Racial Differences in the Natriuretic Peptide Response to Exercise and Beta-blockers
Phase: PHASE2
Conditions: Healthy, Pre Hypertension
Sponsor: University of Alabama at Birmingham

UAB IRB  
Approved 
18-Jan-2023 
 
Study Title: Race, Natriuretic Peptides and Physiological Perturbations 
NCT number: NCT03070184 
UAB IRB Protocol number: IRB-170214001 
Investigator: Dr. Pankaj Arora, MD, FAHA 
 
Study Design 
This was an investigator-initiated single-center clinical trial conducted at the University of 
Alabama at Birmingham. All participants provided written informed consent. The study was 
approved by the University of Alabama at Birmingham Institutional Review Board. The detailed 
study protocol is included in this document. This study was registered on ClinicalTrials.gov as 
NCT03070184. 
 
Rationale and Hypothesis 
There are significant racial disparities in the burden of cardiovascular disease, with hypertension 
and heart failure being more prevalent in Black individuals than in White individuals. We have 
observed lower resting levels of NPs in Black individuals, raising the possibility of impaired NP 
production. Little is known about whether these race-related differences extend to dynamic 
changes in NP levels. Beta-blockers are commonly used drugs in hypertension, especially in 
individuals with co-existing coronary artery disease. They are also a cornerstone of standard 
heart failure therapy. Beta-blockers have been shown to be associated with a short-term increase 
in NPs. Hence, we hypothesize that Black individuals will have reduced release of NPs after 6 
weeks of metoprolol compared with White individuals. 
Similarly, exercise has been shown to increase the plasma concentration of NPs immediately 
after peak exercise in multiple previous human studies of healthy volunteers.73,80,81,97 Although 
the mechanism is incompletely understood, it is thought that exercise causes degranulation of 
secretory granules located within the heart.75,98 The amount of NPs stored within the secretory 
granules is known to rise in parallel to the resting concentrations of NPs.99-102 As mentioned 
above, NP values have been shown to be lower in Black individuals compared with their White 
counterparts. Therefore, Black individuals may have a lower NP response to exercise compared 
with White individuals. 
 
Specific Aims 
The proposed single-center clinical trial will compare the response of the NP system to 
metoprolol and exercise among healthy, young Black and White individuals. 
Primary Aim 
To compare the NP (NT-proBNP, BNP, and MR-proANP) response with metoprolol 
therapy at 6 weeks in Black and White individuals. 

UAB IRB  
Approved 
18-Jan-2023 
 
Secondary Aim 
To compare the NP (NT-proBNP, BNP, and MR-proANP) response immediately after 
standardized exercise in Black and White individuals. 
 
Participant Selection 
Inclusion Criteria: 
1. Self-identified Black or White adults 
2. Age between 18 and 40 years 
3. Body mass index between 18 to 30 kg/m2 
4. No history of hypertension (seated blood pressure <140/90 mm Hg and not taking 
antihypertensive medications) 
5. Willing to take the study medication 
6. Able to exercise 
Exclusion Criteria: 
1. Decreased renal function (estimated glomerular filtration rate <60 mL/min/1.73m2) 
2. Systolic blood pressure <100 mm Hg, diastolic blood pressure <60 mm Hg, or heart 
rate <60/min at screening 
3. Use of antihypertensive medications 
4. History of cardiovascular disease 
5. History of diabetes or use of antidiabetic medications 
6. Anemia (hematocrit <41% in males and <35% in females) 
7. Pregnancy (using urine pregnancy test) 
8. Hormone replacement therapy/oral contraceptive use 
9. Elevated liver function tests (>3x upper normal limit) 
10. Depression 
11. History of smoking or current smoking 
 
Recruitment 
The proposed single-center clinical trial will be conducted at the University of Alabama at 
Birmingham (UAB). UAB is located in Birmingham, AL (metropolitan population ~ 1.2 
million: 29% African-American, 56% white), making this an ideal environment in which to 
conduct studies that include African-American and white individuals. Several recruitment 
approaches will be used: 1) advertisements will be posted in local newspapers and online to 
recruit healthy subjects from the greater Birmingham area; 2) announcements regarding the study 
will be made on radio stations that have high market penetration in African-American 
communities to enhance recruitment; and 3) outreach through the UAB CCTS Community 
Engagement Research Core. 
 
