oxygen Consumption: No Risk.
6.
IV placement: The discomfort associated with a blood draw/IV placement is a slight pinch or pinprick when the 
sterile needle enters the skin. The risks of a blood draw include mild discomfort and/or a black and blue mark 
at the puncture site. Less common risks include infection or bleeding at the puncture site, or on rare occasions, 
dizziness, light-headedness, nausea or fainting during the procedure. To minimize the risk of infection, aseptic 
techniques will be used.
7.
Esmolol infusion: The risks stated by the manufacturer include heart block, hypotension, injection site pain, 
nausea, seizure, bronchospasm, allergic reaction, infusion site reaction, or extravasation (leaking of infusion into 
tissue around the IV site which may cause tissue death).  However, in our experience these symptoms have 
never occurred in our research participants. The infusion will end if HR falls by more than 20 beats/min or below 
40 beats/min or symptoms occur, or if symptomatic hypotension occurs (mean blood pressure drop of more 
than 20mmHg and/or symptoms).
If extravasation would occur, we would proceed as follows: 
1. Stop infusion
2. Apply warm compress over the catheter site 
3. Elevate the arm
4. Observe/monitor for at least 45 minutes (i.e. 5 half-lives for Esmolol)
5. Call subject within 24 hours
8.
Saline infusion:  no risk
9.
Skinfold of the forearm and leg to measure fat thickness:  No risk
10. Recumbent cycling exercise:  Cycling exercise will cause fatigue, shortness of breath, elevated body 
temperature and muscle fatigue. Could also cause chest discomfort and/or dehydration. 
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11. Isometric handgrip exercise: Handgrip exercise will cause fatigue in the forearm. This may be associated with a 
burning sensation in the forearm and possible muscle soreness after the test.
12. Post exercise occlusion:  The upper arm and upper leg cuff occlusions may result in a tingling or burning 
sensation in the limbs.  This will subside once the cuffs are released.
13. NIRS: No risk 
14. DEXA: There is a very small chance of cancer from excessive exposure to radiation. However, given the small 
amount of radiation used, this is very unlikely.
15. Blood Lactate: A slight pinch or pinprick when the sterile needle enters the skin. The risks include mild 
discomfort and/or a black and blue mark at the puncture site. Less common risks include infection or bleeding 
at the puncture site, or on rare occasions, dizziness, light-headedness, nausea or fainting during the procedure. 
To minimize the risk of infection, aseptic techniques will be used.
16. PhysioFlow:  Preparation for the PhysioFlow device requires rubbing the skin where patches will be applied with 
an abrasive gel (Nuprep) that will cause some skin irritation and may cause mild inflammation.
17. Order of measurements:  There are no additional risks to omitting or changing the order of the hemodynamic 
measurements in this study.  
18. Risk of incidental finding:  There is a rare risk of an incidental finding. The testing performed during this study 
is intended solely for research purposes and will not be utilized to detect any medical condition. However, if we 
notice something unusual, we will consult one of the cardiologists on the research team to determine if it merits 
follow-up. If so, we will contact the subject within 48 hours and suggest that the subject follow up with their 
private medical provider. To facilitate follow-up care, a copy of the data may be provided upon request. The 
subject will be monitored continuously for adverse effects and the medical personnel will remain in the room 
during the study.
19. There may be risks that are currently unknown.
11.0
Potential Benefits to Subjects and Others 
11.1
Potential Benefits to Subjects
None.
11.2
Potential Benefits to Others
The knowledge gained in this project is likely to have important scientific and clinical implications. We 
expect these studies will provide important insight into blood pressure regulation and exercise tolerance 
in women.
12.0
Sharing Results with Subjects
Our studies are not intended to diagnose or treat a medical condition. If any of the results from the study are 
concerning, one of the research nurses will consult one of the CRC clinicians and then advise the subject to consult 
their own physician and take along a copy of the results.
13.0
Subject Payment and/or Travel Reimbursements
Visit 1) None 
Visit 2) $50 
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Visit 3) $100
14.0
Economic Burden to Subjects
14.1  Costs 
The subjects will not be charged for any of the research procedures included in this study. 
14.2  Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment for 
research-related injury. In the event of injury resulting from this research, medical treatment is available but 
will be provided at the usual charge. Costs for the treatment of research-related injuries will be charged to 
subjects or their insurance carriers.
15.0
Resources Available 
15.1
Facilities and locations
201 Noll Laboratory and the Clinical Research Center (Located in Noll Laboratory, Elmore Wing).  
124 Noll Laboratory (Biological Specimen Processing and Storage Laboratory):  This lab is divided into 
several workstations for processing and long-term storage of blood samples and includes: six -20 
freezers, 1 refrigerator, 1 Forma Scientific Centrifuge, 1 IEC Centra CL2 centrifuge, and a temperature-
controlled Eppendorf 5804-R centrifuge.
All screening/familiarization and study visits will take place in Noll Laboratory's Integrative Vascular 
Physiology Lab (201 Noll Laboratory) and Clinical Research Center (CRC).  All blood sampling (except 
lactate analysis) will be performed at the CRC.  All other experimental procedures will be performed in 
the Vascular Aging and Exercise Lab.
15.2  Feasibility of recruiting the required number of subjects
Dr. Proctor has more than 20 years of experience screening and recruiting younger and older female 
subjects for cardiovascular exercise studies including invasive catheterization. Our lab has successfully 
recruited the required number of premenopausal and postmenopausal women utilizing the same 
recruitment methods. 
15.3  PI Time devoted to conducting the research
The PI will devote approximately 20% effort to this project.
15.4  Availability of medical or psychological resources
These studies will be conducted on the 2nd floor of Noll laboratory.  A CRC clinician will be present during 
infusion and the CRC is located nearby should medical attention be required.
15.5  Process for informing Study Team
The PI will review the protocol with all members of the study team and will communicate regularly in 
person and through email.
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16.0
Other Approvals
16.1      Other Approvals from External Entities
We have received an IND exemption for Esmolol infusion from the FDA.
16.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.  
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens in 
a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or 
gene therapy).
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-
901 - Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This 
form is available in the CATS IRB Library. 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of CRC 
services in any way.
 Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
 Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a 
copy of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form 
is available in the CATS IRB Library.
