Conditions: Blood Pressure
Keywords: pharmacokinetics pharmacodynamics pharmacogenetics
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 61
Healthy volunteers: no

Brief summary:
Recently, the quality of generic metoprolol extended-release (ER) products has been called into question with reports of inconsistent effects when switching from the brand name product to a generic formulation. Problems with how the body processes these drugs could have serious and widespread consequences given the high frequency of metoprolol ER use in the management of various cardiovascular disorders, including high blood pressure, coronary heart disease, heart failure, and cardiac arrhythmias. Investigators hypothesize that both product- and subject-specific factors lead to variability in the way the body breaks down the drug (pharmacokinetics) and clinical response to generic versus name brand metoprolol ER formulations. Investigators will study the brand name and generic metoprolol ER formulations in subjects with high blood pressure to compare the pharmacokinetics and cardiovascular responses among equivalent labeled doses of each product (brand name and two approved generics).

The study objective is to provide information on how the body breaks down generic and brand name metoprolol ER products (pharmacokinetics) and how the body responds to generic and brand name metoprolol ER products (pharmacodynamics) to better understand if generic metoprolol ER products are as good as the brand name product.

Detailed description:
As a participant in this study the following will happen.

A study nurse will draw 3 teaspoonfuls (15 ml) of blood. Two teaspoons (10ml) will be drawn for basic blood work and one teaspoon (5ml) will be drawn for genotyping. The study physician will perform a physical exam and discuss all medical history.

The study will be randomized to one of two groups like flipping a coin.

* Study Sequence A- start with brand name metoprolol ER, switch to Generic B metoprolol, switch back to brand name metoprolol ER, then switch to Generic A metoprolol
* Study Sequence B- start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol.

Each study sequence will consist of treatment with brand name metoprolol ER for 2 periods, treatment with Generic A metoprolol ER for one period, and treatment with Generic B metoprolol ER for one period. The generic drug periods will be in a different order for each study group. During the times the switch will take place the following tests will be performed: 24-hour pharmacokinetic parameter assessment, 24-hour heart rate monitoring, 24-hour blood pressure monitoring, 24-hour holter monitoring, exercise treadmill to induce heart rate, and a 24-hour gastric potential hydrogen (pH) monitoring via a wireless capsule.

Arms:
arm 1: Start with brand name metoprolol ER, switch to Generic B metoprolol, switch back to brand name metoprolol ER, then switch to Generic A metoprolol arm 2: Start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol.

Interventions: intervention 1: brand name metoprolol ER intervention 2: Generic A intervention 3: Generic B
Intervention descriptions: intervention 1: This medication will be taken for 7 to 28 days intervention 2: This medication will be taken for 7 days intervention 3: This medication will be taken for 7 days

Protocol document:
Prot_SAP_ICF_000.pdf: 
Official Title: Open-Labeled Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of Metoprolol ER 
NCT02417246  
July 13, 2018 


Page 1 of 41 
 
University of Florida 
College of Pharmacy, Department of Pharmacotherapy & 
Translational Research, Department of Pharmaceutical Outcomes and 
Policy, Center for Pharmacogenomics, and Center for 
Pharmacometrics and Systems Pharmacology  
 College of Medicine, Community Health and Family Medicine and 
Division of Gastroenterology, Hepatology, & Nutrition  
Clinical and Translational Science Institute 
 
 
Clinical Research Protocol 
 
Title: Open-Labeled Pharmacokinetic and 
Pharmacodynamic (PK-PD) Studies of Metoprolol ER 
 
Version July 13, 2018 
 
 
Protocol No: 201500092 
Principal Investigator: Larisa Cavallari, Pharm.D. 
                                       Telephone: 352-273-8245 
 
 
 
 


Page 2 of 41 
 
Table of Contents 
1.     Abstract …………………………………………………………………………………..6 
2.     Introduction………………………………………………………………………………7 
        2.1    Background………………………………………………………………………...7 
        2.2    Significance………………………………………………………………………...9 
3.    Credentials of Investigators…………………………………………………………..10 
4.    IRB oversight…………………………………………………………………………….11 
5.    Objectives and aims..…………………………………………………………………..12 
6.    Regulatory status……………………………………………………………………….12 
7.    Background……………………………………………………………………………...13 
8.    Study design and methods……………………………………………………………16 
       8.1    Study design……………………………………………………………………….16  
       8.2    Study population and eligibility requirements…………………………………..17 
                8.2.1    Inclusion criteria…………………………………………………………..17 
                8.2.2    Exclusion criteria………………………………………………………….17 
       8.3    Protocol……………………………………………………………………………..18 
                8.3.1    Enrollment visit……………………………………………………………19  
                8.3.2    Screening visit ……………………………………………………………19 
                8.3.3    Phase 1 ………...………………………………………………………….21 
                8.3.4    PK/PD study visit………………………………………………………….21 
                8.3.5    Phase 2……….……………………………………………………………22 
                8.3.6    Phases 3 and 4………………...…………………………………...…..  22 
                8.3.7    Follow up study procedures……………………………………………...22 
        8.4   Detailed description of PK/PD study procedures……………………………….23 
 


Page 3 of 41 
 
                8.4.1    Ambulatory BP monitoring……………………………………………….23 
                8.4.2    Pharmacokinetic studies………………………………………………..23 
                8.4.3    pH monitoring……………………………………………………………..23 
                8.4.4    Exercise treadmill…………………………………………………………24 
9    Product Information……………………………………………………………………..24 
10  Duration…………………………………………………………………………………...25 
11  Location…………………………………………………………………………………...25 
12.  Subject selection and recruitment…………………………………………………26 
  12.1    Inclusion of women and minorities……..…………………………………….26 
       12.2    Strategies/Procedures for recruitment…..…………………………...………26 
13. Screening tests and interview prior to subject enrollment……………………..26 
14.   Risk/Benefit ratio………………………………………………………………………27 
        14.1    Potential risks……………………………………………………………………28 
        14.2    Potential benefits………………………………………………………………..28 
        14.3    Alternative treatment………………………………………………….…….....28 
        14.4    Adequacy of protection against risks……………………………….………..28 
                  14.4.1    Protection from venipuncture…………………………………….….28 
                  14.4.2    Protection from antihypertensive drug therapy risks……………...28 
                  14.4.3    Protection from SmartPill risks…………………………………….…28 
                  14.4.4    Protection from exercise treadmill testing…………………………..29 
                   14.4.5 Protection against risks from genetic study participation…………..29 
15. Payment for participation……………………………………………………………...29 
16. Adverse event reporting…………………………………………………………….....29 
      16.1 Data safety monitoring…………………………………………………………….30 
       16.1.1 Data safety monitoring plan…………………………………………………....30 


Page 4 of 41 
 
17   Analysis of the study………………………………………………………………….31 
      17.1    Aim 1……………………………………………………………………………. .31 
                17.1.1    Heart rate variability and 24 hr HR…………………………………...32 
                17.1.2    24 hr ambulatory and home BP data…………………………………32 
                17.1.3    Pharmacokinetic and pharmacometric modeling…………………...32 
                17.1.4    Power analysis……………………………………………………….....33 
     17.2     Aim 2………………………………………………………………………………33 
                17.2.1    SmartPill data…………………………………………………………...33 
                17.2.2    Power analysis…………………………………………………………34 
     17.3    Aim 3………………………………………………………………………………..34 
               17.3.1 Genotype data……………………………………………………………...34 
               17.3.2 Power analysis……………………………………………………………..34 
18. Data management/confidentiality of data/records……………………………….35 
19. References………………………………………………………………………………36 
 
Appendix A:  Summary of revisions to original protocol……………………………40 
 
 
 


Page 5 of 41 
 
List of Figures 
Figure 1.    Comparison of plasma concentration time curves for metoprolol IR……....13 
Figure 2.    Comparison of 24-hr systolic, diastolic pressure and frequency variability  
                  ratios between metoprolol IR and metoprolol ER………………………........14 
 
Figure 3.    Effect of metoprolol on daytime diastolic and systolic BP, maximum  
                  exercise HR, and sitting resting HR in responders and nonresponders......15 
 
 Figure 4.   Median (IQR) clinical responses to metoprolol based on CYP2D6  
                  phenotype………………………………………………………………………..16 
 
Figure 5.    Study design……………………………………………………………………..17 
 
List of Tables 
Table 1.    CYP2D6 allele frequencies among ethnic groups…………………………….9 
Table 2.    Schedule of study events……………………………………………………….20  
Table 3.    Submaximal exercise treadmill testing (Modified Bruce Protocol)………….23 
Table 4.    Data power calculation………………………………………………………….27 
 
 


Page 6 of 41 
 
Abstract: 
Recently, the quality of generic metoprolol extended-release (ER) products has been 
called into question with reports of inconsistent effects when switching from the brand 
name product to a generic formulation. Problems with bioequivalence could have serious 
and widespread consequences given the high frequency of metoprolol ER use in the 
management of various cardiovascular disorders, including hypertension, coronary heart 
disease, heart failure, and cardiac arrhythmias. We hypothesize that both product- and 
patient-specific factors lead to variability in the pharmacokinetics and clinical response to 
different metoprolol ER formulations. The study objective is to provide the 
pharmacokinetic and clinical response data necessary to inform optimal bioequivalence 
metrics and criteria for generic metoprolol ER products to ensure availability of high 
quality generic alternatives. We will conduct a prospective, randomized, crossover trial of 
brand name and generic metoprolol ER formulations in hypertensive patients to compare 
pharmacokinetics and cardiovascular responses among equivalent labeled doses of each 
product. Responses will be compared between cytochrome P450 (CYP) 2D6 extensive 
and poor to intermediate metabolizers so that the impact of CYP2D6 genotype on variable 
pharmacokinetics and clinical responses with metoprolol ER products can be determined. 
Responses will also be compared between patients taking and not taking a proton pump 
inhibitor for their clinical care given potential effects of a PPI on drug bioavailability.  
Following treatment with each metoprolol ER formulation, the patient will complete a 24-
hour Holter study for determination of total heart beats and heart rate variability, a 24-
hour blood pressure study, and a 24-hour pharmacokinetic study.  Patient will also be 
administered an FDA-approved SmartPill capsule to monitor gastric pH in order to 
determine the effects of gastric pH on pharmacokinetics and clinical response.  At the 
end of the 24-hour study period, patients will complete sub-maximal exercise treadmill 
testing to determine drug effects on exercise hemodynamics. This proposal is important 
because it will help elucidate factors contributing to variability in the pharmacokinetics 
and effectiveness of metoprolol ER products, which are among the most commonly 
prescribed agents in the U.S.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 7 of 41 
 
Introduction: 
 