Study Procedures 
A participating subject’s study period will span ~13-16 weeks from the screening visit to study 
completion. The timeline and study procedures are shown in Table 1. 

UAB IRB  
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Table 1. Study Flowchart and Timeline 
 
Days 
Days from 
Previous Visit 
Visit 
Location 
Time (hours) 
Procedures 
 
-10 to -8 
0 
Pre-Screening 
Home 
0.5 
-Discuss study objectives, 
inclusion/exclusion criteria, timeline, 
procedures & possible side effects 
- Telephonic pre-screening 
 
 
 
-7 
0 
Screening Visit (Visit 1) 
CRU 
1 
-Written consent 
-History & physical exam 
-Vitals check 
-Screening Labs 
-Urine Pregnancy Test (if applicable) 
-Dietician meeting (to review the 
standardized meals and for meal 
instructions) 
-6 
2 
Exercise Capacity 
Determination Visit (Visit 
2) + 3 days Meal pick up 
UCEM 
2 
-Vitals Check 
-VO2 max test 
- 3 days meal pick up from CRU 
The participants will consume 3 days of standardized meals prior to visit 3 
-3 
4 
Exercise Challenge 
Test(Visit 3) 
UCEM 
3 
-24-hour urine collection prior to the 
visit 
-Vitals check 
-Blood draw & spot urine collection 
-Exercise Challenge test 
0 
1 
Drug Initiation Visit 
(Visit 4) 
CRU 
1 
-24-hour urine collection prior to the 
visit 
-History & physical exam 
-Vitals check and EKG 
-Blood draw 
-Urine Pregnancy Test (if applicable) 
-Adherence & adverse events tracking 
-Provide the participant with 1 pre- 
labeled bottle (15 tablets per bottle) of 
metoprolol succinate XL 50 mg - 
Provide the participant with the 
medication log 
7 
7 
Phone Interview I 
Home 
0.25 
-Adherence & adverse events tracking 
14 
7 
Interim Visit 1 (Visit 5) 
CRU 
1 
-24-hour urine collection prior to the 
visit 
-History & physical exam 
-Vitals check and EKG 
-Blood draw 
-Urine Pregnancy Test (if applicable) 

UAB IRB  
Approved 
18-Jan-2023 
 
 
- Adherence & adverse events tracking 
- Provide the participant with 1 pre- 
labeled bottle (15 tablet per bottle) of 
metoprolol succinate XL 100mg 
-Provide the participant with the 
medication log 
-Pill 
count and drug log check 
21 
7 
Phone Interview II 
Home 
0.25 
-Adherence & adverse events tracking 
28 
7 
Interim Visit 2 (Visit 6) 
CRU 
1 
24-hour urine collection prior to the visit 
-History & physical exam 
-Vitals check and EKG 
-Blood draw 
-Urine Pregnancy Test (if applicable) 
-Adherence & adverse events tracking 
-Provide the participant with 1 pre- 
labeled bottle (15 tablets per bottle) of 
metoprolol succinate XL 200mg 
-Provide the participant with the 
medication log 
-Pill 
count and drug log check 
35 
7 
Phone Interview III 
Home 
0.25 
-Adherence & adverse events tracking 
42 
7 
Final visit (Visit 7) 
CRU 
1 
-History & Physical 
-Vitals check and EKG 
-Blood Draw 
-Urine Pregnancy Test (if applicable) 
-Pill count and drug log check 
49 
7 
Follow-up visit (Visit 8) 
CRU 
1 
-Vitals check 
End of Study 
Abbreviation: CRU, Clinical Research Unit; UCEM: UAB Center for Exercise Medicine 
 