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or intends 
to hold the IND or IDE.
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research 
Center Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific 
Review Committee is required if the study involves cancer prevention studies or cancer patients, 
records and/or tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator 
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17.0
Multi-Site Research
N/A
18.0
Adverse Event Reporting
18.1
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) experienced 
by a subject or other individual, which in the opinion of the investigator is determined to be (1) 
unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
19.0
Study Monitoring, Auditing and Inspecting
19.1
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the Penn State quality 
assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g., 
pharmacy, diagnostic laboratory, etc.).
20.0
Future Undetermined Research: Data and Specimen Banking
Not applicable.  All specimens will be discarded after assay.
21.0
References
1.
Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise 
training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome. Circulation. 
1999 Mar 9;99(9):1173-82. doi: 10.1161/01.cir.99.9.1173. PMID: 10069785. 
2.
Boulton D, Green S, Macefield VG, Taylor CE. A Comparison of Muscle Sympathetic Nerve Activity to Non-
contracting Muscle During Isometric Exercise in the Upper and Lower Limbs. Front Neurosci. 2019 Apr 9;13:341. 
doi: 10.3389/fnins.2019.00341. PMID: 31024247; PMCID: PMC6465607. 
3.
Chen, S.-L., Hu, Z.-Y., Zhang, J.-J., Ye, F., Kan, J., Xu, T., … Chen, M. (2012). Acute Effects of Nicardipine and Esmolol 
on The Cardiac Cycle, Intracardiac Hemodynamic and Endothelial Shear Stress in Patients With Unstable Angina 
Pectoris and Moderate Coronary Stenosis: Results From Single Center, Randomized Study. Cardiovascular 
Therapeutics, 30(3), 162–171. https://doi.org/10.1111/j.1755-5922.2011.00298.x
4.
Epstein S, Robinson BF, Kahler RL, Braunwald E. Effects of beta-adrenergic blockade on the cardiac response to 
maximal and submaximal exercise in man. J Clin Invest. 1965 Nov;44(11):1745-53. doi: 10.1172/JCI105282. 
PMID: 5843708; PMCID: PMC289674.
5.
Fadel PJ, Wang Z, Watanabe H, Arbique D, Vongpatanasin W, Thomas GD. Augmented sympathetic 
vasoconstriction in exercising forearms of postmenopausal women is reversed by oestrogen therapy. J Physiol. 
2004 Dec 15;561(Pt 3):893-901. doi: 10.1113/jphysiol.2004.073619. Epub 2004 Oct 21. PMID: 15498809; 
PMCID: PMC1665388.
6.
Hamer J, Sowton E. Cardiac output after beta-adrenergic blockade in ischaemic heart disease. Br Heart J. 
1965;27(6):892-895. doi:10.1136/hrt.27.6.892
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7.
Harvey, R. E., Hart, E. C., Charkoudian, N., Curry, T. B., Carter, J. R., Fu, Q., … Barnes, J. N. (2015). Oral 
Contraceptive Use, Muscle Sympathetic Nerve Activity, and Systemic Hemodynamics in Young Women. 
Hypertension, 66(3), 590–597. https://doi.org/10.1161/HYPERTENSIONAHA.115.05179
8.
Hearon CM Jr, Dinenno FA. Regulation of skeletal muscle blood flow during exercise in ageing humans. J Physiol. 
2016 Apr 15;594(8):2261-73. doi: 10.1113/JP270593. Epub 2015 Nov 2. PMID: 26332887; PMCID: PMC4933119.
9.
Hughson RL, Tschakovsky ME. Cardiovascular dynamics at the onset of exercise. Med Sci Sports Exerc. 1999 
Jul;31(7):1005-10. doi: 10.1097/00005768-199907000-00013. PMID: 10416562.
10. Iannetta D, Inglis EC, Pogliaghi S, Murias JM, Keir DA. A "Step-Ramp-Step" Protocol to Identify the Maximal 
Metabolic Steady State. Med Sci Sports Exerc. 2020 Sep;52(9):2011-2019. doi: 
10.1249/MSS.0000000000002343. PMID: 32205678.
11. Kaiser, P., Tesch, P. A., Frisk-Holmberg, M., Juhlin-Dannfelt, A., & Kaijser, L. (1986). Effect of beta 1-selective and 
non-selective beta-blockade on work capacity and muscle metabolism. Clin Physiol,6(2),197–207.
12. Lalande S, Sawicki CP, Baker JR, Shoemaker JK. Effect of age on the hemodynamic and sympathetic responses at 
the onset of isometric handgrip exercise. J Appl Physiol (1985). 2014 Jan 15;116(2):222-7. doi: 
10.1152/japplphysiol.01022.2013. Epub 2013 Dec 12. PMID: 24336882; PMCID: PMC3921359.
13. Limberg, J. K., Peltonen, G. L., Johansson, R. E., Harrell, J. W., Kellawan, J. M., Eldridge, M. W., … Schrage, W. G. 
(2016). Greater beta-adrenergic receptor mediated vasodilation in women using oral contraceptives. Frontiers in 
Physiology, 7(JUN), 1–8. https://doi.org/10.3389/fphys.2016.00215
14. Muller, M. D., Ahmad, T. A., Vargas Pelaez, A. F., Proctor, D. N., Bonavia, A. S., Luck, J. C., … McQuillan, P. M. 
(2017). Esmolol infusion versus propranolol infusion: effects on heart rate and blood pressure in healthy 
volunteers. Journal of Applied Physiology, 122(3), 511–519. https://doi.org/10.1152/japplphysiol.00940.2016
15. Pawelczyk JA, Hanel B, Pawelczyk RA, Warberg J, Secher NH. Leg vasoconstriction during dynamic exercise with 
reduced cardiac output. J Appl Physiol (1985). 1992 Nov;73(5):1838-46. doi: 10.1152/jappl.1992.73.5.1838. 
PMID: 1474060.
16. Pirnay, F. , Lamy M., Dujardin J., Doroanne R., and Petit J. M.. 1972. Analysis of femoral venous blood during 
maximum muscular exercise. J. Appl. Physiol. 33:289–292.
17. Poole DC, Behnke BJ, Musch TI. The role of vascular function on exercise capacity in health and disease. J 
Physiol. 2021 Feb;599(3):889-910. doi: 10.1113/JP278931. Epub 2020 Mar 3. PMID: 31977068; PMCID: 
PMC7874303.
18. Poole DC, Hirai DM, Copp SW, Musch TI. Muscle oxygen transport and utilization in heart failure: implications 
for exercise (in)tolerance. Am J Physiol Heart Circ Physiol. 2012 Mar 1;302(5):H1050-63. doi: 
10.1152/ajpheart.00943.2011. Epub 2011 Nov 18. PMID: 22101528; PMCID: PMC3311454.
19. Proctor DN, Koch DW, Newcomer SC, Le KU, Leuenberger UA. Impaired leg vasodilation during dynamic exercise 
in healthy older women. J Appl Physiol (1985). 2003 Nov;95(5):1963-70. doi: 10.1152/japplphysiol.00472.2003. 
Epub 2003 Jul 25. PMID: 12882993.
20. Proctor, D. N., Luck, J. C., Maman, S. R., Leuenberger, U. A., & Muller, M. D. (2018). Esmolol acutely alters oxygen 
supply-demand balance in exercising muscles of healthy humans. Physiological Reports, 6(8), 1–9. 
https://doi.org/10.14814/phy2.13673
21. Proctor DN, Newcomer SC, Koch DW, Le KU, MacLean DA, Leuenberger UA. Leg blood flow during submaximal 
cycle ergometry is not reduced in healthy older normally active men. J Appl Physiol (1985). 2003 
May;94(5):1859-69. doi: 10.1152/japplphysiol.00898.2002. Epub 2003 Jan 24. PMID: 12547841.
22. Rossiter HB. Exercise: Kinetic considerations for gas exchange. Compr Physiol. 2011 Jan;1(1):203-44. doi: 
10.1002/cphy.c090010. PMID: 23737170.
23. Saltin B, Mortensen SP. Inefficient functional sympatholysis is an overlooked cause of malperfusion in 
contracting skeletal muscle. J Physiol. 2012 Dec 15;590(24):6269-75. doi: 10.1113/jphysiol.2012.241026. Epub 
2012 Sep 17. PMID: 22988143; PMCID: PMC3533189.
24. Watanabe H, Watanabe K, Wadazumi T, Yoneyama F. Effect of exercise intensity on mild rhythmic-handgrip-
exercise-induced functional sympatholysis. J Physiol Anthropol. 2007 Nov;26(6):593-7. doi: 
10.2114/jpa2.26.593. PMID: 18174667.
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22.0 Confidentiality, Privacy and Data Management
22.1
Which of the following identifiers will be recorded for the research project? Check all that apply. If none of 
the following identifiers will be recorded, do not check any of the boxes.
Hard 
Copy 
Data
Electronic 
Stored 
Data 
Names and/or initials (including on signed consent documents)
 