Background: 
Metoprolol ranks among the top five most commonly prescribed medications, with an 
estimated 84 million prescriptions written in 2013.1 Metoprolol is a β-1 selective agent 
indicated for the treatment of hypertension, angina pectoris, heart failure and post-
myocardial infarction based on evidence that it reduces mortality and morbidity in these 
populations.2-4 The extended-release (ER) formulation of metoprolol was approved in 
1992, and is formulated as a succinate salt. Generic formulations of metoprolol ER 
became available in the late 2000s, and at least 3 products are currently marketed by 
various manufacturers:  Dr. Reddy’s Laboratories, Inc (India), Mylan Inc (Canonsburg, 
PA), and Actavis PLC (Formerly Watson, Parsippany, NJ). The availability of generic 
metoprolol ER offers a more affordable alternative for patients requiring β-blocker 
therapy. However, bioequivalence is essential to ensure that the quality of the generic 
product is similar to that of the brand name product.  
The manufacturer of a generic product must provide data to the Food and Drug 
Administration (FDA) showing that the generic is bioequivalent to the brand name 
product. Bioequivalence is used as a surrogate for therapeutic equivalence and is defined 
under the Code of Federal Regulations Title 21 Part 320 (21 C.F.R. §320).  The FDA 
proposes a two-pronged approach for testing bioequivalence consisting of in vitro 
dissolution testing and in vivo pharmacokinetic studies of the active substance. For the 
latter, two products are considered bioequivalent when any differences in the rate or 
extent of bioavailability of the active moiety are viewed as clinically insignificant (usually 
within 80% to 125% of the branded product).5,6 Cross-over studies in healthy volunteers, 
where single doses of the reference and generic products are administered at the same 
labeled strength and under similar testing conditions, with quantification of area under the 
plasma concentration time curve (AUC) and peak plasma concentration (Cmax), are the 
most frequently used in-vivo studies to establish bioequivalence, and this is what is 
recommended in the FDA’s draft guidance for bioequivalence studies for metoprolol.7 
However, as acknowledged in a separate draft guidance dated March 2014, for extended 
release products, such as metoprolol ER, bioequivalence studies may not be sufficient to 
ensure similar safety and efficacy if the pharmacokinetic profiles of the two products differ. 
This draft guidance specifically cited differences in Tmax as potentially problematic.8  In 
this case, the guidance states that additional studies may be needed to ensure 
therapeutic equivalence between products.   
Recently, the quality of generic metoprolol ER formulations has been called into 
question with reports of inconsistent effects when switching from the brand name to 
generic formulation. Whether this is actually a problem with bioequivalence and 
differences in therapeutic efficacy between products or is representative of the 
misperception that generic products are of poorer quality than the brand name formulation 
is unclear. However, if the products are truly not bioequivalent, this could compromise 
clinical outcomes and impact the risk for adverse events following generic 
substitution. A previous formulation of metoprolol ER (manufactured by Sandoz Inc.) 
was removed from the market after the FDA discovered failures in the process validation 
studies for metoprolol succinate tablets and variability among lots.  The FDA recently 
issued a warning letter to Wockhardt Ltd, another manufacturer of generic metoprolol ER, 


Page 8 of 41 
 
citing violations of good manufacture practice regulations and for adulterated drug 
products. These actions, in addition to the March 2014 draft guidance referenced above, 
point to a need to further investigate the bioequivalence of generic metoprolol ER 
products.   
 
Factors potentially compromising bioequivalence of metoprolol products.  For in-
vitro dissolution testing of most products, including metoprolol ER, the FDA requests that 
testing be conducted using a US Pharmacopeia method and include at least 3 dissolution 
media (e.g. pH 1.2, 4.5, and 6.8 buffers) to demonstrate that the drug is stable in acidic 
stomach conditions and will release in the intestine.7  However, even with comprehensive 
in-vitro testing, predicting in-vivo performance of drug can be challenging given that 
various physiological parameters can influence drug bioavailability. These include 
regional pH, bile acid and pancreatic secretions, luminal and mucosal enzymes, gastric 
emptying, intestinal permeability, gut transit time, and fluid volume. For in-vivo 
pharmacokinetic studies, the FDA recommends single dose studies in healthy volunteers 
because they are more sensitive in assessing drug release characteristics.6 However, 
such studies may not necessarily reflect drug bioavailability after multiple drug doses in 
patients with disease. A combination of patient- and product-specific factors may 
compromise the dissolution and bioequivalence of generic metoprolol ER products.  
Specifically, concomitant medications or diseases that alter gut pH or transit time, and 
dietary factors that influence solubility could influence drug dissolution and bioavailability.9 
In addition, for modified-release products, such as metoprolol ER, there is a concern for 
alcohol-induced dose dumping, which can pose serious safety concerns.10  In terms of 
product-specific factors, excipients in the product may lead to variability in pKa, solubility, 
stability, and molecular weight, which could potentially influence the degree to which 
alterations in physiologic conditions affect drug  dissolution and bioavailability.11   
 
Effect of CYP2D6 genotype on metoprolol metabolism.  Genotype may also impact 
the bioavailability of metoprolol.  O-demethylation via the cytochrome P450 2D6 
(CYP2D6) enzyme is the principal route of metoprolol metabolism, with metabolites 
having no significant β-blocking effect.13 The gene for CYP2D6 is highly polymorphic, with 
over 100 alleles defined (http://www.cypalleles.ki.se). The CYP2D6*1 and *2 alleles are 
associated with normal enzyme activity.  Individuals with one or two copies of normally 
functioning alleles are deemed extensive metabolizers (EMs). The *9, *10, *17, *29, and 
*41 alleles occur secondary to nonsynonymous single nucleotide polymorphisms (SNPs) 
and lead to a reduction in enzyme activity. The *3, *4, *5, *6, *7, *8, *11, and *15 alleles 
are examples of loss-of-function alleles that occur secondary to frameshift mutations (*3, 
*6), splicing defects (*4), gene deletion (*5), or other mutations.  Individuals with one loss-
of-function and one reduced-function allele are intermediate metabolizers (IMs), while 
those with two copies of loss-of-function alleles (e.g. *3 /*4) are poor metabolizers (PMs).  
At the opposite extreme, duplication or multiplication of functional alleles confers the ultra-
rapid metabolizer (UM) phenotype with marked increases in CYP2D6 activity. 
Frequencies of commonly described 


Page 9 of 41 
 
CYP2D6 alleles are shown in Table 1.  There is 
marked ethnic variability in the prevalence of 
CYP2D6 phenotypes, with the prevalence of 
PMs ranging from 0-10% and UMs ranging from 
0-29%. In a multi-ethnic clinical trial population 
with hypertension, we found that 5% of 
participants were PMs, 7% were IMs, and 4% 
were UMs.14    
 
Our group and others have shown that CYP2D6 
PMs and IMs have several-fold higher plasma 
concentrations of metoprolol and a longer 
elimination half-life compared to EMs.15-18 
However the data suggest that CYP2D6 genotype/phenotype may not significantly impact 
BP or adverse responses to metoprolol but may impact the HR response, and so may be 
important for some indications.14,16-19  Additionally, because metoprolol is a high first-pass 
effect drug, differences in dissolution rate/absorption may impact the absolute 
bioavailability, and these differences in first pass effect between products may also differ 
by CYP2D6 genotype.  The effect of CYP2D6 genotype on the bioequivalence of 
metoprolol products has not been examined and thus is important to define.  
 
Significance:  
Over 77 million Americans have hypertension, over 15 million have coronary heart 
disease, over 6 million have atrial fibrillation, and over 5 million have heart failure.20 In 
addition, over 700,000 Americans suffer a new or recurrent myocardial infarction each 
year.  Metoprolol is commonly used in the management of all of these diseases, and 
considered the standard of care for some, making it one of the most often prescribed 
medications in this country.   
The significance of this project is that it aims to elucidate whether there are 
important differences in the pharmacokinetics and therapeutic efficacy of FDA-approved 
metoprolol ER products, and if so, to identify the patient- and product-specific factors 
contributing to differences.  The line of research is important because differences in 
pharmacokinetics and therapeutic efficacy could increase the risk of therapeutic failure or 
adverse effects when patients switch from one metoprolol ER product to another.  
Metoprolol ER is considered the only appropriate metoprolol dosage form for treatment 
of heart failure, and the once daily dosing with metoprolol ER makes it a popular choice 
in the other conditions.  As such, differences among metoprolol ER formulations could 
have far reaching consequences. Furthermore, knowledge gained from this study will help 
inform bioequivalence metrics and criteria for generic metoprolol ER products to ensure 
availability of high quality generic alternatives. We have established expertise in 
pharmacokinetic and pharmacodynamics studies of metoprolol and other β-blockers in 
patients with hypertension and heart failure; pharmacokinetic and pharmacodynamic 
modeling; clinical trial research in the hypertensive and heart failure populations; and 
pharmacogenomics research. We believe our experience and publications strongly 
support our application and well position us to identify factors impacting bioequivalence 
and causing variability in response to ER metoprolol products. 
 
 
 
Table 1. CYP2D6 allele frequencies among 
ethnic groups12 
CYP2D6 
allele 
European 
African 
American 
East 
Asian 
*3 
1.3 
0.3 
0.0 
*4 
18.5 
6.2 
0.4 
*5 
2.7 
6.1 
5.6 
*6 
1.0 
0.2 
0.0 
*10 
3.2 
4.2 
42.3 
*17 
0.3 
18.2 
0.0 
*41 
8.6 
9.4 
2.0 
*1xN 
0.8 
0.4 
0.3 
*2xN 
1.3 
1.6 
0.4 


Page 10 of 41 
 
Credentials of Investigators: 
Investigator  
Contact Information  
Address  
Statement of Qualifications 
Larisa H. Cavallari  Tel: 352-273-8245 
Email: 
lcavallari@cop.ufl.edu 
 
PO Box 100486 
Gainesville, FL   
32610-0486 
 
Dr. Cavallari (PharmD), Associate Professor, Dept of 
Pharmacotherapy & Translational Research and 
Director of the Center for Pharmacogenomics at 
the University of Florida (UF), is an expert in 
cardiovascular 
pharmacology 
and 
pharmacogenetics and has extensive experience 
leading 
clinical 
research 
studies 
assessing 
pharmacokinetic 
and 
pharmacodynamics 
endpoints. 
Reginald Frye 
Tel: 352-273-5453 
Email: 
frye@cop.ufl.edu 
Box 100484, 
Gainesville, FL 
32610-0484 
Dr. Frye (PharmD, PhD) Professor and Chair, Dept 
of Pharmacotherapy & Translational Research at UF 
is an expert in clinical pharmacology and drug 
metabolizing 
enzymes 
that 
contribute 
to 
pharmacokinetic variability. 
Yan Gong  
Tel: 352-273-6297 
Email: 
gong@cop.ufl.edu 
PO Box 100486 
Gainesville, FL   
32610-0486 
Dr. Gong (PhD), Research Associate Professor, Dept 
of Pharmacotherapy & Translational Research at 
UF, is an expert in biostatistics and statistical 
genetics. 
Siegfried O.F. 
Schmidt 
Tel: 352-265-9475 
Email:   
siggy@shands.ufl.edu 
200 SW 62nd 
Blvd Suite D 
Gainesville, FL 
32607 
Dr. Schmidt (MD, PhD), Professor of Family 
Medicine at UF and Medical Director of Family 
Medicine at the UF Hampton Oaks clinic has 
extensive experience participating in hypertension 
clinical trials 
Taimour Langaee 
Tel:  352-273-6357 
Email:  
Langaee@cop.ufl.edu 
PO Box 100486 
Gainesville, FL   
32610-0486 
Dr. Langaee (MSPH, PhD), Research Associate 
Professor, 
Dept 
of 
Pharmacotherapy 
and 
Translational Research at UF and Director of the UF 
Center for Pharmacogenomics Genotyping Core 
Laboratory has extensive experience in genotyping 
and genetic technology. 
Stephan Schmidt  
Tel: 407 313 7012 
Email: 
sschmidt@cop.ufl.edu 
6550 Sanger 
Road, Office 
467 
Orlando, FL 
32827 
Dr. Schmidt (PhD), Assistant Professor, Department 
of Pharmaceutics, UF and faculty in the UF Center 
for Pharmacometrics and Systems Pharmacology 
(CPSP) 
is 
an 
expert 
in 
pharmacometrics, 
physiologically-based pharmacokinetic modeling, 
and drug-disease models. 
David Estores Jr. 
Tel: 352-273-9400 
Email:  david.estores 
@medicine.ufl.edu 
PO Box 100214 
Gainesville, FL   
32610-0214 
Dr. Estores (MD), Assistant Professor of Medicine 
and Director of Endoscopy at UF Health is an expert 
in gastroenterology and has experience with use of 
wireless capsule systems for pH monitoring in the 
research and clinical settings. 
Nihal El Rouby 
Tel: 352-273-6038 
Email: 
nihalelrouby@ufl.edu 
PO Box 100486 
Gainesville, FL   
Nihal El Rouby (PharmD, PhD), Pharmacogenomics 
Fellow,  Dept of Pharmacotherapy & Translational 