Visit # 1 (Screening Visit):  
During the screening visit, the study investigator(s) will obtain consent from the study subjects. 
After obtaining the consent of the study subjects, personal and medical history will be taken. 
Physical examination, including vitals (like blood pressure and heart rate), will be performed by 
the study investigator(s). A urine pregnancy test will be administered to the female subjects to 
confirm their pregnancy status. In addition to these, 25cc (5 teaspoons) of blood will be drawn 
for screening labs, including baseline metabolic profile, complete blood count, and liver function 
tests. Furthermore, the dietician will explain the 3 days of a standardized diet. If the subject 
agrees to adhere to the study diet, follow the study protocol, and meet the inclusion criteria, then 
they will be enrolled in the study. 
 
Visit # 2 (Baseline visit-Meal Pick-up):  

UAB IRB  
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Subjects will come for a baseline visit (scheduled according to subjects’ convenience) to 
the UCEM for determination of maximal oxygen capacity (VO2 max). Subjects will be asked to 
fast overnight (>6 hours) prior to this visit and not to drink caffeine and alcoholic beverages 24 
hours prior to this visit. 
 
• A maximal modified Bruce treadmill protocol will be used to determine aerobic fitness/VO2 
max. Monitoring will consist of a 12-lead electrocardiogram and BP measurements will be taken 
every two minutes. 
• Oxygen uptake and carbon dioxide production will be measured continuously using a TrueOne 
2400 metabolic cart. 
• Achievement of maximal oxygen uptake (VO2 max) was ascertained by the exercise 
physiologist based on standard criteria for heart rate (HR within 10 beats/min of estimated 
maximum), respiratory exchange ratio (RER >1.2), and plateauing of VO2/min/kg. 
• After determining the VO2 max, subjects will pick up 3 days of standardized diet from the 
metabolic kitchen of CRU. Meals will be provided to subjects at no cost. The daily standardized 
diet will be composed of 51% carbohydrate, 31% fats, 18% proteins, ~4.5 gm sodium, and ~2.5 
gm potassium. All meals will be prepared in the CRU metabolic kitchen. A menu and food 
records form included in the packet. 
• A container for 24-hour urine collection will be provided. Instruction for the collection of 24- 
hour urine will be provided by the study coordinator. 
 
Prior to 3rd/Exercise Challenge visit: 
Three days prior to 3rd visit, subjects will consume the meals that were provided by the CRU. 
Subjects will be asked to collect 24-hour urine and fast overnight (>6 hours) prior 
to 3rd visit. Subjects will be asked not to drink caffeine and alcoholic beverages 24 hours prior to 
this visit. Before coming for 3rd visit, subjects will drop off their 24-hour urine sample at the 
Outreach Lab. 
 
Visit # 3/ Exercise Challenge visit:  
• Subjects will come to the PAC and rest for 1 hour in supine position. Medical history and vital 
sign measurements (blood pressure and heart rate) will be collected. After 1 hour of rest, 20cc of 
blood or 4 teaspoons will be drawn by a nurse for the assays. Blood samples will be tested for 
natriuretic peptide levels, insulin, and glucose. 
• Afterward, subjects will be asked to perform the exercise challenge test. The exercise challenge 
is designed to give each subject comparable amounts of physiological stress. Each subject will 
walk at 70% of his/her VO2 max for 20 minutes. 
• The exercise challenge has a 4-minute warmup starting with 3 mph at zero grade for two 
minutes, progressing to 3 mph at a 3% grade for 1 minute, followed by 3 mph at a 6% grade for 
one minute. 