All geographic subdivisions smaller than a State, including street address, city, county, precinct, zip 
code, and their equivalent geocodes,
 
All elements of dates (except year) for dates directly related to an individual, including birth date, 
admission date, discharge date, date of death; and all ages over 89 and all elements of dates 
(including year) indicative of such age, except that such ages and elements may be aggregated into 
a single category of age 90 or older
 
Telephone numbers
 
Fax numbers
 
Electronic mail addresses
 
Social security numbers
 
Medical record numbers
 
Health plan beneficiary numbers
 
Account numbers
 
Certificate/license numbers
 
Vehicle identifiers and serial numbers, including license plate numbers
 
Device identifiers and serial numbers
 
Web Universal Resource Locators (URLs)
 
Internet Protocol (IP) address numbers
 
Biometric identifiers, including finger and voice prints
 
Full face photographic images and any comparable images
 
Any other unique identifying number, characteristic, or code (such as the pathology number)
 
Study code number with linking list
 
Genomic sequence data
State ID numbers
Passport numbers
Driver’s license numbers
22.2
If storing paper records of research data, answer the following questions:
22.2.1 Where will the paper records, including copies of signed consent forms, associated with this 
research study will be stored?
Noll 201
22.2.2 How will the paper records be secured? 
Locked in filing cabinets
22.2.3 How will access to the paper records be restricted to authorized project personnel?
Only member of the Integrative and Vascular Physiology Laboratory will have access to the key 
for the locked filing cabinets.
22.3
If storing electronic records of research data, indicate where the electronic data associated with this 
research study will be stored. Check all that apply.       
 Penn State-provided database application.  Check which of the following database applications 
are being used (check all that apply):
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  Penn State REDCap  
  Other – Specify - provided and approved database application: 
     
      
  Penn State, College, or Department IT file server 
       
  Box.psu.edu (To be retired Sept. 2021; see https://storage.psu.edu/)      
  Web-based system provided by the sponsor or cooperative group - Specify URL and contact 
information: 
     
       
  Other – Specify the database application or server:
     
Provide details about the data security features or attach security documentation provided 
by sponsor or group:
     
22.4
Is there a list/key that links code numbers to identifiers? 
  Yes - explain how the list that links the code to identifiers is stored separately from coded data:
The list linking the code to identifiers is maintained by the CRC.
 Not applicable, there is no list that links code numbers to identifiers. Skip to section 22.6.
22.5
Is there a list of people who have access to the list/key?
  Yes – explain how access to that list is restricted and why certain persons require access.
Access to the list is maintained by the CRC
  No – explain why not:
     
22.6
Describe the mechanism in place to ensure only approved research personnel have access to the 
stored research data (electronic and paper).
  Password-protected files
  Role-based security 
  Specify all other mechanisms used to ensure only permitted users have access to the stored 
research data.
     
22.7
Will any research data (such as survey data) be collected on a mobile device, such as an electronic 
tablet, cell phone, or wireless activity tracker? 
 No
 Yes - answer the following questions:
22.7.1 Specify the provider of the mobile devices(s)
 Supplied by the sponsor
 Penn State owned device
 A personal device
 Other – Please specify source:      
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22.7.2 Specify the type(s) of mobile device(s) that will be used to capture data and all identifiers 
captured on the mobile device(s). Please list all devices, and if more than one, the identifiers 
to be collected on each.
     
22.7.3 Specify the type of data collected on the mobile devices(s). 
     
22.7.4 Specify the application or website used to collect the data from the mobile device, if 
applicable.
     
22.7.5 Describe the measures taken to protect the confidentiality of the data collected on mobile 
device(s). Please address physical security of the device(s), electronic security, and secure 
transfer of data from device(s) to the previously indicated data/file storage location provided 
in section 22.3.
     
22.8
Will any research data be directly entered/sent by subjects over the internet or via email (e.g., data 
capture using on-line surveys/questionnaires, surveys via email, observation of chat rooms or blogs)?
 No
 Yes - answer the following questions:
22.8.1 Specify the identifiers collected over the internet or via email (Including IP addresses if IP 
addresses will be collected).
     
22.8.2 Specify the type of data collected over the internet or via email.
     
22.8.3 Describe the measures taken to protect the confidentiality of the data collected?
     
22.8.4 Describe how the research team will access the data once data collection is complete.
     
22.8.5 If the research involves online surveys, list the name(s) of the service provider(s) that will be 
used for the survey(s) (e.g., REDCap, Penn State licensed Qualtrics, Survey Monkey, 
Zoomerang)? (Note: The IRB strongly recommends the use of REDCap for online surveys that 
obtain sensitive identifiable human subjects data.)
 Penn State REDCap
 Penn State Qualtrics (de-identified data only)
 Other - Please specify:
Application:      
URL (If applicable):       
22.8.6 If the answer above is “Other” contact security@psu.edu for approval of an alternative data 
capture method
     
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22.9
Will any type of recordings (e.g., audio or video) or photographs of the subjects be made during this 
study?
 No - skip to section 22.10
 Yes - answer the following questions:
22.9.1 What will be used to capture the audio/video/images? Give a brief description of content.
 Audio – Describe the intended content of the audio recording:
     
 Video – Describe the intended content of the video recording:
     
 Photographs of the subjects – Describe the intended content of the photographs:
     
 3-D Images – Describe the intended content of the of 3-D images:
      
 Other - Specify: 
     
22.9.2 How will the recordings/photographs/images be stored (electronically or physically)?
22.9.3 Where will the recordings/photographs/images be stored?
     
22.9.4 Who will have access to the recordings/photographs/images?
     
22.9.5 Will any of the recordings be transcribed?
 Not applicable
 No
 Yes – indicate who will be doing the transcribing? 
     