Page 11 of 41 
 
 
 
Research Facility: 
Clinical and Translational Science Institute, University of Florida 
Tel:  352-273-8700; Fax: 352-273-8703; Email: info@ctsi.ufl.edu 
 
Enrollment visit will be conducted at: 
UF Health Family Medicine at Hampton Oaks clinic 
200 SW 62nd Blvd 
Gainesville, FL 32607 
 
Screening, follow-up outpatient visits, and overnight study visits will be conducted at: 
Clinical and Translational Research Building 
2004 Mowry Road 
Gainesville, FL 32610 
 
Overnight study visits may also be conducted at: 
UF Health Shands Hospital  
1600 SW Archer Rd 
Gainesville, FL 32608  
 
IRB Oversight: 
University of Florida Institutional Review Board-1 (UF IRB-01) 
Ruth K and Shepard Board Building 
1300 Center Drive, Room 130  
Gainesville, FL 32610 
 
FDA RIHSC Oversight: 
U.S. Food and Drug Administration 
White Oak Building 32 Room4286 
10903 New Hampshire Ave, 
Silver Spring, MD 20993 
 
 
Objectives: 
 
Metoprolol succinate is widely used in the management of heart diseases and is available 
in generic formulations. However, there are mounting data suggesting potential issues 
with the bioequivalence and therapeutic equivalence of different generic metoprolol ER 
products, which could compromise clinical outcomes and impact the risk for adverse 
events with generic substitution. Studies used to establish bioequivalence between brand 
name and generic products are conducted in healthy volunteers rather than in patients 
 
32610-0486 
 
Research at UF has experience in clinical and 
laboratory research. 
 
 
 
 
 
 
 
 


Page 12 of 41 
 
with underlying disease. Alterations in drug absorption or metabolic function secondary 
to disease processes or patient-specific factors, such concomitant therapies, may lead to 
variable response to products thought to be bioequivalent. Variation in gastric pH and 
product dissolution could further affect the bioequivalence of metoprolol products. Genetic 
polymorphism for CYP2D6, which is responsible for metoprolol metabolism, may provide 
additional contribution to variability in the pharmacokinetics and clinical response to 
metoprolol. We hypothesize that both product- and patient-specific factors lead to 
variable pharmacokinetics and cardiovascular responses to metoprolol ER 
formulations. The goal of this project is to provide the pharmacokinetic and clinical 
response data necessary to inform optimal bioequivalence metrics and criteria for 
generic metoprolol ER products to ensure availability of high quality generic 
alternatives. 
 
Aim 1.  Compare the pharmacokinetics and cardiovascular effects of brand name 
and generic metoprolol ER products in patients with hypertension.  We will conduct 
a prospective, randomized, crossover trial of brand name and generic metoprolol ER and 
compare pharmacokinetics and cardiovascular responses with equivalent labeled doses 
of each product.  
 
Aim 2.  Determine the impact of gastric pH variation on the concentration-response 
relationship with different metoprolol ER products. Among patients in the Aim 1 
study, we will examine the association between gastric pH, concomitant use of proton 
pump inhibitors, pharmacokinetics, and clinical response. 
 
Aim 3.  Examine the effect of CYP2D6 genotype on the pharmacokinetics of 
different metoprolol ER products.  CYP2D6 extensive and poor metabolizers will be 
preselected to participate in the Aim 1 study in order to examine the impact of CYP2D6 
genotype on variable pharmacokinetics and clinical responses with metoprolol ER 
products. 
 
Regulatory Status: 
 
An IND/IDE is not required to conduct this study. 
 
Background (past findings and relevant literature):   
 
The research team has substantial experience with clinical pharmacokinetic and 
pharmacodynamic studies. The research team has significant experience studying β-
blockers, including research in healthy volunteers and patients with hypertension, heart 
failure and ischemic heart disease and comprising assessment of numerous clinical 
responses, pharmacokinetics, pharmacodynamics, and pharmacogenetics.  Data from 
selected publications relevant to the proposal herein are described below.  
 


Page 13 of 41 
 
Comparison of metoprolol formulations in a heart failure population and 
relationship of clinical responses to pharmacokinetics.  Based on questions at the 
time regarding differences in clinical outcomes for heart failure patients treated with 
immediate release (IR) versus ER metoprolol, we conducted a crossover study to 
evaluate possible mechanisms for the perceived differences in clinical outcomes by 
metoprolol formulation.21  A total of 13 chronic systolic heart failure patients were 
randomized to a 2-way crossover study of equal total daily doses of the IR (generic 
metoprolol 
tartrate) 
and 
ER 
metoprolol 
(Toprol 
XL®) 
formulations. 
 
After 
3-week 
treatment with each formulation, 
patients underwent pharmacokinetic 
evaluation at various time points 
during the dosing interval, 24 hour 
ambulatory BP monitoring, and 24-
hour Holter monitoring.  Metoprolol 
IR concentrations exceeded those of 
the ER formulation approximately 
60% of the time, as shown in Figure 
1.  Despite this, both systolic and 
diastolic BPs were significantly lower 
for metoprolol ER versus IR over the 
entire 24-hr period (Figure 2, left 
panel). These data demonstrate that 
the antihypertensive effects of metoprolol are unrelated to plasma drug concentration.  
These findings are consistent with our previous observations in patients with 
hypertension.22  An explanation for the poor plasma concentration-response relationship 
may be due to the sigmoidal nature of the concentration response curve for β-blockers. 
Specifically, once maximal antihypertensive response is achieved (Emax), concentrations 
above this level do not result in any additional BP lowering effect. 
 
We also observed greater HR variability with the ER formulation21. Mean 24-hr HR was 
similar between groups. However, the high to total frequency ratio (high-frequency HR 
variability) and the high to low frequency ratio were significantly greater with metoprolol 
ER versus IR. The low to total frequency ratio (low-frequency HR variability) was 
significantly lower for the ER formulation. These data are consistent with increased 
parasympathetic activity and decreased sympathetic activity (indicated by lower low-
frequency HR variability) with metoprolol ER compared to IR. Reduced HR variability is 
an independent risk factor for increased mortality in heart failure.23-25  Evidence that 
metoprolol ER is associated with increased HR variability suggests that this mechanism 
may contribute to the greater survival benefits observed with metoprolol ER over 
metoprolol IR in patients with heart failure. Importantly, the differences in HR variability 
were observed despite similar 24-hr HRs between products, indicating that HR variability 
is a better discriminator of clinical benefits between β-blockers.    
Figure 1. Comparison of plasma concentration time 
curves for metoprolol IR (MIR, open circles) and 
metoprolol ER (MXL, black circles) 


Page 14 of 41 
 
 
 
Discordant β-blocker effects on BP and HR.  Additional data from our group suggest 
that response rates to β-blocker therapy differ depending on the clinical response 
studied26. We initiated metoprolol in patients with hypertension, with clinic BP, ambulatory 
BP monitoring, and exercise treadmill testing assessed before and after treatment. 
Patients were classified as responders or nonresponders to metoprolol if the diastolic BP 
decreased by ≥10% or <10%, respectively.  When classified based on clinic BP response, 
71% of patients were considered responders to metoprolol. However, only 47% met this 
definition based on ambulatory data. In addition, BP response to metoprolol was not 
predictive of HR response. As shown in Figure 3, both responders and nonresponders 
to metoprolol based on BP data, had significant reductions in HR, whether measured at 
Figure 2. The left panel shows comparison of 24-hr (A) systolic blood pressure and (B) diastolic blood 
pressure between metoprolol IR (MIR, open circles) and metoprolol ER (MXL, black circles).  Right 
panel shows comparison of (A) high to total frequency variability ratios and (B) low to total frequency 
variability ratios for metoprolol IR (MIR, open circles) and ER (MXL, closed circles).   


Page 15 of 41 
 
rest or with exercise. These data suggest 
that patients with little to no BP reduction 
with metoprolol may still derive significant 
benefit from β-blocker management of 
disease where HR reduction is important, 
such as in atrial fibrillation, heart failure, 
and ischemic heart disease. Overall, 
these data highlight the importance of 
assessing multiple clinical endpoints to 
clearly define response to metoprolol.   
 
Clinical response to metoprolol by 
CYP2D6 genotype.  As part of the PEAR-
2 study, we examined the influence of 
CYP2D6 genotype on the efficacy and 
tolerability of metoprolol tartrate in a 
subset of 281 patients, including 73 
enrolled from UF.27 The CYP2D6*2, *3, *4, *6, *10, *17, and *41 alleles were detected via 
PCR and pyrosequencing using a PSQ HS96A SNP reagent kit. Additionally, copy 
number variation was estimated by the TaqMan Copy Number Assay (Life Technologies) 
and a pyrosequencing-based method27. Quantification of CYP2D6 gene copy number 
was performed using CopyCaller Software (Applied Biosystems). Phenotypes were 
assigned based on genotype. Poor and intermediate metabolizers were found to have 
significantly greater HR response to metoprolol, consistent with these CYP2D6 
phenotypes being the ones that result in the highest plasma drug concentrations (Figure 
4). In contrast, these impaired metabolism phenotypes were not associated with 
differences in the BP response or tolerability/adverse effects to metoprolol.  Based on 
these data, we will enroll both PMs and IMs to compare against EMs.    
 
 
The lack of difference in BP and adverse responses is consistent with previous reports 
from our laboratory on metoprolol pharmacokinetics and response in heart failure and 
hypertensive patients.28, 29 Consistent with our most recent report, in both of the previous 
studies we showed the expected differences in S-metoprolol concentration by CYP2D6 
phenotype, but did not show differences in tolerability or response to metoprolol. 
Collectively, these data (and others in the literature for metoprolol and CYP2D6) suggest 
that CYP2D6 genotype-derived phenotype is associated with dramatic differences in 
metoprolol pharmacokinetics and yet these differences translate into minimal differences 
in efficacious or adverse responses to the drug, with HR being the one response 
phenotype with a possible difference by CYP2D6 genotype.30, 31  The latter is also 
consistent with other data in the literature which document the strongest PK-PD 
relationship with the HR response.31 Thus, the primary analyses by CYP2D6 phenotype 
will focus on pharmacokinetic differences between the formulations.  
 
 
Figure 3. Effect of metoprolol on daytime diastolic and 
systolic BP, maximum exercise HR, and sitting resting 
HR in responders and nonresponders according to 
ambulatory diastolic BP. 


Page 16 of 41 
 
Use of PEAR-2 patients to facilitate 
recruitment into this trial.  Dr. Johnson 
was the PI for the PEAR (ClinicalTrials.gov 
identifier: 
NCT00246519) 
and 
PEAR-2 
(ClinicalTrials.gov Identifier: NCT01203852) 
clinical trials of hypertensive patients.  PEAR 
and PEAR-2 were funded by the NIH 
Pharmacogenomics Research Network, and 
both involved the enrollment of hypertensive 
patients at UF, Emory University and Mayo 
Clinic.  PEAR enrolled 1701 patients, of 
whom 768 met all inclusion criteria and 
completed all aspects of the approximately 6 
month clinical trial. PEAR-2 was recently 
completed (March 2014) and enrolled 836 
patients, with 418 completing the trial.  In the 
context of the proposed study, 127 patients 
completed the PEAR-2 trial at UF, of which 
we have complete metoprolol response data 
on 108 (the remaining 19 had a β-blocker 
contraindication and so were only studied on 
chlorthalidone). 
 