UAB IRB  
Approved 
18-Jan-2023 
 
• Using the American College of Sports Medicine metabolic equations, treadmill grade and speed 
will be adjusted to attain 70% VO2 max. Each subject will walk at 70 % of their VO2 max for 
20 minutes. At the end of the exercise challenge, participants will undergo a 4-minute cool- 
down by walking at 2 mph at 0 grade. 
• Subjects will be asked to take a rest for 30 minutes. Before, immediately, 15 minutes, and 30 
minutes after the exercise challenge, blood samples will be collected to measure NP levels. 
Participants were asked to provide urine samples to measure urinary sodium levels at the start 
and 30 minutes after the end of the exercise challenge. 
• During the exercise challenge visit, subjects will be asked not to drink water. Subjects can drink 
water after completing the exercise challenge. 
• A container for 24-hour urine collection will be provided. Instruction for the collection of 24- 
hour urine will be provided by the study coordinator. 
 
Visit # 4/ Drug initiation visit:  
• Three to seven days after 3rd visit, subjects will come for 4th visit. 
• Subjects will be asked to fast overnight (>6 hours) prior to this visit and not to drink caffeine and 
alcoholic beverages 24 hours prior to this visit. 
• Before coming for the 4th visit, subjects will drop off 24-hour urine samples at the outreach 
lab. A urine sample will be tested for sodium, protein, and creatinine levels. 
• Subjects will come to the CRU and will be asked to take a rest for 1 hour. 
• If a female is in the reproductive age group, a urine pregnancy test will be performed to rule out 
pregnancy. BP and heart rate (HR) will be measured and venous blood will be drawn. 
• If the systolic blood pressure is >100 mmHg, diastolic blood pressure is >50 mm Hg, and heart 
rate is >60 bpm, then a two-week supply of 50 mg of metoprolol succinate will be provided. The 
local Investigational Drug Services will dispense pre-labeled bottles (15 tablets per bottle) of 
metoprolol succinate XL 50 mg in bulk (6 bottles for each dose). A study physician/study 
coordinator will obtain these pre-labeled bottles from the research pharmacy. Drug bottles will 
be kept in locked cabinets. A study physician will dispense each bottle to the study subjects 
according to the study visits. A total of 15 capsules will be dispensed at this time, which 
provides sufficient supply for 2 weeks plus 1 additional pill in the event that the visit cannot be 
scheduled exactly 2 weeks to reach the interim visit 1 (Visit #5). Subjects will be instructed to 
take one capsule once a day. 
• Subjects will be called by the study doctor to assess medicine side effects within 7 days after this 
visit. 
• Drug compliance and side effects will be assessed through a telephone call after 7 days of visit 
and a medication log. 
 
Visit # 5/Interim visit 1:  
• 
Two weeks after visit #4, subjects will come for this visit 

UAB IRB  
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• 
Subjects will be asked to fast overnight (>6 hours) prior to this visit and not to drink caffeine and 
alcoholic beverages 24 hours prior to this visit. 
• 
Subjects will come to the CRU and will be asked to take a rest for 1 hour. 
• 
Blood pressure and heart rate will be measured and venous blood will be drawn after 1 hour of 
rest. Blood samples will be tested for natriuretic peptide levels, insulin, and glucose. 
• 
Compliance will be assessed by doing a pill count and reviewing the medication log. 
• 
Subjects will be asked about any possible side effects from the metoprolol use in the previous 2 
weeks. 
• If compliant and have no side effects, subjects will be given a 2-week supply of 100 mg/day of 
metoprolol succinate. The local Investigational Drug Services will dispense pre-labeled bottles 
(15 tablets per bottle) of metoprolol succinate XL 100 mg in bulk (6 bottles for each dose). A 
study physician/study coordinator will obtain these pre-labeled bottles from the research 
pharmacy. Drug bottles will be kept in locked cabinets. A study physician will dispense each 
bottle to the study subjects according to the study visits. A total of 15 capsules will be dispensed 
at this time, which provides sufficient supply for 2 weeks plus 1 additional pill in the event that 
the visit cannot be scheduled exactly 2 weeks to reach the interim visit 2 (Visit 6). Subjects will 
be instructed to take one capsule once a day. 
• Subjects will be called by the study doctor to assess medicine side effects within 7 days after this 
visit. 
• Drug compliance and side effects will be assessed through a telephone call after 7 days of visit 
and a medication log. 
 