22.9.6 Will the recordings/photographs be used for purposes other than this research study?
 No
 Yes - specify purpose(s) (e.g., publication, presentations, educational training, future
 undetermined research):
     
22.10
Certificate of Confidentiality (COC) - Is the research biomedical, behavioral, clinical or other research 
that is funded by the National Institutes of Health (NIH)?
 Yes - check one of the following: 
  The research involves human subjects as defined by the DHHS regulations (See Worksheet 
HRP-310).
  The research involves collecting or using biospecimens that are identifiable to an individual.
  If collecting or using biospecimens as part of the research, there is a small risk that some 
combination of the biospecimen, a request for the biospecimen, and other available data 
sources could be used to deduce the identity of an individual.
  The research involves the generation of individual level, human genomic data.
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Note:  If any of the 4 items above are checked, a COC is automatically issued by NIH and 
applies to the research. Information about the COC must be included in the consent form.
 No - answer the following question.
If the research is not funded by NIH, will the investigator apply for a COC for this research study? 
 No
 Yes
Note:  For research not funded by NIH, the IRB may require a COC if the research is collecting 
personally identifiable information and the information is sensitive and/or the research is 
collecting information that if disclosed could significantly harm or damage the subject. 
22.11
What steps will be taken to protect subjects’ privacy interests? (Check all that apply.)
  Identification and recruitment of potential subjects follows procedures consistent with privacy 
standards
  Consent discussion and research interventions will take place in a private setting
  Limiting the information being collected to only the minimum amount of data necessary to 
accomplish the research purposes 
  Limiting the people with access to the identifiable research data to the minimum necessary as 
specified in the application and consent process
  Other – Specify: 
     
22.12
What is the process for ensuring correctness of data entry?
  Double data entry to reduce risk of errors
  Electronic edit checks to ensure data being entered are not obviously incorrect
  Random internal quality and assurance checking of research data
  Direct entry by subjects
  Other - Specify: 
     
22.13
Does this research involve the generation of large-scale human genomic data as defined in NIH 
Genomic Data Sharing Policy (http://gds.nih.gov)?
  No
  Yes – If Yes, describe the plan for de-identifying the dataset before sharing it with NIH-designated 
data repositories. 
     
22.14
The European Union (EU) General Data Protection Regulation (GDPR) 
22.14.1 To determine if the research is subject to the GDPR answer the following questions:
22.14.1.1
Will the Penn State principal investigator, or another entity under the 
Penn State principal investigator’s direction, be collecting, recording, 
storing, using, any personal data* of any subjects physically located in the 
European Economic Area (EEA)** at the time of data collection (even if the 
subject is NOT an EEA resident) or any EEA citizens? (This includes 
recruitment through social media sites, use of third party internet sites, 
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mobile devices or apps to collect data, and/or direct receipt of data from 
subjects.)
  No
  Yes (This research may be subject to the GDPR)
22.14.1.2
Does this research involve the transfer of personal data collected under 
the GDPR from an EEA country? (This includes direct transfer of data from 
research collaborators.)
  No
  Yes (This research may be subject to the GDPR)
22.14.2 If the research may be subject to the GDPR as indicated in the answers to the questions 
above, answer the following:
22.14.2.1
Will any of the data fall into one of the following categories: health data, 
racial or ethnic origin, political opinions, religious or philosophical beliefs, 
trade union membership, genetic data, biometric data used for purpose of 
identifying an individual, sex life or sexual orientation?
  No
  Yes
22.14.2.2
Will any of the data be related to criminal convictions or offenses?
  No
  Yes
Comments on any of the above responses:
     
* “Personal data” means any information relating to an identified or identifiable natural person; an identifiable 
natural person is one who can be identified, directly or indirectly, by reference to an identifier such as a name, an 
identification number, location data, an online identifier or to one or more factors specific to the physical, 
physiological, genetic, mental, economic, cultural or social identity of that natural person.
** European Economic Area (EEA) – Includes the 28-member states of the European Union (Austria, Belgium, 
Bulgaria, Croatia, Republic of Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, 
Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, 
Slovenia Spain, Sweden, UK) and Norway, Iceland, Lichtenstein. 
22.15
Does this research involve transfer or disclosure of data and/or specimens to and/or from Penn State?
  No - skip the rest of section 22.15.
  Yes - answer the following questions.
Check all that apply:
 Data are being transferred or disclosed to Penn State 
What is the name of the third party(ies) (the institution, sponsor, etc.) sending or providing the 
data?
     
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Is the third party requiring us to sign a contract regarding the data? 
 Yes - If Yes, this contract must go through the Office of Sponsored Programs 
https://www.research.psu.edu/osp/overview-pages/data-use-agreements
 No
 Data are being transferred or disclosed from Penn State 
What is the name(s) of the third party(ies) (the institution, sponsor, etc.) receiving or accessing 
the data?
     
Note: Data transfers or disclosures may require a Data Use Agreement (DUA).
 Specimens are being transferred to Penn State 
What is the name(s) of the third party(ies) (the institution, sponsor, etc.) sending the specimens?
     
 Specimens are being transferred from Penn State 
What is the name(s) of the third party(ies) (the institution, sponsor, etc.) receiving the specimens? 
     
Note: All material transfers, either sending or receiving, require a Material Transfer Agreement 
(MTA).  Please contact the Office of Technology Management for more information. 
22.15.1 Describe how the data/specimens will be securely transferred or disclosed to/from the third 
party(ies).
       
22.15.2 How are the research data/specimens being transferred from and/or sent to the third 
party(ies)? Complete the appropriate section(s) and check all that apply within each 
completed section.
22.15.2.1
Data being transferred or disclosed to Penn State:
  Data are being received in aggregate/metrics (just counts, no individual 
data)
  De-identified individual data are being received and there is no linking 
list at either institution (no identifiers, or links to identifiers, such as code 
numbers)
  Coded research data without any identifiers are being received and the 
linking list remains with the entity sending the data; the recipient of the 
data will not have access to the linking list
  Coded research data with identifiers (such as dates and/or any of the 
identifiers listed in section 22.15.3 aside from Study Code) are being 
received and the linking list remains with the entity sending the data; the 
recipient of the data will not have access to the linking list 
  Data with identifiers (such as dates and/or any of the identifiers listed in 
section 22.15.3) are being received and the linking list remains with the 
entity sending the data; the recipient of the data will have access to the 
linking list 
  Data with identifiers along with the linking list are being received 
  Other – Specify: 
     
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22.15.2.2
Data being transferred or disclosed from Penn State:
  Data are being sent in aggregate/metrics (just counts, no individual data)
  De-identified individual data are being sent and there is no linking list at 
either institution (no identifiers, or links to identifiers, such as code 
numbers)
  Coded research data without any identifiers are being sent and the linking 
list remains with the entity sending the data; the recipient of the data will 
not have access to the linking list
  Coded research data with identifiers (such as dates and/or any of the 
identifiers listed in section 22.15.3 aside from Study Code) are being sent 
and the linking list remains with the entity sending the data; the recipient 
of the data will not have access to the linking list 
  Data with identifiers (such as dates and/or any of the identifiers listed in 
section 22.15.3) are being sent and the linking list remains with the entity 
sending the data; the recipient of the data will have access to the linking 
list 
  Data with identifiers along with the linking list are being sent
  Other – Specify: 
     