We 
have 
call-back 
information on these patients, and based on 
our 9 years of conducting hypertension 
clinical trials with the UF Department of 
Community Health and Family Medicine, we 
have established excellent rapport with these 
patients. In the PEAR trial (for which we 
studied atenolol), we studied β-blocker 
response in 312 unique hypertensive patients at UF, who also provided call back 
information.  These patients will be targeted for recruitment specifically targeting those 
with known tolerability to metoprolol or atenolol based on experience from PEAR-2 and 
PEAR studies, respectively.  We will further select patients based on CYP2D6 genotype, 
which is available from the PEAR studies, and clinical use of a proton pump inhibitor.  
Study Design and Methods: 
 
Study design.  This will be a randomized, cross-over study of equal doses of different 
formulations of metoprolol succinate: Toprol XL, brand name metoprolol succinate; Dr. 
Reddy’s, generic metoprolol succinate product 1 (Gx metoprolol ER 1); and Actavis, 
generic metoprolol succinate product 2 (Gx metoprolol ER 2) in hypertensive patients as 
Figure 4.  Median (IQR) clinical responses to 
metoprolol based on CYP2D6 phenotype. 
Shown are changes in (a) heart rate, (b) 
systolic BP, and (c) diastolic BP from 
baseline.   


Page 17 of 41 
 
illustrated in Figure 5.  We anticipate that 50 patients may need to be enrolled to complete 
studies on a target of 38 patients.   
 
Study Treatment Length. The 7 day duration was chosen for Phase 2 and 3 because 
there are multiple lines of evidence that the therapeutic effect of β-blockers is fully evident 
within a 7-day period.32,33 Secondly, we have shown in our formulation crossover study 
that this is a sufficient period to document difference between formulations.21   
 
Study population and eligibility requirements. The primary target for recruitment will 
be participants from the recently completed PEAR-1 and PEAR-2 studies who were 
recruited from the UF site and provided call-back information. 
 
Inclusion criteria to enroll study participants include: 
 Age 18-years or older 
 Diagnosed with Essential Hypertension 
 
Patients will be targeted for enrollment based on current treatment of their hypertension 
with a β-blocker or known tolerability to a β-blocker based on their previous participation 
in the PEAR studies. If necessary to meet enrollment targets, additional patients will be 
recruited from the patient population in the UF Health Family Medicine – Hampton Oaks 
clinic at UF, UF HealthStreet, UF Integrated Data Repository (IDR), Oak Hammock and 
through advertisements placed in local classified services.  More detailed recruitment 
methods are described below under “Subject Selection and Recruitment”.  Patients 
enrolled in the PEAR studies provided consent for genotyping, and most of those from 
PEAR-2 have been genotyped for CYP2D6 variants. Participants with the PM, IM, or EM 
phenotype will be enrolled based on CYP2D6 genotype-derived phenotype. We anticipate 
that 40% to 60% of patients enrolled will be taking a proton pump inhibitor for clinical care, 
which will be taken into account in the data analysis. 
 
Exclusion criteria: These criteria match those of PEAR studies and include the following: 
Figure 5.  Study design 


Page 18 of 41 
 
 Documented secondary forms of HTN 
 Known cardiovascular disease (including history of angina pectoris, myocardial 
infarction, coronary revascularization procedure, heart failure, or presence of a cardiac 
pacemaker) 
 Known cerebrovascular disease (including stroke and TIA) 
 Known peripheral vascular disease 
 Diabetes mellitus (Type 1 or 2) (defined as a diabetes diagnosis in the medical record 
or fasting blood glucose ≥ 126 mg/dl or nonfasting blood glucose ≥ 200 mg/dl on 
screening laboratories) 
 Systolic blood pressure (SBP) >170 mm Hg on screening visit 
 Heart rate <55 bpm on screening visit (in the absence of treatment with a β-blocker)  
 Renal insufficiency (serum creatinine >1.5 in men or >1.4 in women on screening 
laboratories) 
 Liver enzymes (ALT and/or AST) >3 times the upper limit of normal on screening 
laboratories. 
 Known Raynaud’s phenomenon 
 Current diagnosis of asthma or chronic obstructive pulmonary disease, unless patient 
is currently tolerating or has previously tolerated metoprolol 
 
Pregnancy or lactation 
 Concomitant treatment with non-dihydropyridine calcium channel blockers (diltiazem 
or verapamil), digoxin, or clonidine because of additive HR suppression 
 Concomitant treatment with catecholamine depleting drugs, reserpine or monoamine 
oxidase inhibitors  
 Concomitant treatment with the potent CYP2D6 inhibitors quinidine, fluoxetine, or 
propafenone  
 
With the exception of concomitant therapies listed in exclusion criteria, the use of other, 
non β-blocker, anti-hypertensives and other drug therapy will be allowed as long as 
therapy is held constant during study participation 
 
Additional contraindications, which pertain to administration of the SmartPill capsule 
in Aim 2, include a history of any of the following, as documented in the electronic health 
record: 
 History of gastric bezoars 
 Swallowing disorders 
 Strictures 
 Fistulas  
 GI obstruction 
 History of gastrointestinal surgery within the past three months 
 Severe dsyphasgia 
 Crohn’s disease  
 Diverticulitis 
 Any implantable electromedical device 
 


Page 19 of 41 
 
Protocol. The protocol is described in detail below. Patients will be randomized at the 
baseline visit to one of two groups using the blocked randomization method with a block 
size of 4: 
 
Study group A 
 
Study group B 
 
Both study arms consist of 4 metoprolol succinate treatment phases and 3 overnight study 
visits.  Randomization will be stratified by CYP2D6 genotype.  Toprol XL will be 
administered in the first phase/period for all participants. The rationale for this is that 
the problems with the generic formulation are reported after the switch from the brand 
name to generic product.  Thus, we want to capture the switch from brand name to each 
generic.   
 
Screening visit.  Patients will be asked to come to the UF Clinical Translational Science 
Institute (CTSI) located in the Clinical Translational Research Building in Gainesville.     
After obtaining written, informed consent, the following will be done: 
 Demographics, medical history and concomitant medication will be obtained, 
 Vitals, Height and weight will be collected. 
 
The study nurse will draw 15 mL of blood total. 10 mL (2 teaspoonful) of venous blood 
for a basic metabolic panel, AST, and ALT and 5 mL (1 teaspoonful) of venous blood 
for genotyping. A urine pregnancy test will be done for women of childbearing 
potential. 
In the absence of exclusion criteria from medical history, vitals and lab results, patients 
will be scheduled for the enrollment study visit within 2 weeks.    
 
Enrollment visit.  The enrollment visit will be conducted in the UF Health Family Medicine 
- Hampton Oaks clinic in Gainesville.  
 The study physician will perform a physical exam on each patient.   
 Patients meeting inclusion criteria will be randomized to study group A or study group 
B using a block randomization with a block size of 4. 
 Patients will be provided with a supply of Toprol XL. There will be no washout phase. 
Patients taking metoprolol succinate will be asked to stop taking their supply of drug 
and will be supplied with the same dose of the study drug to take instead for the 
duration of the study. The study physician may adjust metoprolol succinate doses up 
or down to achieve or maintain each patient's goal blood pressure. Patients taking a 
beta-blocker that is not metoprolol succinate on enrollment, will be switched to an 
“equivalent” Toprol XL dose (i.e. 200 mg Toprol XL daily for 100 mg atenolol daily; 
200 mg Toprol XL daily for 50 mg carvedilol daily, etc.), which will be determined by 
the study physician during the physical exam. The patient will be provided with up to 
a 2-week supply of study drug and asked to return once a week for a blood pressure 
check and additional supply of study drug, if necessary, until the first overnight 
pharmacokinetic (PK)/pharmacodynamic (PD) visit. Patients not currently taking a β-
blocker will either have Toprol XL added if not at goal BP, or Toprol XL substituted for 
another antihypertensive medication. In either case, Toprol XL will be started on 50 
mg/day.  This is within the recommended initial dose range in the drug labeling of 25-


Page 20 of 41 
 
100 mg/day. Toprol XL will be provided by the Investigational Drug Service (IDS), and 
patients will be instructed to take their Toprol XL dose at 9 A.M. each morning.  
 Patients will be asked to bring their study medication pill bottle and leftover pills to 
each study visit for pill counts to assess adherence. 
 Patients will be provided with a home BP monitor and appropriate sized cuff.  Patients 
from PEAR-1 and PEAR-2 underwent extensive training by research personnel on the 
use of the home BP monitor. Patients will be provided additional training as needed 
and instructed to monitor BP at home upon arising in the morning and just before 
retiring in the evening daily (with the exception of overnight study visits) until the study 
is completed.     
 Patients will be instructed to contact the study nurse for a BP check if their home BP 
monitor shows two consecutive resting BP measurements taken 5 minutes apart >170 
or <100 mmHg for SBP and/or >110 mmHg for diastolic blood pressure (DBP), or 
pulse <50 beats/minute at any time during the study. The dose will be reduced by half 
for a systolic BP <100, symptoms of hypotension, or pulse <50BPM following initiation 
of therapy. Home BP data will be collected using the Microlife 3 AC1-PC (Minneapolis 
MN), set in triplicate mode. Each activation of the device will lead to the measurement 
of BP in triplicate, and the HR and BP readings are electronically recorded and time-
stamped. The data will then be downloaded by the study coordinator when the study 
participant reports to the clinical research center (CRC) for BP checks during dose 
titration or for overnight studies. 
 
The schedule of events is shown below in Table 2.   
 


Page 21 of 41 
 
 
Table 2. Schedule of events 
 
Screening  
 
Enrollment 
Dose Titrationa 
followed by 
Phase 1 
PK-PD 
#1 / 
Phase 2 
 PK-PD 
#2  
 
Phase 3 
    
Phase 4 
 PK-PD 
#3 
Follow 
up  
Visitf  
1 
2 
3 (3a, 3b, 3c) 
4 
5 
6 (6a, 6b, 
6c) 
7 
8 
9 (9a, 9b, 
9c) 
Study week  
0 
1-2 
2 to 5 
2 to 6b 
3 to 7b 
4 to 12c 
4 to 13 
5 to 
14c 
6-15 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
Body Weight 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Sitting Vital 
Signs 
X 
X 
X 
 
 
X 
X 
 
X 
Basic 
metabolic 
panel  
X 
 
 
 
 
 
 
 
 
AST/ALT 
X 
 
 
 
 
 
 
 
 
Genetic whole 
blood sample  
X 
 
 
 
 
 
 
 
 
Urine 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Physical Exam 
 
X 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
 
 
X 
 
 
 
 
 
 
 
Randomization  
  
X 
 
 
 
 
 
 
 
Dispense Study 
Drug 
  
X 
X 
X 
X 
X 
X 
X 
X d 
Medication 
compliance  
 
 
X 
X 
X 
X 
X 
X 
 
PK sample  
 
 
 
X e 
X e 
 
 
X e 
 
Holter monitor  
 
 
 
X 
X 
 
 
X 
 
Ambulatory BP 
monitoring 
 
 
 
X 
X 
 
 
X 
 
pH monitoring 
 
 
 
X 
X 
 
 
X 
 
Treadmill 
exercise 
 
 
 
X 
X 
 
 
X 
 
Adverse 
events 
assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
Study drug 
tapering  
 
 
 
 
 
 
 
X 
X 
a: Includes up to 3 weekly visits for dose titration to 100 mg  
 qd, 150 mg qd, and 200 mg qd as tolerated or until BP <140/90 mm Hg 


Page 22 of 41 
 
 
Phase 1. Phase 1 will consist of treatment with Toprol XL for 7 to 28 days.  The range in 
duration of Phase 1 is to allow for -blocker up-titration if needed to achieve a BP < 140/90 
mm Hg and to allow flexibility in scheduling the first overnight visit.  Patients not on a β-
blocker prior to the study (i.e. patients starting Toprol XL 50 mg/day) will be asked to 
come to the CRC in the Clinical and Translational Research Building (CTRB) each week 
for a BP check and dose titration to a maximum dose of 200 mg/day or BP <140/90 mm 
Hg.  At least one titration visit, documenting BP < 140/90 mm Hg, will be required before 
scheduling the first PK/PD study visit. This optimized dose will be used for all PK-PD 
visits. 
 