Visit # 6/Interim Visit 2:  
• Two weeks after visit #5, subjects will come for this visit. The same protocol as that for visit 
# 5 will be followed. Compliance will be assessed and if no side effects are reported, subjects 
will be given a 2-week supply of 200 mg/day of Metoprolol succinate. The local Investigational 
Drug Services will dispense pre-labeled bottles (15 tablets per bottle) of metoprolol succinate XL 
200 mg in bulk (6 bottles for each dose). A study physician/study coordinator will obtain these 
pre-labeled bottles from the research pharmacy. Drug bottles will be kept in locked cabinets. A 
total of 15 capsules will be dispensed at this time, which provides sufficient supply for 2 weeks 
plus 1 additional pill in the event that the visit cannot be scheduled exactly 2 weeks to reach the 
final visit (Visit 7). Subjects will be instructed to take one capsule once a day. 
• Subjects will be called by the study doctor to assess medicine side effects within 7 days after this 
visit. 
• Drug compliance and side effects will be assessed through a telephone call after 7 days of visit 
and a medication log. 
A container for 24-hour urine collection will be provided. 
 
Visit # 7/Final Visit: 

UAB IRB  
Approved 
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Two weeks after visit #6, subjects will come for this visit. On this visit, subjects will drop off 
24-hour urine collection at the outreach lab. The urine sample will be tested for sodium, protein, 
and creatinine levels. The same protocol as that for visit # 5 will be followed. Blood will 
be drawn. Blood samples will be tested for natriuretic peptide levels, insulin, and glucose.  At 
the end of this visit, the subject’s participation will be complete. 
 
Visit # 8/Follow-up Visit: 
One week after visit #7, subjects will come to the CRU for their follow-up visit. After 15 min of 
rest, blood pressure and heart rate (three times) will be measured to evaluate subjects’ well- 
being. 
 
Early Termination/Discontinuation Visit: 
At every visit, blood pressure and heart rate will be measured. Metoprolol will be discontinued 
for any systolic BP< 80 mm Hg and HR < 40 beats/minute at any visit. If the subject develops 
intolerance or any side effects from increasing the dose of metoprolol, they will go back to the 
maximally tolerated last dose to finish the 6-week duration. 
 

UAB IRB  
Approved 
18-Jan-2023 
 
 
 
Study Outcomes 
The primary endpoint in this study is the change in the NP levels, including NT-proBNP, BNP, 
and MR-proANP, in response to 6 weeks of metoprolol between young, healthy Black and White 
individuals. As the assessment of each NP is not independent of each other, we did not use the 
statistical correction of multiple testing. 
The secondary outcome of this study was the change in the NP levels, including NT-proBNP, 
BNP, and MR-proANP, in response to a standardized exercise challenge between young, healthy 
Black and White individuals. 