22.15.2.3
Specimens being transferred or disclosed to Penn State:
  De-identified specimens are being received and there is no linking list at 
either institution (no identifiers, or links to identifiers, such as code 
numbers)
  Coded specimens without any identifiers are being received and the 
linking list remains with the entity sending the specimens; the recipient 
of the specimens will not have access to the linking list
  Coded specimens with identifiers (such as dates and/or any of the 
identifiers listed in section 22.15.3 aside from Study Code) are being 
received and the linking list remains with the entity sending the 
specimens; the recipient of the specimens will not have access to the 
linking list 
  Coded specimens with identifiers (such as dates and/or any of the 
identifiers listed in section 22.15.3) are being received and the linking list 
remains with the entity sending the specimens; the recipient of the 
specimens will have access to the linking list 
  Coded specimens with identifiers along with the linking list are being 
received 
  Other – Specify: 
     
22.15.2.4
Specimens being transferred or disclosed from Penn State:
  De-identified specimens are being sent and there is no linking list at 
either institution (no identifiers, or links to identifiers, such as code 
numbers)
  Coded specimens without any identifiers are being sent and the linking 
list remains with the entity sending the specimens; the recipient of the 
specimens will not have access to the linking list
  Coded specimens with identifiers (such as dates and/or any of the 
identifiers listed in section 22.15.3 aside from Study Code) are being 
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sent and the linking list remains with the entity sending the specimens; 
the recipient of the specimens will not have access to the linking list 
  Coded specimens with identifiers (such as dates and/or any of the 
identifiers listed in section 22.15.3) are being sent and the linking list 
remains with the entity sending the specimens; the recipient of the 
specimens will have access to the linking list 
  Coded specimens with identifiers along with the linking list are being 
sent 
  Other – Specify: 
     
22.15.3 If transferring data/specimens with identifiers to or from Penn State, which of the following identifiers will 
be included with the data/specimens? Check all that apply:
 Names
 Medical record numbers 
 Initials
 Health plan beneficiary numbers 
 Street address 
 Account numbers 
 City
 Certificate/license numbers
 Driver’s License numbers
 Passport numbers
 State
 State ID numbers
 Zip Codes  
 Vehicle identifiers and serial numbers, including license plate numbers 
 County
 Device identifiers and serial numbers 
 Geocodes
 Web Universal Resource Locators (URLs)
 Precincts
 Internet Protocol (IP) address numbers
 All elements of dates (except year) for dates 
directly related to an individual, including birth date, 
admission date, discharge date, date of death 
 Biometric identifiers, including finger and voice prints
 Ages > 89 and all elements of dates (including 
year) indicative of such age, except that such ages 
and elements may be aggregated into a single 
category of age 90 or older 
 Full face photographic images and any comparable images 
 Telephone numbers
 Any other unique identifying number, characteristic, or code (such as 
the pathology number)
Specify:      
 Fax numbers
 Study code numbers 
 Electronic mail addresses
 Master list linking study code numbers to subject(s)
 Social security numbers
 Genomic sequence data
 Other – specify:      
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ICF_001.pdf: 
Version Date: 01/28/2022
Page 1 of 11 (v.12/19/2018)
STUDY 00010736
CONSENT FOR RESEARCH
The Pennsylvania State University 
Title of Project:  Age Comparisons of Exercising Muscle O2 Supply in Healthy Adults:  Effects of Esmolol 
Infusion
Principal Investigator: 
David N. Proctor, PhD
Address: 
105 Noll Laboratory
Penn State University
University Park, PA  16802
Telephone Numbers: 
Weekdays: 8:00 a.m. to 5:00 p.m., (814) 571-5234 or (814) 863-0724 
Subject’s Printed Name: _____________________________
We are asking you to be in a research study.
Whether or not you take part is up to you. You can choose not to take part. You can agree to take part 
and later change your mind. Your decision will not be held against you, and there will be no penalty or 
loss of benefits to which you are entitled.
This form gives you information about the research. Please ask questions about anything that is 
unclear to you and take your time to make your choice.
KEY INFORMATION  
The following is a short summary of this study to help you decide whether or not to be a part of this 
research.  More detailed information is provided later in this form. If you have any questions, be sure to 
ask the study team. 
Why am I being invited to take part in this research study?
We invite you to take part in a research study because we want to understand how the leg muscles use 
oxygen during exercise.
What is the purpose of this research study?
The purpose of this voluntary research study is to quantify how blood pressure and muscle oxygen delivery 
are controlled during exercise in young and older women.  By using a specific medication that blocks the “fight 
or flight response” during exercise, we will determine how the human body controls this process.
How long will the research study last?
You will come to the laboratory three times and each visit will take 3 to 4.5 hours. 
What will I need to do?   
For this study, you will be asked to perform bicycle exercise and handgrip exercise on several occasions while 
we measure your breathing, blood pressure, heart rate, and leg muscle oxygen level.  During one session, you 
will receive an infusion of esmolol (a heart rate lowering medication) into an arm vein. 
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What are the main risks of taking part in the study?
For this study, the main risks to know about are:  fatigue and leg muscle discomfort due to the bicycle 
exercise, forearm soreness from the handgrip exercise, and soreness and bruising from the infusion of 
esmolol (a heart rate lowering medication) into an arm vein.
What are the possible benefits to me that may reasonably be expected from being in the research? 
There are no benefits to you from taking part in this research. Results of the study may benefit other people 
in the future by helping us learn more about how to body controls blood pressure and leg blood flow during 
exercise.
What happens if I do not want to be in this research?
Participation in research is completely voluntary. You can decide to participate or not to participate. 
DETAILED INFORMATION
The following is more detailed information about this study in addition to the information listed above.
1.   Why is this research study being done?   
This research is being done to find out how age affects oxygen delivery during exercise in women 
when the amount of blood their heart can pump is reduced. To do this, we will infuse an FDA 
approved drug called esmolol (through an arm vein) which temporarily blocks beta-1 receptors 
(receptors in the heart which are involved in the “fight or flight response”) during recumbent cycling 
exercise. 
   