Patients will be reminded at each visit to take their Toprol XL dose at 9 A.M. each morning 
and to continue to monitor their BP at home with the monitor provided as described above.  
At the end of Phase 1, patients will be asked to stay overnight at the CRC or the UF 
Health Shands Hospital for the first pharmacokinetic (PK)/ pharmacodynamics (PD) study 
visit. A pill count will also be conducted during this visit and subsequent visits to ensure 
patient adherence.  
 
PK/PD study visit.  Subjects will be instructed to abstain from caffeine and alcohol 
beginning at 8 P.M. the night before the study and for the entire study day, and fast (no 
food or beverage except water) beginning at 12 midnight before the study. Patients will 
be asked to wear and/or bring comfortable clothing and shoes suitable for walking on a 
treadmill. Patients will arrive to the CTSI CRC or at Shands Hospital at the University of 
Florida the morning of their scheduled visit.   
The following will be placed:   
 
Holter monitor for determination of total 24-hour heart beat and HR variability  
 
ambulatory BP monitor for 24-hour blood pressure 
 
an indwelling venous catheter for a 24-hour pharmacokinetic study  
 
Patients will not be allowed to shower while wearing the monitors, but can do other normal 
activities. Patients will be asked not to leave the unit until completion of the study the 
following day. Patients will be given a SmartBar® (Given Imaging, Duluth GA) 
standardized meal to eat before taking the SmartPill to initiate post-prandial motility. 
Immediately afterward, participants will be asked to swallow a disposable SmartPill® 
capsule (Given Imaging), designed to continuously measure pH and motility as it moves 
through the gastrointestinal track until it is excreted.   
 
Patients will be provided a regular diet, or any diet appropriate to their needs, for 
the duration of the overnight stay. Patients will be given a similar type of diet for each 
subsequent PK/PD visit to minimize any impact of meals on the pharmacokinetics of the 
metoprolol formulation.   
b: Study week is dependent on duration of Toprol XL treatment in Phase 1, which many range from 7 to 28 days 
c: Study week is dependent on duration of Toprol XL treatment in Phase 3, which many range from 7 to 28 days  
d: Study drug will be dispensed for patients undergoing dose tapering 
e: Immediately before the dose (baseline) ± 5min, then 30min ± 5min, 60min ± 5min, 2hr ± 10min, 3hr ± 10min, 4hr ± 10min, 
6hr ± 20min, 8hr ± 20min,  12hr ± 30min, 16hr ± 30min, 20hr ± 30min, 24hr ± 30min after the dose 
f. Study visits window +/- 2 days 


Page 23 of 41 
 
 
At the end of the 24-hour study period, the Holter monitor, ambulatory BP monitor, 
and venous catheter will be removed. Patients will be given another dose of their 
metoprolol succinate 2 hours before their scheduled submaximal exercise treadmill test. 
Patients will be taken to the Shands Heart Center where they will undergo a submaximal 
exercise treadmill test. The PD studies will conclude following completion of their treadmill 
testing. Details of each PK and PD measurement are described below.   
 
Phase 2.  At the end of the first overnight study visit, the patient will be crossed over to 
the first generic metoprolol succinate formulation to which they are randomized.  A 7-day 
supply of the generic product will be supplied by the IDS at the same dose as the final 
dose of Toprol XL for the patient in Phase 1. The overnight PK/PD studies will be repeated 
at the end of Phase 2.   
 
Phase 3.  Patients will then be placed back on Toprol XL at the same dose as determined 
in Phase 1.  Toprol XL will be dispensed in 7 day supplies, and patients will come to the 
CRC for BP checks each week and another 7 day supply of study drug until Phase 4. The 
range in length of Phase 3 treatment is to allow flexibility in scheduling the final overnight 
study visit after Phase 4.  During Phase 3, data collection from the Holter monitor or the 
ambulatory blood pressure monitor may be repeated on an outpatient basis to replace 
erroneous or missing data collected during PK/PD Study Visit 1 (Phase 1). This repeated 
data collection will only be necessary if there were errors in heart rate variability or 
ambulatory blood pressure data collection during Phase 1, and the patient agrees to wear 
the monitor(s) as an outpatient during Phase 3. 
 
Phase 4. 
After Phase 3, patients will come to the CRC for a BP check. They will be given a 7-day 
supply of the final generic product for Phase 4, at the same dose as determined in Phase 
1, followed by the final overnight PK/PD studies.  After the overnight PK/PD studies, 
patients taking metoprolol or any other β-blocker prior to study enrollment will be placed 
back on their pre-study medication. On the other hand, patients who were not on a β-
blocker before study enrollment, will have the metoprolol dose reduced by 50% initially 
as part of a weekly tapering regimen, and will be restarted on any medication that was 
withdrawn or dose adjusted on study enrollment. 
 
Follow-up study procedures.  Patients will be scheduled for a follow up visit for a BP check 
at the CRC one week after the last overnight study visit.  Patients will be asked to return 
the SmartPill® data recorder to the study nurse at this visit. Patients who are undergoing 
a metoprolol taper will have their metoprolol dose reduced by 50% each week until 
completely withdrawn, with an outpatient visit for a BP check scheduled with each dose 
reduction. Patients will be asked to continue to measure BP in the A.M. and P.M. and to 
call the study nurse for a BP check in the CTSI if two consecutive resting SBP 
measurements are above 170 or below 100 mmHg, and/or DBP measurements are 
above 110 mmHg when taken at least 5 minutes apart, or pulse below 50 BPM.  The 
study nurse will call the patient between 3 to 5 weeks after the final overnight study visit 
for a safety check, which will include asking about home BP readings and the occurrence 


Page 24 of 41 
 
of any adverse effects. This will end the patient’s study participation. Patients may keep 
the home blood pressure monitor after the study for their personal use. 
    
Detailed description of PK/PD study procedures: 
 
Ambulatory BP monitoring.  On admission to the CRU, patients will be fitted with a 
SpaceLabs 90227 OnTrak ambulatory BP monitor (Spacelabs Healthcare, Snoqualmie, 
WA) and a MindWare Mobile Cardio/GSR holter monitor (MindWare  Technologies LTD, 
Gahanna, OH).  The ambulatory BP monitor will be programmed to randomly measure 
BP 4 times per hour during the day (6 A.M.-11 P.M.) and 2 times per hour during the 
nighttime (11 P.M.-6 A.M.), as in previous trials.21,19,34,35   
 
Pharmacokinetic studies.  The metoprolol dose will be administered between 8 A.M and 
12 P.M.  A 6-ml blood sample will be drawn from the venous catheter into EDTA collection 
tubes at the following times: immediately before the dose (baseline), and at 30 mins  5 
mins, 60 mins  5 mins, 2 hrs  10 mins, 3 hrs  10 mins, 4 hrs  10 mins, 6 hrs  20 
mins, 8 hrs  20 mins, 12 hrs  30 mins, 16 hrs  30 mins, 20 hrs  30 mins, and 24 hrs 
 30 mins after the dose.  A total of 72 mls (almost 5 tablespoonfuls) of blood will be 
drawn from the catheter during the overnight study visit.  Blood will be immediately 
centrifuged, and the plasma separated and stored at -20ºC or -80 ºC until analysis. 
Metoprolol enantiomer concentrations will be determined by a validated chiral high-
performance liquid chromatography tandem mass spectrometric method, modified based 
on a fluorescence detection method previously published by our group.22  
 
pH monitoring. The SmartPill® Capsule and GI Monitoring System offers a noninvasive, 
nonradioactive, well tolerated means of assessing gastrointestinal pH and motility.  The 
SmartPill is an ingestible, single-use capsule and is FDA-cleared to aid in the evaluation 
of gastrointestinal motility conditions.  As it moves through the GI tract, it wirelessly and 
continuously transmits data to a recorder worn on the belt or lanyard for up to 5 days or 
when it passes with a regular bowel movement. Dr. Estores (Co-Investigator) has 
extensive experience in gastrointestinal and esophageal pH monitoring via a number of 
techniques.36-42 Most relevant to this proposal, he has experience with wireless capsule 
systems to monitor pH in both the research and clinical settings.36,40  Immediately after 
ingesting a SmartBar®, participants will be given a SmartPill® capsule to swallow, and 
fitted with the wireless Data Recorder to wear on a belt or lanyard until the SmartPill® 
capsule passes with a regular bowel movement.   The participant will be discharged with 
the Data Recorder to be worn at all times except while bathing or sleeping. The recorder 
should be removed while bathing and placed close by where it will not get wet. While 
sleeping, the participant will be instructed to place the data recorder under the pillow or 
on a nightstand by the bed.  The SmartPill® is expected to pass within 5 days of ingestion, 
and participants will be asked to return the Data Recorder at the next scheduled study 
visit.  
 
Exercise treadmill.   Patients will undergo submaximal graded exercise testing to 
gradually reach 85% of their maximum predicted exercise HR calculated as:  0.85 * (220-
age).  A 12-lead ECG will be placed to monitor HR and conduction during exercise, and 


Page 25 of 41 
 
a BP monitor will also be placed.  HR will first be recorded in the supine, sitting, and 
standing position after at least 5 minutes of rest between readings. Treadmill exercise will 
begin at 1.7 mph with a 0% incline.  The speed and slope of the incline will be increased 
as shown below.  
 