UAB IRB  
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Statistical Analysis 
All analyses will be conducted using SAS 9.4 (Cary, NC) and the latest version of R Statistical 
Software (R core team 2020). Participants’ demographic and baseline clinic characteristics will 
be summarized with mean and standard deviations (SD) for continuous variables and frequency 
and proportion for categorical variables. The 95% confidence interval (95%CI) will also be 
provided where appropriate. Statistical plots (scatters, histograms, Q-Q, bar charts, etc.) will be 
used to examine the distribution of data. Extreme values will be identified for validation or 
correction. The baseline differences between groups will be compared using a two-sample t-test 
for continuous variables or a Chi-square test for categorical variables. A nonparametric Wilcoxon 
test will be applied for skewed continuous data. For the primary and secondary outcomes, we will 
conduct a complete case analysis. The analysis will be conducted in individuals who completed 
both phases of the study i.e., exercise and medication. A sensitivity analysis will be conducted, 
including participants who completed a single phase (medication or exercise) of the study. All the 
tests will be two-sided with a significance level of 0.05. 
Multivariable linear mixed models using change in log-transformed NP levels as the dependent 
variable and race as the independent variable (white will be chosen as reference) will be employed. 
Participants were taken as random effects. The fixed effects included race, time, a multiplicative 
interaction term of time and race, age, sex, body mass index, and insulin levels. Percentage 
difference and 95% confidence intervals in plasma NP levels after 6 weeks of metoprolol by race 
was calculated: ([eβ–1]×100 multiplied by 6 weeks [where β is the beta coefficient from linear 
regression]). 
Power Analysis 
In the proposed study, we aim to recruit 40 Black individuals and 40 White individuals. Figure 
presents the power estimates for the detectable mean fold-change in log NT-proANP levels 
between groups (Black vs. White) from pre to post-6 weeks of metoprolol at a two-sided p-value 
of 0.05. In a prior study evaluating NP response after 6 weeks of metoprolol (similar dose and 
protocol), the mean ± SD relative change (measured in log units) in NT-proANP levels was 0.66 
± 0.45. Based on preliminary data from 5 subjects who have already completed the proposed 
study, we have measured NPs and found a 110% increase in NT-proBNP levels after 6 weeks of 
metoprolol. As shown, we have excellent power to detect relatively small-medium differences 
(28%) between Black individuals and White individuals pre and post-metoprolol. Even if we 
reduce the sample size by 20% (32 in each group) due to loss to follow-up or withdrawal, the 
detectable difference changes minimally, from 28% to 32%. 

UAB IRB  
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For the secondary outcome, we anticipate 80% power to detect a 39% (medium effect size) 
difference between groups (Black vs. White) in mean fold-change in BNP from before and after 
exercise challenge using the two-sided P value of 0.05. This is based upon data from Barletta et 
al. in which the mean ± SD relative change (measured in log units) in BNP between pre and post- 
exercise in white individuals was 0.42 ± 0.61.79 
 
 
Potential Risks 
General. Risks related to overnight fasting include hypovolemia. Subjects will be instructed to 
drink plenty of fluids the day before the visit, and will have baseline blood pressure measured 
upon arrival at the clinical research unit (CRU). Risks related to venous blood draw include 
hematoma formation and phlebitis. This is a routine procedure that is considered standard of 
care in clinical medicine. At each visit, subjects will undergo a single venous blood draw with 
removal of approximately 4 teaspoons (20 ml) of blood. All blood draws will be performed by 
trained personnel using universal precautions to protect both the subject and personnel. The 
risks to subjects are minimal, but may include pain, allergic reaction, infection, or bleeding at the 
needle stick site. These usually resolve without any specific medical therapy over the course of 
minutes to days. 
Tolerability and safety of study drug (Metoprolol). Common side effects reported in 3% or 
more cases of metoprolol use in the literature include dizziness, fatigue, and depression, 
shortness of breath, pruritus and diarrhea. Less frequent but serious side effects include 
wheezing, bronchospasm, bradyarrythmia and heart failure. However, since we are enrolling 

UAB IRB  
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healthy volunteers the frequency of any side effects is less than 1%. All subjects will be 
monitored for adverse effects and during the study visits a physician will be present to monitor 
the safety of the subject through the protocol and between study visits, a physician will be 
available 24 hours a day by phone and/or pager to subjects. Metoprolol will be discontinued for 
any systolic blood pressure< 80 mm Hg and heart rate < 50 beats/minute at any visit. If the 
subject develops intolerance or any side effects from increasing the dose of metoprolol, they will 
go back to the maximally tolerated last dose to finish the 6-week duration. 
Tolerability and safety of determination of VO2 max and performing exercise challenge. The 
risks associated with the proposed study are minimal since moderate amounts of exercise 
generally promote good health, not endanger. Our eligibility criteria are established to exclude 
individuals for whom exercise is not appropriate. However, there is still moderate to high 
likelihood of fatigue, muscle soreness, or shortness of breath during and/or after performance of 
VO2 max. There is an extremely low likelihood of injury to muscle, joint, ligaments, tendons or 
bone, tripping or falling, feeling faint or dizzy, chest pain, arrhythmia, and inconvenience. 
Furthermore, there is a very rare risk of cardiac ischemia or arrest during the peak VO2 test or 
exercise challenge. 
Tolerability and safety of standardized diets. While there is theoretic risk of eliciting 
hypertensive or hypotensive responses with standardized diets, Dr. Arora and the study team 
have decades of experience giving diets and have demonstrated that the standardized diets are 
well tolerated and safe. 
Device complications. Not applicable 
Psychosocial risks. We do not anticipate psychosocial risks to the subjects from participation in 
the proposed protocol. Strict confidentiality will be maintained to the fullest extent by the 
research team, including keeping all data in a secure, locked cabinet with limited access. All 
specimens and files will be coded after they are obtained and the code key kept in a locked 
cabinet. 
Radiation risks. No additional radiation exposure will be required by the protocol. 
Financial and legal risks. Those are felt to be minimal given the lack of expected clinical 
information relevant to employment, insurability or paternity. 
Private health information. This information will be collected during the course of the study. 
However, only key study personnel will have access to this information, which will be stored in a 
HIPAA compliant, password protected REDCap database. No protected health information will 
be shared with employers, insurers, or non-research personnel. 
 