Approximately 28 people will take part in this research study in the State College area. 
2.   What will happen in this research study?
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Visit 1 (screening visit) 
You will be asked to avoid alcohol, over the counter cold prep and NSAIDs, and strenuous exercise for 
24 hours, and to eat a small meal 2-3 hours prior to coming to the laboratory. You will also be asked 
to refrain from items containing caffeine 12 hours prior to this visit. For your safety, you must tell the 
study doctor or nurse about all the prescription drugs, herbal products, over-the-counter drugs (OTC), 
vitamins and other supplements you are taking.  Check with the study doctor before starting any new 
medicines (including prescription, OTC drugs, vitamins and herbal supplements) or changing doses of 
medications that you are already taking.
Women who are currently taking hormone therapy of any kind (oral contraceptives, estrogen 
replacement, etc) will not be excluded from participation in this study.  However, we will ask 1) pre-
menopausal women to indicate their current menstrual status and oral contraceptive use and 2) post-
menopausal women to self-report their history and duration of sex hormone replacement.  This 
information will be collected at the time of your medical history/physical exam.
During this first visit, you will be given sufficient time to read this consent form and ask questions.  If 
you are a woman of childbearing potential (pre-menopausal), you will take a urine pregnancy test to 
ensure you are not pregnant.  Your participation in this research will end if you test positive. Medical 
personnel will then perform a brief physical examination and you will then complete a medical history 
questionnaire and a physical activity history questionnaire. While filling out these questionnaires, you 
are free to skip any questions you would prefer not to answer. A venous blood draw will then be 
performed (7.5 mL total) by a CRC nurse and sent for analysis to ensure your blood cell counts and 
kidney and liver function are within normal limits before continuing the study. This will be followed 
by measurements of your height, weight, waist circumference, blood pressure and a resting EKG 
(tracing of your heart electrical activity). During this first study visit, you will also be asked to squeeze 
a handgrip device as hard as you can 3 times, with approximately 1 minute of rest between each.  
After a short recovery, you will then be asked to squeeze the handgrip device for approximately 90 
seconds at 40% of your maximum effort. Immediately after, we will ask you how difficult you found 
the 40% grip task using a rating of perceived effort scale. 
You will then lay on an exam bed for placement of EKG pads and a doppler ultrasound device will be used 
to determine skinfold thickness of your thigh. NIRS sensors will then be placed (one on the forearm, one 
on the forehead, and two on the leg). You will then be assisted onto the recumbent bike. A silicone face 
mask will be placed over your nose and mouth to monitor your oxygen consumption and breathing 
frequency, and blood pressure devices will be placed over your arm (SunTech Tango) and finger 
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2 min
5 min
5 min
1-2 min
(Finometer). After all instrumentation is in place, baseline measurements of heart rate, cardiac output, 
oxygen consumption, blood pressure, and NIRS will begin.
You will then be asked to complete three exercise bouts on a recumbent (feet behind the pedals) 
bike.  The first bout will consist of very light pedaling for 2 minutes (warm-up) followed by approximately 
6 minutes of pedaling at what should be a moderate effort for you.  After a few minutes of rest and/or 
light pedaling (recovery), you will be asked to perform a second bout of exercise, which will consist of a 
very gradual increase in workload (“ramp”) until you can no longer maintain the required pedal speed or 
need to stop due to fatigue.  This second bout will likely last between 6 and 12 minutes.  After a few 
minutes of light pedaling, we will remove your face mask and let you recover in a comfortable chair.  After 
30 minutes of recovery, we will assist you back on the bike and will reattach your facemask.  We will then 
have you pedal for 2 minutes at a very light workload, followed immediately by up to 12 minutes of 
pedaling at moderately heavy workload.  After a brief cool-down of light pedaling, we will remove the 
facemask and other sensors (e.g., EKG, NIRS, etc).  At several points throughout this visit (minimum of 3, 
maximum of 6) we will collect a small drop of blood from your fingertip to measure the level of lactate in 
your blood.  The measurements obtained during this first study visit will determine the exercise 
workloads that will individually selected for you during study visits 2 and 3.  
Analysis of the blood tests, EKG and medical history/exam results, and your tolerance to the handgrip 
and cycling exercise will collectively determine if you are eligible to continue the study. Eligible 
participants will be asked to return to the CRC for two experimental visits (non-infusion visit and infusion 
visit) at least 48 hours apart. Visit 1 will take up to 3 hours to complete.
Visit 2 (non-infusion)
As with the screening visit, you will be told to avoid alcohol, over the counter cold prep and NSAIDs, and 
strenuous exercise for 24 hours, and to eat a small meal 2-3 hours prior to coming to the laboratory. 
Women of childbearing potential (pre-menopausal) will take a urine pregnancy test to ensure they are 
not pregnant. 
You will then be asked to lay still while you are scanned with a Dual-energy X-ray absorptiometry (DEXA) 
device to determine your body composition (fat, muscle, bone). 
Then you will lay on an exam bed for placement of EKG pads and near-infrared sensors (NIRS) will be 
taped over a forearm muscle, your forehead, and two leg muscles (thigh and calf).
We will then assist you onto the recumbent bike. After repeating your peak grip strength test from visit 
1, a silicone face mask will be placed over your nose and mouth to monitor your breathing. A blood 
pressure cuff will be placed over your arm and a small blood pressure device will be placed on a finger. 
After all instrumentation is in place, baseline measurements will begin.
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All measurements will continue to be collected throughout the exercise trials. Once these 
measurements have stabilized, you will be asked to squeeze the handgrip device at 40% of the 
maximum force during the maximum grip testing for 1 to 2 minutes. Once all measurements have 
returned to baseline, you will then begin the cycling exercise protocol (see figure above). You will 
be asked to pedal for 2 minutes at a very light intensity, followed immediately by 5 minutes of 
cycling at a light intensity, and 5 minutes of cycling at a moderate intensity. Finally, the you will 
continue cycling at the same intensity for 1 to 2 minutes while simultaneously squeezing a 
handgrip device at 40% of your maximal effort. You will then rest for 45 mins, after which you will 
repeat the exercise protocol. Immediately following the second exercise bout, cuffs will be placed 
on the upper arm and on the upper thigh of the limbs with the NIRS probes attached. The cuffs 
will then be inflated to ~250 mmHg until the limbs have been completely deoxygenated 
(approximately ~5 minutes).
At least three lactate measurements will be collected during each trial (6 total); one during rest, 
one after 4 mins of light intensity exercise, and one after 4 mins of moderate intensity exercise.
  