Product Information: 
 
Product 
 
 
 
Toprol XL  
Metoprolol 
succinate 
Actavis  
Metoprolol 
succinate Dr. 
Reddy’s 
Laboratories  
SmartPill 
capsule 
SmartBar 
Chemical 
name  
di-[(±)-1-
(isopropylami
no)-3-[p-(2-
methoxyethyl
) phenoxy]-2-
propranol] L-
(+)-tartrate 
di-[(±)-1-
(isopropylamino
)-3-[p-(2-
methoxyethyl) 
phenoxy]-2-
propranol] L-
(+)-tartrate 
di-[(±)-1-
(isopropylamino
)-3-[p-(2-
methoxyethyl) 
phenoxy]-2-
propranol] L-
(+)-tartrate 
Contains 
sensors 
which 
transmit pH 
and 
pressure 
measure-
ments to a 
data 
receiver via 
ASK 
modulated 
RF signal 
at 434 MH  
Contains whey 
crisp, rolled 
oats, rice 
syrup, corn 
syrup, invert 
sugar, 
concentrated 
whey protein, 
puffed wheat, 
apple juice 
concentrate, 
glycerine, 
molasses 
Table 3.  Submaximal Exercise Treadmill Testing (Modified Bruce protocol)  
 
Stage Time (min) 
Speed (mph) 
Grade (%) 
Pretest 
 
 
 
   Supine 
- 
0 
0 
   Standing 
- 
1.0 
0 
   Warm-up 
- 
1.0 
0 
Exercise 
 
 
 
   Stage 0 
3:00 
1.7 
0 
   Stage ½ 
3:00 
1.7 
5 
   Stage 1 
3:00 
1.7 
10 
   Stage 2 
3:00 
2.5 
12 
   Stage 3 
3:00 
3.4 
14 
   Stage 4 
3:00 
4.2 
16 
   Stage 5 
3:00 
5.0 
18 
   Stage 6 
3:00 
5.5 
20 
   Stage 7 
- 
6.0 
22 
Recovery 
- 
1.5 
0 


Page 26 of 41 
 
Drug 
information  
Selective 
beta-1 
blocker for  
treatment of 
hypertension, 
heart failure 
and angina 
pectoris  
Selective beta-
1 blocker for  
treatment of 
hypertension, 
heart failure 
and angina 
pectoris 
Selective beta-
1 blocker for  
treatment of 
hypertension, 
heart failure 
and angina 
pectoris 
FDA- 
cleared 
ingestible, 
disposable 
capsule; 26 
mm x 13 
mm in size 
(slightly 
larger than 
a multi-
vitamin)  
FDA-cleared 
Standardized 
meal similar to 
a granola bar 
(75% 
carbohydrate 
21% protein, 
3% fat) to be 
consumed 
immediately 
before 
ingesting the 
SmartPill 
capsule 
Formulation  
 
Extended 
release tablet 
Extended 
release tablet 
Extended 
released tablet  
Ingestible, 
disposable 
capsule 
Nutritional bar 
Manufacturer 
AstraZeneca  
Actavis 
(Formerly 
known as 
Watson 
Pharma, Inc) 
Dr. Reddy’s 
Laboratories, 
Ltd  
Given 
Imaging 
Given Imaging 
# of doses to 
be 
administered  
14-56 doses 
(7-28 doses 
during 1st 
phase of 
study and 
then 7-28 
doses in 3rd 
phase of the 
study) 
7 doses  
7 doses  
3 
3 
Planned 
maximum 
dosage  
200 mg  
200 mg  
200 mg  
Not 
applicable 
Not applicable 
Duration of 
subject 
exposure  
14-56 days  
7 days  
7 days  
Up to 15 
days (takes 
up to 5 
days for 
the capsule 
to pass) 
3 bars to be 
consumed over 
course of study 
 
Duration:  
 
The estimated study duration ranges between 6-15 weeks.  This includes the drug 
treatment duration of 4 to 10 weeks plus 1-2 weeks between then enrollment and 
screening visit, and 1-3 additional weeks for follow up. 
 
Location: 
 


Page 27 of 41 
 
The study will be conducted in the UF Health Family Medicine – Hampton Oaks clinic for 
the enrollment visit, UF CRC in the CTRB for the screening visit, and the CRC or UF 
Health Shands Hospital for overnight visits for PK/PD studies.  
 
Subject Selection and Recruitment: 
Subjects 
will 
be 
recruited 
among 
participants 
in 
the 
recently 
completed 
Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study from the 
University of Florida site.  Participants in PEAR-2 previously provided a genetic sample, 
and the target population will be selected based on cytochrome P450 (CYP) 2D6 
genotype, targeting at least 10 patients with the PM or IM genotype and remained of 
patients with the EM genotype. Participants will be targeted for enrollment based on 
current treatment of their hypertension (HTN) with a β-blocker, or known tolerability to a 
β-blocker based on their previous participation in PEAR-2. 
   
Inclusion of Women and Minorities: The investigators have no planned limitations to 
enrollment based on race or ethnicity.  However, based on the population demographics 
of the PEAR-2 study, from which subjects will be recruited, the subjects will primarily be 
non-Hispanic whites or African Americans.  Specifically, the PEAR-2 subjects enrolled 
from the University of Florida site were 58% whites, 43% African Americans, and 3% 
Hispanics.  We anticipate enrolling 50 subjects with a similar number of men and women 
and similar ethnic and racial representation as subjects from PEAR-2.   
 
Strategies/Procedures for Recruitment.  Many strategies will be used for recruitment: 1.) 
Patients in the PEAR-2 study who provided call-back information and meet eligibility 
criteria will be contacted by a study investigator to assess interest in study participation. 
If a sufficient number of patients cannot be recruited from among those enrolled in PEAR-
2, investigators will screen patients from PEAR-1 for eligibility.  Those meeting eligibility 
criteria will be contacted by a study investigator to assess interest in study participation.  
If a sufficient number of patients cannot be recruited through the PEAR-1 and PEAR-2 
studies, patients with hypertension will be recruited by other methods including: 2.) The 
UF Health Family Medicine – Hampton Oaks clinic via an IRB-approved flyer placed in 
clinic waiting rooms and clinical rooms. 3.) HealthStreet will be an additional mechanism 
for patient recruitment.  HealthStreet will be provided with an IRB-approved flyer and 
information to give to participants that may be interested in the study. Potentially 
interested patients may call a number provided on the postcard.    4.) Potential participants 
will also be identified by accessing the IDR provided through the NIH-funded i2b2 tool, 
which provides UF researchers access to a HIPAA-compliant and IRB-approved data set. 
Our query for the i2b2 data set will identify cohorts that meet our inclusion and exclusion 
criteria. 5.) Advertisements will be placed with classified advertisements services 
including “Craigslist”, “The Gainesville Sun”, and “Alligator”.  6.) Oak Hammock will be 
provided with an IRB-approved flyer and information to give to participants that may be 
interested in the study. Potentially interested patients may call a number provided on the 
flyer. 
 


Page 28 of 41 
 
For all avenues of recruitment, a study investigator will follow-up with potentially 
interested patients to describe the study.  Interested patients will be invited to the study 
center to further discuss the details of participation with an investigator, as described 
under the Screening Test and Interview section below. 
 
Screening Tests and Interview Prior to Subject Enrollment: 
 
Candidates who express interest in study participation will be invited to the UF Health 
Family Medicine - Hampton Oaks clinic to meet with the study team and further discuss 
the details of participation. At this visit, the study objectives, procedures, and risks of 
participation will be explained in detail.  After the candidate has been given an opportunity 
to ask questions, the candidate will be asked to sign the informed consent form, which 
will contain language appropriate to satisfy the rules and regulations surrounding HIPAA 
requirements.  The signed informed consent will become part of the subject’s medical 
record and will serve as documentation of the patient’s willingness to participate. Patients 
will then be screened at the CRC for exclusion criteria (stated in the study population and 
eligibility criteria) based on a complete medical history, BP and HR assessment, and lab 
results.  Patients without exclusion criteria will be scheduled for the enrollment study visit 
within 14 days where they will complete the physical exam with the study physician and 
if eligible, they will be randomized and begin the study. 
   
Study Drug Management 
Patients will be provided with a supply of Toprol XL. There will be no washout phase. 
Patients taking metoprolol succinate will be asked to stop taking their supply of drug and 
will be supplied with the same dose of the study drug to take instead for the duration of 
the study. The study physician may adjust metoprolol succinate doses up or down to 
achieve or maintain each patient's goal blood pressure. Patients taking a beta-blocker 
that is not metoprolol succinate on enrollment, will be switched to an “equivalent” Toprol 
XL dose (i.e. 200 mg Toprol XL daily for 100 mg atenolol daily; 200 mg Toprol XL daily for 
50 mg carvedilol daily, etc.), which will be determined by the study physician during the 
physical exam. The patient will be provided with up to a 2-week supply of study drug and 
asked to return once a week for a blood pressure check and additional supply of study 
drug, if necessary, until the first overnight pharmacokinetic (PK)/pharmacodynamic (PD) 
visit. Patients not currently taking a β-blocker will either have Toprol XL added if not at 
goal BP, or Toprol XL substituted for another antihypertensive medication upon 
physician’s discretion. In either case, Toprol XL will be started at 50 mg/day.  This is 
within the recommended initial dose range in the drug labeling of 25-100 mg/day. Toprol 
XL will be provided by the Investigational Drug Service (IDS), and patients will be 
instructed to take their Toprol XL dose at 9 A.M. each morning. Dosage strength will be 
established during Phase 1 and will remain the same throughout the study duration.  If 
further blood pressure management is needed during the study, the study physician will 
be consulted. 
Risk/Benefit Ratio: 


Page 29 of 41 
 
Potential Risks: Risks are those associated with venipuncture, placement of an indwelling 
venous catheter, treatment with metoprolol, administration of the SmartPill, exercise 
treadmill testing, and genetic information disclosure.  
i. Venipuncture. The risks of placing a catheter in your arm for drawing blood include 
discomfort at the site of puncture; possible bruising and swelling around the puncture 
site; uncommonly, faintness from the procedure, and rarely an infection. The total 
amount of blood drawn during the entire study is 25 tablespoonsfuls (less than 1 
pint). 
ii. Metoprolol. Risks with metoprolol include hypotension (over response), continued 
HTN (under response), bradycardia, and worsening of asthma or bronchitis.  
Hypertension from under response increases the risk of acute coronary syndrome 
and stroke.  Metoprolol may also cause the side effects of fatigue, impotence, 
dizziness, light-headedness, drowsiness, lethargy, tiredness, depression, diarrhea, 
nausea, vomiting, and vivid dreams.   
iii. SmartPill capsule. The risks associated with taking the SmartPill are capsule 
retention and aspiration. These risks are greatest in patients with gastrointestinal 
obstruction or severe dsyphasgia, and such patients will be excluded from 
participation. If a SmartPill capsule is in the body during an MRI test, there is a risk 
of damage to the GI tract. Subjects will be warned of this risk and the importance 
of avoiding an MRI until the capsule has passed.   
iv. BP monitoring.  There are no risks associated with wearing an ambulatory BP or 
Holter monitor.  However, these devices may be uncomfortable and disturb sleep.  
v. Exercise treadmill testing.  Side effects of the exercise treadmill test can include 
shortness of breath, light headedness, hypotension, or abnormal heart rhythm.  In 
rare cases, these side effects can be serious or life-threatening.  Medical staff 
trained in emergency response will be present for the studies.  Also possible are 
direct injuries such as bruises, sprains, and strains and indirect problems such as 
worsening of pain from arthritis.  
vi. Genetic study risks.  Genetic study risks include those related to confidentiality 
surrounding the genetic information and the chance that the genetic information 
could in some way expose the patient to increased risk regarding employment or 
that future life, health, disability or long term care insurance providers could 
potentially use this genetic information to deny, limit or raise rates for insurance 
coverage.  
 
Potential Benefits 
 
Study participation may not result in any direct benefit for the participant. However, risks 
associated with participation are minimal, and there are potential societal benefits from 
this study.  Specifically, the results of this study may help the FDA better understand 
which factors should be considered in bioequivalence studies of metoprolol succinate, 
leading to safer and more effective generic alternatives. 
 
Alternative Treatment 
 


Page 30 of 41 
 
The alternative is not to participate in the study.  Patients who do not want to participate 
in this study can receive a blood pressure lowering medication via a prescription from 
their doctor and can obtain a blood pressure monitor from their local drug store to monitor 
blood pressure at home.  
 