Protection Against Risk 
Bodily fluids and biohazards. As phlebotomy for venous blood samples and urine collections 
will be performed, standard universal precautions will be utilized to protect both subjects and 
members of the research team. If discomfort, swelling, infection, or bleeding occurs in relation 
to the venous blood draw, appropriate medical therapy will be provided under the direction of the 
supervising physician. Most symptoms or side effects related to venous blood draw are 
temporary, self-resolving, and do not require any specific medical therapy. 

UAB IRB  
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Data Protection and prompt reporting of adverse events. The University of Alabama at 
Birmingham regularly reviews its policies and procedures regarding the confidentiality of study 
subjects. All staff receive training on the critical importance of maintaining confidentiality. 
Data are stored and analyzed according to subject identification numbers, and in no instances are 
subjects’ names or other identifying information available in publicly accessible files or in 
published material. Every effort is made to keep such data from being accessed inappropriately, 
but this possibility always remains, however remote. UAB Hospital has 24-hour security to 
protect all participants’ data. 
Location. The study protocol will be conducted in the UCEM and the UAB CRU (within the 
hospital with all available emergency medical personnel) under the direct supervision of a study 
physician. Portable defibrillators are present, and all staff members are certified for their use and 
CPR. Appropriate reporting, as described below, will be done in the event of an adverse event. 
Informed consent forms, case report forms, and data will be reviewed by the principal 
investigator and an independent data and safety monitor (details below) following enrollment of 
every 10 patients to ensure completeness, accuracy, and adherence to the protocol. Data to be 
reviewed includes appropriate handling and processing of blood samples and maintenance of 
patient confidentiality throughout the study. Specifically, for the interventional study, serious 
adverse events will be reported by phone, fax or e-mail within 24 hours to the UAB Human 
Research Committee, followed by a full written report within 10 working days/14 calendar days. 
Mild or moderate adverse events will be presented in progress reports at continuing reviews. 
 
Potential for Benefit to Subjects and Others 
It is not anticipated that the participants of the study will directly benefit from the proposed 
research. However, the potential benefit to society is great. As hypertension and heart failure 
are common, particularly among Black individuals, the results of the proposed studies may 
provide important knowledge regarding the biological mechanisms and inform novel preventive 
and therapeutic strategies to be tested in future trials. 
 