After the recovery period, most instrumentation will be removed (except for the blood pressure 
cuffs and EKG). You will then be asked to sit up slowly and will be offered juice and crackers.  Once 
your blood pressure and heart rate have returned to normal, we will remove the remaining 
monitoring equipment and you may leave. Visit 2 will take up to 3.5 hours to complete.
Visit 3 (Infusion)
As with the previous visits, you will be told to avoid alcohol, over the counter cold prep and NSAIDs, 
and strenuous exercise for 24 hours, and to eat a small meal 2-3 hours prior to coming to the 
laboratory.  You will also be asked to refrain from items containing caffeine 12 hours prior to this visit. 
Women of childbearing potential (pre-menopausal) will take a urine pregnancy test to ensure they 
are not pregnant.  Then you will lay on an exam bed for initial instrumentation (placement of EKG 
pads and blood pressure cuffs) and measurement of vital signs.  A nurse will then insert a catheter 
into one of your arm veins.  This catheter will be used to infuse the drug (Esmolol or saline) and to 
withdraw a blood sample at the beginning and end of the study. 
Final instrumentation will include 1) placing a silicone face mask over your nose and mouth to 
monitor your oxygen consumption and breathing frequency, and 2) taping a near-infrared sensors 
(NIRS) over your forearm muscle, on your forehead, over a thigh muscle and over one of your calf 
muscles.
After all instrumentation is in place, you will be seated on the recumbent ergometer and baseline 
measurements of heart rate, cardiac output, oxygen consumption, blood pressure, and NIRS will 
begin.
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A CRC clinician will join the research team immediately before it is time to start the infusion. The 
CRC clinician will be able to review the EKG results at that time if there are any concerns.  You will 
then be randomly assigned to one of two treatment orders. You will either receive an infusion of 
esmolol during the first exercise trial and saline during the second trial or you will receive and 
infusion of saline during the first trial and esmolol during the second trial. Neither you nor the 
research team will know which treatment order you have been assigned until after all participants 
have completed the study. Only the clinician operating the infusion pump will know your 
treatment order. Esmolol dose will be based on your fat free mass (determined by DEXA).
All measurements will continue to be collected throughout the exercise protocol. Once these 
measurements have stabilized (approximately 10 minutes into the infusion), you will be asked to 
squeeze the handgrip device at 40% of your maximum force for 1 to 2 minutes. Once all 
measurements have returned to baseline, you will then begin the cycling exercise protocol. You 
will be asked to pedal for 2 minutes at a very light intensity, followed immediately by 5 minutes 
of cycling at a light intensity, and 5 minutes of cycling at a moderate intensity. Finally, you will 
continue cycling at the same intensity for 1 to 2 minutes while simultaneously squeezing a 
handgrip device at 40% of your maximal effort. Once the infusion stops, the IV line will be flushed. 
You will then rest for 45 mins, after which you will repeat the exercise protocol while receiving 
the second infusion (esmolol or saline). Immediately following the second exercise bout, a cuff 
will be placed on your upper arm and upper thigh of the limbs with the NIRS probes attached. The 
cuffs will then be inflated to ~250 mmHg until your limbs have been completely deoxygenated 
(approximately 5 minutes).
  
After the recovery period, most instrumentation will be removed (except for the blood pressure 
cuffs and EKG).  You will then sit up slowly and will be offered juice and crackers.  Once your blood 
pressure and heart rate have returned to normal, we will remove the remaining monitoring 
equipment and you may leave. Visit 3 will take up to 4.5 hours to complete.
What are your responsibilities if you take part in this research? 
For your safety, you must tell the study doctor or nurse about all the prescription drugs, herbal 
products, over-the-counter drugs (OTC), vitamins and other supplements you are taking.  Check with 
the study doctor before starting any new medicines (including prescription, OTC drugs, vitamins and 
herbal supplements) or changing doses of medications that you are already taking.
3.   What are the risks and possible discomforts from being in this research study?  

Confidentiality: There is a risk of loss of confidentiality if your information or your identity is 
obtained by someone other than the investigators, but precautions will be taken to prevent this 
from happening. The confidentiality of your electronic data created by you or by the researchers 
will be maintained to the degree permitted by the technology used. Absolute confidentiality 
cannot be guaranteed.

Pregnancy: It is important that a fetus not be exposed to any unnecessary risks; therefore, 
pregnant women will not be studied. A urine pregnancy test will be administered at the 
beginning of all experimental visits to all women of childbearing potential to ensure they are not 
pregnant.
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
Blood pressure, heart rate: Minimal risk of skin irritation from EKG patches.

Oxygen Consumption: No risk

IV placement: The discomfort associated with a blood draw/IV placement is a slight pinch or 
pinprick when the sterile needle enters the skin. The risks of a blood draw include mild 
discomfort and/or a black and blue mark at the puncture site. Less common risks include 
infection or bleeding at the puncture site, or on rare occasions, dizziness, light-headedness, 
nausea or fainting during the procedure. To minimize the risk of infection, aseptic techniques 
will be used.

Esmolol infusion: The risks stated by the manufacturer include heart block, hypotension, 
injection site pain, nausea, seizure, bronchospasm, allergic reaction, infusion site reaction, or 
extravasation (leaking of infusion into tissue around the IV site which may cause tissue death).  
However, in our experience these symptoms have never occurred in our research participants. 
The infusion will end if HR falls by more than 20 beats/min or below 40 beats/min or symptoms 
occur, or if symptomatic hypotension occurs (mean blood pressure drop of more than 20mmHg 
and/or symptoms). If extravasation would occur, we would proceed as follows: 
o
Stop infusion
o
Apply warm compress over the catheter site 
o
Elevate the arm
o
Observe/monitor for at least 45 minutes (i.e. 5 half-lives for Esmolol)
o
Call subject within 24 hours

Saline infusion:  no risk

Skinfold of the forearm and leg to measure fat thickness:  No risk

Recumbent cycling exercise:  Cycling exercise will cause fatigue, shortness of breath, elevated 
body temperature and muscle fatigue. Could also cause chest discomfort and/or dehydration. 
These effects typically disappear shortly after exercise.

Isometric handgrip exercise: Handgrip exercise will cause fatigue in the forearm. This may be 
associated with a burning sensation in the forearm and possible muscle soreness after the test.

Post exercise occlusion:  The upper arm and upper leg cuff occlusions may result in a tingling or 
burning sensation in the limbs.  This will subside once the cuffs are released.

NIRS: No risk 

DEXA: There is a very small chance of cancer from exposure to radiation. However, given the 
small amount of radiation used, this is very unlikely.

Finger blood lactate measurement: A slight pinch or pinprick when the sterile needle enters the 
skin. The risks include mild discomfort and/or a black and blue mark at the puncture site. Less 
common risks include infection or bleeding at the puncture site, or on rare occasions, dizziness, 
light-headedness, nausea or fainting during the procedure. To minimize the risk of infection, 
aseptic techniques will be used.
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
PhysioFlow: Preparation for the PhysioFlow device requires rubbing the skin where patches will 
be applied with an abrasive gel (Nuprep) that will cause some skin irritation and may cause mild 
inflammation.

Order of measurements:  There are no additional risks to omitting or changing the order of the 
hemodynamic measurements in this study.  

Risk of incidental finding:  There is a rare risk of an incidental finding. The testing performed 
during this study is intended solely for research purposes and will not be utilized to detect any 
medical condition. However, if we notice something unusual, we will consult one of the 
cardiologists on the research team to determine if it merits follow-up. If so, we will contact you 
within 48 hours and suggest that you follow up with your private medical provider. To facilitate 
follow-up care, a copy of the data may be provided upon request. You will be monitored 
continuously for adverse effects and the medical personnel will remain in the room during the 
study.

There may be risks that are currently unknown.
4.   What are the possible benefits from being in this research study?   
4a.  What are the possible benefits to me?
You will not directly benefit from this study.
    