Adequacy of Protection Against Risks 
 
i. Protection from venipuncture. Venipuncture will be performed by a trained and 
experienced phlebotomist or nurse using standard techniques, and venous 
catheter insertion will be performed by a trained and experience nurse using 
standard techniques.   
ii. Protections from antihypertensive drug therapy risks. Several measures will be in 
place to protect from adverse effects with metoprolol.  First, patients already taking 
a β-blocker or with known tolerability to a β-blocker based on their previous 
participation in PEAR-2 will be targeted to minimize the likelihood for adverse drug 
effects. Second, we will exclude populations are most at risk for adverse effects 
with metoprolol (e.g. patients with heart disease, bronchospastic disease). Third, 
patients will undergo laboratory screening at baseline, and patients with elevated 
blood glucose, serum creatinine, or liver enzymes (ALT, AST) will also be excluded 
to minimize risk. Regular laboratory testing is not part of standard of care with use 
of this long established drug, and thus will not be done after the initial screening. 
However, as an additional important measure of safety, throughout the period of 
metoprolol therapy, patients will be encouraged to monitor their BP at home and 
report any SBP >180 mmHg or <100 mm Hg, DBP >110 mm Hg, or HR <55 bpm.  
At each study visit, BP will be checked, home BP data will be assessed, and 
patients will be evaluated for adverse effects, including symptoms of hypotension. 
Patients experiencing intolerable adverse effects at any time will be discontinued 
from the study immediately. All study medication will be stopped, and patients will 
be placed back on any blood pressure medications adjusted or stopped at the 
beginning of the study. The patient’s primary physician will be contacted for follow-
up  
iii. Protections from SmartPill risks. Patients with gastrointestinal obstruction or 
severe dsyphasgia, who are at the highest risk for capsule retention and aspiration 
will be excluded.  Patients will be instructed to immediately report any unusual 
symptoms and will be warned of risk of damage to GI tract if an MRI is done before 
the capsule is passed.   
iv. Protections from exercise treadmill testing.  Medical staff trained in emergency 
response will be present for the studies.   
v. Protections against risks from genetic study participation.  Genetic testing results 
will not be provided to any of the patients, and thus will not be included in the 
patient’s medical record, and will not be available to insurance providers. All data 
will be stored in a secure, password protected database with access limited to key 
investigators only. All records will link only a code number and no patient specific 
identifiers will be used.  
 
Payment for Participation: 


Page 31 of 41 
 
 
Patients will receive a $250 VISA gift card at the completion of each overnight study 
visit and a $10 VISA gift card after the enrollment visit, screening visit, each outpatient 
visit needed for medication adjustment repeating, holter monitor on an outpatient basis, 
or repeating ambulatory blood pressure on an outpatient basis, for a total compensation 
up to $850 for patients completing all study procedures.  Parking at both the clinic and 
CTRB is free, and the patient will be provided with a home blood pressure monitor at 
the baseline visit, which they may keep after study participation ends.   
If a patient withdraws on his/her own before completing the 24-hr PK and PD studies, or 
if the patient is withdrawn by study investigators prior to completing the 24-hr PK and PD 
studies because of an adverse event or intolerance to the procedures, he/she will receive 
$75 for that study visit.  If the patient withdraws on his/her own or is withdrawn by study 
investigators after completing the 24-hr PK/PD studies but before completing the exercise 
treadmill test, he/she will be compensated in the amount of $200.   
 
Patients will be responsible for paying income taxes on any payments provided by the 
study that total $600 or more or if the patients is a nonresident alien.  Payment will be 
processed through the University of Florida Accounts Payable department and the 
University must report the amount received to the Internal Revenue Service (IRS).  
 
Adverse Event Reporting: 
 
Women of child bearing potential will be instructed to use an acceptable method of 
contraception during study participation. 
Monitoring for documentation of an adverse event, whether anticipated or unanticipated, 
is the responsibility of the principal investigator who will maintain oversight but may 
delegate collection of information related to this function to other study team member. In 
term of SAFETY monitoring, all adverse events spontaneously reported, elicited, or 
observed by the investigators will be recorded. 
 
All Serious Adverse Events, should they occur, whether study-related or expected, will be 
documented on a Case Report Form, under Adverse Event section in the Patient’s binder, 
reported by the principal investigator to the IRB within five (5) working days. The principal 
investigator will follow the reporting requirements for serious and unexpected adverse 
events outlined in the UF IRB Adverse Event Evaluation and Reporting Guide. All 
unanticipated, serious, fatal and/or life-threatening adverse events will be reported to the 
UF IRB. Aggregate reports of adverse events will be prepared on an annual basis or at 
the end of the study, whichever may occur earlier and forwarded to the IRB at annual 
review. 
 
In addition, the principal investigator will report to the RIHSC (FDA IRB) through the FDA 
Sponsor any unanticipated problems involving risk to human subjects or others 45 CFR 
46.103(b)(5)(i). Per the RIHSC definition, the following adverse events will be reported to 
the RIHSC within 10 working days of the discovery of the event: 


Page 32 of 41 
 
 An adverse event that is not expected, i.e. not listed in the informed consent document 
or the investigator’s brochure;  
 An expected adverse event that occurs at a greater frequency or duration than 
expected;  
 Any adverse event that would require modification of the protocol and/or informed 
consent document.  
 
Data Safety Monitoring.  According to the UF IRB assessment for potential risk for 
subject form (Appendix N), our study is considered low risk in that it meets the following 
criteria: the study is therapeutic but the agent to be studied has a known safety profile 
and is to be used for an indication and population already approved by the FDA. 
Expected adverse events are of low severity and reversible with low chance of serious 
harm.  Thus, a DSMB is not required and we do not feel that it is necessary since we 
are targeting patients who have demonstrated tolerance to beta-blocker therapy and are 
excluding those at increased risk for adverse effects with metoprolol.  In addition, 
metoprolol has a wide therapeutic index and will be titrated up with close monitoring for 
those not on a beta-blocker at baseline.   
Data Safety Monitoring Plan.  Planned assessments for individual patient safety are as 
follows: 
Safety Assessment 
 Criteria leading to 
alteration 
or discontinuation of subject 
participation 
Personnel responsible for 
assessment 
Home blood pressure 
measurement 
Subject is instructed to 
contact study nurse for any 
SBP > 170, DBP > 110, or 
HR <50 on 2 consecutive 
measurements at least 5 
minutes apart for a BP/HR 
check. 
Subject measures BP.  Reports high 
values to research nurse; who 
reports to study physician. 
 
Manual. 15 minutes of rest 
prior to HR measurement.   
 
If HR <55 bpm on screening 
visit in absence of treatment 
with a β-blocker, the subject 
is withdrawn. 
 
If HR<50 bpm during beta-
blocker treatment, reduce 
the dose by half 
 


Page 33 of 41 
 
Resting heart rate 
measurement 
Manual. 15 minutes of rest 
prior to HR measurement.   
If HR <55 bpm on screening 
visit in absence of treatment 
with a β-blocker, the subject 
is withdrawn. 
If HR<50 bpm during beta-
blocker treatment, reduce 
the dose by half  
 
Pregnancy test 
Test done in CTSI lab. 
If positive, subject is 
withdrawn 
CTSI Lab Technologist 
Study nurse or PI withdraws subject 
Blood glucose 
If fasting blood glucose ≥ 
126 mg/dl or nonfasting 
blood glucose ≥ 200 mg/dl, 
subject is withdrawn 
Drawn by CTSI nurse. Physician 
evaluates labs for subject inclusion. 
Serum creatinine 
If SCr >1.5 in men or >1.4 
in women, subject is 
withdrawn 
Drawn by study nurse.  Results 
checked by study nurse or PI. Study 
nurse or PI withdraws subject. 
   
The study physician, Dr. Schmidt, and study PI, Dr. Cavallari, will evaluate adverse 
events for seriousness, expectedness, severity, and relationship to study intervention. 
An adverse event will be defined as any untoward occurrence (physical, psychological, 
behavioral) that occurs during the course of the study regardless of its causal 
relationship with the treatment being studied.  The IRB will confirm the causative 
relationship afterward. 
 
Analysis of the Study: 
 
Aim 1: Compare the pharmacokinetics and cardiovascular effects of brand name 
and generic metoprolol ER products in patients with hypertension: 
 
Heart rate variability and 24 hour HR.  Data will be analyzed by an expert in analysis of 
heart rate variability data who will be blinded to the metoprolol formulation the patient was 
taking and to patient genotype and other characteristics.  For holter monitor analysis, one 
5-min epoch from each hour of the quartile will be selected based on absence of a 
significant number of ectopic beats and artifact.  Spectral measures of HR variability will 
be calculated over each 5-min epoch. These absolute measures will consist of: high-
frequency variability (parasympathetic activity), low-frequency variability (primary 
sympathetic activity), and total variability.43 Ratios of HR variability will include: high to low 
(parasympathetic/sympathetic balance), high to total (normalized measure of 
parasympathetic activity), and low to total (normalized measure of sympathetic activity).  
Spectral measures of HR variability will be compared between brand name and each 


Page 34 of 41 
 
generic treatments (and over quartiles of the day for HR variability) using an analysis of 
variance model with measures repeated on 2 factors (treatment and quartile). Treatment 
order will be included as a covariate in the model to test for any differences in response 
based on the sequence of drug administration.  Significance levels will be adjusted for 
violation of the assumption of compound symmetry using the Greenhouse-Geiser 
correction.     
 
24 hour ambulatory and home BP data.  Data will be analyzed by an investigator blinded 
to the metoprolol formulation the patient was taking and to patient genotype and other 
characteristics.  The BP data will be analyzed as previously described.35 24 hour 
ambulatory data will be cleaned for artifactual readings and then hourly averages taken. 
These data can be used with the PK data for PK/PD modeling.  Additionally, these data, 
along with the AM and PM home BP data across multiple days will be analyzed to create 
a composite BP, as previously described.35 Composite BP will be compared between 
brand name and each generic product over each of the 24-hour recording periods using 
analysis of variance for repeated measures, with measures repeated on treatment and 
time of day. 
 
Pharmacokinetic and pharmacometric modeling. Data will be analyzed by an investigator 
blinded to the metoprolol formulation the patient was taking and to patient genotype and 
other characteristics.  A non-compartmental analysis will be performed in Phoenix® 
WinNonlin® (version 6.1 or higher, Pharsight, www.pharsight.com) to determine the basic 
pharmacokinetic parameters of generic metoprolol succinate 1, generic metoprolol 
succinate 2 and Toprol XL following oral administration. Log-transformed values of the 
key pharmacokinetic parameters (AUC, Cmax) for each drug product will then be used for 
bioequivalence testing.  Ratios of geometric means and arithmetic means as well as 
respective 90% CI (0.8-1.25 limits) will be computed for each drug product.  
Bioinequivalence is declared when the 90%CI for PK parameters of the test product is 
completely outside the limits of 80-125% of the reference (brand name) product. In 
addition, a fully-parametric population pharmacokinetic (pop-PK) model will be developed 
in NONMEM® (version 7.2 or higher, ICON Development Solutions, Ellicott City, MD, 
USA) to simultaneously estimate the population pharmacokinetic parameters 
characterizing the absorption, distribution, metabolism, and elimination of metoprolol 
succinate as well as the interindividual and residual variability associated with them.  The 
developed pop-PK model will then be linked to the corresponding pharmacodynamic (PD) 
endpoints to: i) characterize the dose-concentration-response relationship of all three 
drug products on both a patient level as well as a population level and ii) to determine if 
potential differences in PK between drug products translate into statistically significant 
differences in the dose-concentration-response relationship.  We will also include 
treatment with a proton pump inhibitor and CYP2D6 genotype as parameters in the 
model.   
 
Power analysis. Due to the cross-over design, each participant will have responses to 3 
different metoprolol ER products. The comparisons we are most interested in are the 
paired comparisons between the brand name and each of the two generic products. 
 


Page 35 of 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In determining the sample size needed for the Aim 1 analysis, we used the reported mean 
and standard deviation of all the endpoints: Tmax (6 ± 2.3 hr), AUC (3260 ± 993 ng*hr/mL), 
Cmax (163 ± 34 ng/mL), and HR variability (13,886 ± 1,479 ms2).33,34  With a sample size 
of 38, at an alpha level of 0.025 (0.05/2 comparisons), using a 2-sided paired t test, we 
would have >80% power to detect a 20% difference in Tmax, 16% difference in AUC, and 
6% difference in HR variability (Table 2).  We will target 50 total patients for enrollment to 
allow for drop-outs.  
 