Monitoring and Quality Assurance 
The risks associated with the study assessments are minimal. However, we will institute a three- 
member Data and Safety Monitoring Board (DSMB), comprised of experts in cardiology (Dr. 
David A. Calhoun, MD), biostatistics (Charity J. Morgan, Ph.D.), and pulmonary medicine (Dr. 
Surya P. Bhatt, MD), who will be charged with reviewing data and safety throughout the study, 
in addition to the Principal Investigator. Informed consent, case report forms and data will be 
reviewed by the principal investigator and DSMB. The DSMB will meet at least twice a year, 
either by phone or in person, to ensure the safety of study participants. The DSMB will be 
provided access to blinded safety data, including adverse events (AEs) by frequency and by body 
system, and study withdrawals following enrollment of every 10 patients to ensure completeness, 
accuracy, and adherence to the protocol. Other data to be reviewed include appropriate handling 
and processing of blood samples, laboratory data, and maintenance of patient confidentiality. 
Safety monitoring will be performed throughout the course of the study. During and between all 
study visits and procedures, Dr. Arora will be available to address subject-related medical 
questions and ensure subject safety. At every subject visit, a study physician will carefully 

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screen for any side effects from the study drug, record vital signs and monitor compliance. Any 
study-related injuries will be promptly addressed and treated using resources available at UAB. 
All data will be recorded and stored in password-protected REDCap databases that can only be 
accessed by key study personnel. Data integrity and quality will be checked at the time of 
acquisition and entry. Prior to analyses, queries regarding missing data or extreme values will be 
addressed by checking against case report forms. Data handling and analytic methods will be 
recorded to ensure reproducibility of results. Results, when reported in any form, will be 
summarized without any patient identification. Standards for Personal Health Information will 
be followed to assure confidentiality. 
Adverse Events (AE). The investigator or study physician will be responsible for detecting, 
documenting and reporting events that meet the definition of an AE. All Serious AEs (SAEs) 
and others will be collected from the time of the first dose of metoprolol through the final study 
visit. All-cause mortality and SAEs will be reported to the DSMB, and the local regulatory 
authority within 24 hours by the study monitor (principal investigator and/or study physician at 
UAB). 
Definition of an AE. Any untoward or unfavorable medical occurrence in a participant, including 
any abnormal sign (for example, abnormal physical exam), symptom, or disease, temporally 
associated with the use of metoprolol, whether or not considered related to the participant’s 
participation in the research. Three types of adverse event data will be reported: “All-Cause 
Mortality”, “Serious”, and “Other (Not Including Serious)” Adverse Events. 
 
All-Cause Mortality 
The occurrence of death due to any unrelated cause during the 
course of the study. 
Serious Adverse Events 
(SAEs) 
Bronchospasm (1%) 
Other (Not Including 
Serious) Adverse Events 
Cardiovascular: Bradycardia (3%), Hypotension (1%), Cold 
extremities (1%) 
Dermatologic: Pruritus (5%), Rash (5%) 
Gastrointestinal: Constipation (1%), Diarrhea (5%), and 
Indigestion (1%) 
Neurologic: Dizziness (10%), Fatigue (10%), Headache 
Psychiatric: Depression (5%) 
Respiratory: Dyspnea (3%), Wheezing (1%) 
 
Events meeting the definition of an AE include. New conditions detected or diagnosed after 
metoprolol administration, even though they may have been present prior to the start of the 
study. Signs, symptoms, or the clinical sequelae of a suspected interaction. Signs, symptoms, or 
the clinical sequelae of a suspected overdose of either metoprolol or concomitant medication 
(overdose per se will not be reported as SAEs and others). 
Other Safety Assessment Abnormalities Reported as SAEs and others. Any abnormal safety 
assessments (e.g., vital sign measurements), including those that worsen from baseline and are 

UAB IRB  
Approved 
18-Jan-2023 
 
felt to be clinically significant in the medical and scientific judgment of the investigator, are to 
be recorded as SAEs and others. 
The review and decision regarding altering or stopping the protocol will be performed by the 
Principal Investigator, DSMB, and the study physician at UAB. Reasons to stop the study 
include an unexpected incidence of AEs attributed to metoprolol. The principal investigator will 
review any AEs immediately following their occurrence and report them to the Institutional 
Review Board (IRB) in accordance with their guidelines. All SAEs will be reported by phone, 
fax, or email within 24 hours to both the IRB and DSMB by the study monitor (principal 
investigator and/or study physician at UAB) followed by a full written report within 10 
business/14 calendar days.