4b. What are the possible benefits to others?
Scientists may better understand how aging in women affects oxygen delivery when the heart’s 
ability to pump blood is reduced.
5.   What other options are available instead of being in this research study?
You may choose not to be in this research study.
6.   How long will I take part in this research study?
Overall, your participation in this research study should involve 3 study visits. Visit one will last up to 3 
hours. Visit two will last up to 3.5 hours. Visit 3 will last up to 4.5 hours. We anticipate that all study 
visits will be completed within one month.
7.   How will you protect my privacy and confidentiality if I decide to take part in this research study?
7a.  What happens to the information collected for the research?
Efforts will be made to limit the use and sharing of your personal research information to people 
who have a need to review this information.  Reasonable efforts will be made to keep the personal 
information in your research record private. However, absolute confidentiality cannot be 
guaranteed.

A list that matches your name with your code number will be kept by the research nurses on a 
protected network program called RedCap.

Your research records will be kept on a password-protected computer in the Cardiology research 
lab and only labeled with your study ID code. The paper copy of your chart will be kept in locked 
file cabinets in locked rooms in the Clinical Research Center (CRC). 
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This research is covered by a Certificate of Confidentiality from the National Institutes of Health. This 
means that the researchers cannot disclose information that identifies you to anyone not connected 
with the research.  This protection also prevents this information from being used or disclosed for legal 
proceedings, such as being accessed through a court order. The Certificate of Confidentiality however 
does not prevent disclosures required by law, such as information about child abuse or neglect and 
harm to yourself or others.  Also, your information may be disclosed in accordance with any consent 
you provide, including for your medical treatment or use in other research.  Additionally, the Certificate 
of Confidentiality does not prevent your information from being disclosed to the National Institutes of 
Health in order for it to evaluate or audit the research, or prevent disclosures required to meet FDA 
requirements.  For additional information ask the principal investigator or a member of the study team 
or contact the Human Research Protection Program at (814) 865-1775.
In the event of any publication or presentation resulting from the research, no personally 
identifiable information will be shared.
We will do our best to keep your participation in this research study confidential to the extent 
permitted by law. However, it is possible that other people may find out about your participation in this 
research study. For example, the following people/groups may check and copy records about this 
research.  

The Office for Human Research Protections in the U. S. Department of Health and Human 
Services 

The research study sponsor, the National Institutes of Health.

The Institutional Review Board (a committee that reviews and approves research studies) and 
Penn State’s Human Research Protection Program.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.
U.S. Food and Drug Administration may check and copy records about this research.
7b. What will happen to my research information and/or samples after the study is completed?
Your information or samples that are collected as part of this research will not be used or 
distributed for future research studies, even if all of your identifiers are removed.
Most tests done on samples in research studies are only for research and have no clear meaning for 
health care.  If the research with your identifiable information or samples gives results that do have 
meaning for your health, the researchers will contact you to let you know what they have found.
8.   What are the costs of taking part in this research study?
8a. What will I have to pay for if I take part in this research study? 
You will not be charged for any test or procedure performed as part of this research study.
8b. What happens if I am injured as a result of taking part in this research study?
In the unlikely event you become injured as a result of your participation in this study, medical 
care is available. It is the policy of this institution to provide neither financial compensation nor 
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free medical treatment for research-related injury. By signing this document, you are not 
waiving any rights that you have against The Pennsylvania State University for injury resulting 
from negligence of the University or its investigators.
9.
Will I be paid to take part in this research study?
You will receive a total of $150 for completing this study.

You will not be paid for completing visit 1.

You will be paid $50 for completing visit 2.

You will be paid $100 for completing visit 3.
If you do not complete the study for any reason, you will be paid for the visits you have completed. 
You will need to provide your social security number and address to receive a check for payment 
and for tax reporting purposes. 
10.
Who is paying for this research study?
The investigators are receiving a grant from The National Institutes of Health (NIH) to support this 
research.
11.
What are my rights if I take part in this research study?
Taking part in this research study is voluntary. 

You do not have to be in this research. 

If you choose to be in this research, you have the right to stop at any time. 

If you decide not to be in this research or if you decide to stop at a later date, there will be no 
penalty or loss of benefits to which you are entitled. 
If you stop being in the research, already collected data may not be removed from the study database. 
You will be asked whether the investigator can collect medical information from your routine medical care.  
If you agree, this data will be handled the same as research data. If you withdraw completely from the 
research study, no further information will be collected and your participation will end. You may discontinue 
taking part at any time without penalty or loss of benefits to which you are otherwise entitled.
The person in charge of the research study or the sponsor can remove you from the research study 
without your approval. Possible reasons for removal include not being able to place an intravenous 
catheter or not being able to perform the exercises in this study.
During the course of this research, you will be provided with any new information that may affect your 
health, welfare or your decision to continue participating in this research.
12. If I have questions or concerns about this research study, whom should I call?    
Please call the head of the research study (principal investigator), Dr. Proctor at 814-863-0724 (office) or 
814 571-5234 (cell) or the staff at the CRC 814-865-5811 if you:

Have questions, complaints or concerns about the research.

Believe you may have been harmed by being in the research study.  
You may also contact the Human Research Protection Program at (814) 865-1775, IRB-ORP@psu.edu if 
you:

Have questions regarding your rights as a person in a research study.

Have concerns, complaints, or general questions about the research. 
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
You may also call this number if you cannot reach the research team or wish to offer input or 
to talk to someone else about any concerns related to the research. 
You may visit the Human Research Protection Program website at 
https://www.research.psu.edu/irb/participants for:

Information about your rights when you are in a research study; 

Information about the Institutional Review Board (IRB), a group of people who review the 
research to protect your rights; and 

Links to the federal regulations and information about the protection of people who are in 
research studies. If you do not have access to the internet, copies of these federal regulations 
are available by calling the HRPP at (814) 865-1775.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time
INFORMED CONSENT AND AUTHORIZATION TO TAKE PART IN RESEARCH 
Signature of Person Obtaining Informed Consent
Your signature below means that you have explained the research to the subject or subject 
representative, provided the subject or subject representative an opportunity to discuss and consider 
whether or not to participate in the research, and have answered any questions about the research.
______________________________
__________
______
________________
Signature of person who explained this research Date
Time
Printed Name
(Only approved investigators for this research may explain the research and obtain informed consent.)  
Signature of Person Giving Informed Consent and Authorization
Before making the decision about being in this research you should have:

Discussed this research study with an investigator, 

Read the information in this form, and

Had the opportunity to ask any questions you may have. 
Your signature below means that you have received this information, have asked the questions you currently 
have about the research and those questions have been answered. You will receive a copy of the signed and 
dated form to keep for future reference.
Signature of Subject
By signing this consent form, you indicate that you voluntarily choose to be in this research and authorize 
your information to be used and shared as described above. 
___________________________
__________
______
________________ 
Signature of Subject
Date
Time
Printed Name
STUDY00010736
Approval: 11/18/2022
Approval End Date: 11/16/2023