Aim 2: Determine the impact of gastric pH variation on the concentration-response 
relationship with different metoprolol ER products  
 
SmartPill data.  Data will be analyzed by an investigator blinded to the metoprolol 
formulation the patient was taking and to patient genotype and other characteristics.  
Analyses of SmartPill data will be performed via MotiliGI™ software (Given Imaging).  
Only data during the time of the 24-hour studies will be used for analysis. Mean 
intragastrointestinal pH for every hour and 24 hours will be obtained from the raw pH data.  
Data on gastric transit time and pH will be explored as potential covariates for the PK/PD 
model developed in Specific Aim 1, particularly with respect to their influence on the rate 
and extent of metoprolol absorption from the 3 different formulations.  Additionally, we will 
use the median pH value to create a dichotomous variable for pH and then test for 
differences between formulations.  For example, the mean difference in Cmax for generic 
#1 versus the reference product will be compared between the two pH groups using 
analysis of covariance controlling for effects of baseline characteristics.   
 
Power analysis: According to a prior study using the SmartPill,44 the mean (SD) gastric 
pH among healthy subjects without GI diseases was 2.79 (1.39). Based on these data, at 
an alpha level of 0.025, with 38 subjects, we will have >80% power to detect an effect 
size of ≥ 0.65 (variability in gastrointestinal pH of ≥ 0.9 unit) between subjects.  Therefore 
this sample size should provide us with adequate interpatient variability in pH to assess 
Table 4. Data for power calculation 
Effect 
size 
N 
HR variability,  
SD =1,479,  
mean=13,886 
Tmax (hr),  
SD =2.3,  
mean=6 
AUC, 
SD=993, 
mean=3230 
Cmax,  
SD = 34, 
mean=163 
∆ 
∆ % 
∆ 
∆ % 
∆ 
∆ % 
∆ 
∆ % 
0.5 
41 
740 
5% 
1.2 
19% 
497 
15% 
17 
10% 
0.53 
38 
784 
6% 
1.22 
20% 
526 
16% 
18 
11% 
0.6 
29 
887 
6% 
1.4 
23% 
596 
18% 
20 
13% 
0.65 
25 
961 
7% 
1.5 
25% 
645 
20% 
22 
14% 
0.7 
22 
1035 
7% 
1.6 
27% 
695 
22% 
24 
15% 
0.8 
18 
1183 
9% 
1.8 
31% 
794 
25% 
27 
17% 
0.9 
15 
1331 
10% 
2.1 
35% 
894 
28% 
31 
19% 
1 
13 
1479 
11% 
2.3 
38% 
993 
31% 
34 
21% 
1.1 
11 
1627 
12% 
2.5 
42% 
1092 
34% 
37 
23% 
1.2 
10 
1775 
13% 
2.8 
46% 
1192 
37% 
41 
25% 


Page 36 of 41 
 
whether pH is contributing to any differences in pharmacokinetics for the various 
metoprolol ER formulations. 
 
Aim 3 Examine the effect of CYP2D6 genotype on the pharmacokinetics of different 
metoprolol ER products 
 
Genotype data.  We will determine whether formulation differences are greater within a 
CYP2D6 phenotype group. Since CYP2D6 would be expected to only affect the 
pharmacokinetics, and not the PK-PD relationship, then analyses will first include 
comparison of the deltas in the various PK parameters between the generic versus 
reference product in PMs/IMs versus EMs. For example, the mean difference in Cmax for 
generic #1 versus the reference product will be compared between the CYP2D6 
phenotype groups using analysis of covariance controlling for effects of baseline 
characteristics. Secondary analyses will compare the PK-PD relationships across 
formulations between the two CYP2D6 phenotype groups.  In addition, CYP2D6 genotype 
will be explored as potential covariate for the PK/PD model developed in Specific Aim 1 
to determine if the rate and extent of oral metoprolol absorption is changed as a result of 
e.g. altered first-pass metabolism in the liver or in the gut. 
 
Power analysis.  We plan to recruit a total of 50 participants to allow for drop-out, with a 
target of 38 who complete all studies.  We will target enrollment of at least 10 PMs/IMs 
and the remainder EMs. This will be possible due to targeted recruitment of participants 
with known genotypes. According to a meta-analysis of 13 studies,45 the PK parameters 
such as Cmax and  AUC in PMs were at least doubled compared to EMs: 2.3 fold for Cmax 
and 4.9 fold for AUC. For IMs, Cmax was 1.6-fold higher and AUC was 2.5-fold higher 
compared to EMs. Based on the information presented in this meta-analysis, we 
estimated the mean and standard deviation of Cmax and AUC for 200 mg of metoprolol to 
be: Cmax: 312 ± 338 and AUC: 1462 ± 1522 for EMs, Cmax: 512 ± 572 and AUC: 3692 ± 
4491 for IMs; Cmax: 710 ± 504 and AUC: 7106 ± 3478 for PMs.  For comparison of PK 
parameters across formulations between the CYP2D6 phenotype groups, with at least 10 
PMs/IMs and the remainder of the study population composed of EM individuals, at alpha 
of 0.05, we would have >80% power to detect effect size of ≥ 1.2, which is equivalent to 
Cmax difference of 405 (1.3 fold) or AUC difference of 1754 (1.2 fold). These numbers 
were smaller than those differences reported in the meta-analyses.15 
 
Data Management/Confidentiality of Data/Records: 
 
Case Report Form (CRF) will be used for each subject. To protect the participant’s right 
of privacy, the Patient Identification Number will identify patients’ individual records 
related to the study and will be stored in locked cabinets with limited access, and 
electronic files will be kept in secured database. A de-identified dataset from the database 
using a patient identification number will then be shared with statistician for analysis. 
During the study, data will be analyzed as it becomes available by Dr. Larisa Cavallari. 
No early closure is planned because of the limited scope and projected low risk of the 
study. 
 


Page 37 of 41 
 
If subject consents to banking, samples from the study subjects will be stored at the Center 
for Pharmacogenomics Laboratory with limited access for authorized personnel only. All 
samples will be identified by a code that can be linked to the patient’s identity only by the 
reference information file and separately on the secure server with limited access and 
password protected. After completion of the study, all left over samples from subjects who 
consented to banking will be stored in the Center for Pharmacogenomics. All other samples 
and data will be destroyed upon completion of the study according to the University of 
Florida’s Human Subjects Protections requirements. 
 
 


Page 38 of 41 
 
References: 
 
1. 
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O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr., Chung MK, de Lemos JA, Ettinger 
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Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised 
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Zhang X, Zheng N, Lionberger RA, Yu LX. Innovative approaches for demonstration of 
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Panakanti R, Narang AS. Impact of excipient interactions on drug bioavailability from solid 
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Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, Haidar CE, 
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Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF. Oxidation 
phenotype--a major determinant of metoprolol metabolism and response. N Engl J Med. 
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Hamadeh IS, Langaee TY, Dwivedi R, Garcia S, Burkley BM, Skaar TC, Chapman AB, 
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20.      Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox 
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21.     Aquilante CL, Terra SG, Schofield RS, Pauly DF, Hatton PS, Binkley PF, Johnson JA. 
Sustained restoration of autonomic balance with long- but not short-acting metoprolol in 
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22.    Johnson JA, Burlew BS, Stiles RN. Racial differences in beta-adrenoceptor-mediated 
responsiveness. J Cardiovasc Pharmacol. 1995;25:90-6. 
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Galinier M, Pathak A, Fourcade J, Androdias C, Curnier D, Varnous S, Boveda S, 
Massabuau P, Fauvel M, Senard JM, Bounhoure JP. Depressed low frequency power of 
heart rate variability as an independent predictor of sudden death in chronic heart failure. 
Eur Heart J. 2000;21:475-82. 
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La Rovere MT, Pinna GD, Maestri R, Mortara A, Capomolla S, Febo O, Ferrari R, 
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rate variability strongly predicts sudden cardiac death in chronic heart failure patients. 
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26.       Beitelshees AL, Zineh I, Yarandi HN, Pauly DF, Johnson JA. Discordant beta-blocker 
effects on clinic, ambulatory, resting, and exercise hemodynamics in patients with 
hypertension. Pharmacotherapy. 2006;26:1247-54. 
27.      Hamadeh IS, Langaee TY, Dwivedi R, Garcia S, Burkley BM, Skaar TC, Chapman AB, 
Gums JG, Turner ST, Gong Y, Cooper-Dehoff RM, Johnson JA. Impact of CYP2D6 


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Polymorphisms on Clinical Efficacy and Tolerability of Metoprolol Tartrate. Clin 
Pharmacol Ther. 2014. 
28.       Zineh I, Beitelshees AL, Gaedigk A, Walker JR, Pauly DF, Eberst K, Leeder JS, Phillips 
MS, Gelfand CA, Johnson JA. Pharmacokinetics and CYP2D6 genotypes do not predict 
metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther. 
2004;76:536-44. 
29.      Terra SG, Pauly DF, Lee CR, Patterson JH, Adams KF, Schofield RS, Belgado BS, 
Hamilton KK, Aranda JM, Hill JA, Yarandi HN, Walker JR, Phillips MS, Gelfand CA, 
Johnson JA. beta-Adrenergic receptor polymorphisms and responses during titration of 
metoprolol controlled release/extended release in heart failure. Clin Pharmacol Ther. 
2005;77:127-37. 
30.       Fux R, Morike K, Prohmer AM, Delabar U, Schwab M, Schaeffeler E, Lorenz G, Gleiter 
CH, Eichelbaum M, Kivisto KT. Impact of CYP2D6 genotype on adverse effects during 
treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther. 
2005;78:378-87. 
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Nozawa T, Taguchi M, Tahara K, Hashimoto Y, Igarashi N, Nonomura M, Kato B, Igawa 
A, Inoue H. Influence of CYP2D6 genotype on metoprolol plasma concentration and 
beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol. J 
Cardiovasc Pharmacol. 2005;46:713-20. 
32.      Abrahamsson B, Lucker P, Olofsson B, Regardh CG, Sandberg A, Wieselgren I, 
Bergstrand R. The relationship between metoprolol plasma concentration and beta 1-
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CR/ZOK formulations. J Clin Pharmacol. 1990;30:S46-54. 
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pH capsule affect esophageal motor function? Dis Esophagus. 2007;20:406-10. 
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IRB Project #: 201500092 
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INFORMED CONSENT FORM 
to Participate in Research, and 
AUTHORIZATION  
to Collect, Use, and Disclose Protected 
Health Information (PHI) 
 
INTRODUCTION 
 
Name of person seeking your consent: 
 
 
Place of employment & position:  
 
 
Please read this form which describes the study in some detail. A member of the research 
team will describe this study to you and answer all of your questions.  Your participation is 
entirely voluntary.  If you choose to participate you can change your mind at any time and 
withdraw from the study.  You will not be penalized in any way or lose any benefits to which 
you would otherwise be entitled if you choose not to participate in this study or to withdraw.  
If you have questions about your rights as a research subject, please call the University of 
Florida Institutional Review Board (IRB) office at (352) 273-9600.    
GENERAL INFORMATION ABOUT THIS STUDY 
1. Name of Participant ("Study Subject") 
 
___________________________________________________________________  
2. What is the Title of this research study? 
Open-Labeled Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of 
Metoprolol ER  
3. Who do you call if you have questions about this research study? 
Principal Investigator: Larisa Cavallari, PharmD at (352) 273-8245 
Other research staff: Study Physician: Dr. Siegfried Schmidt at (352) 265-9475 


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4.  Who is paying for this research study?  
The sponsor of this study is the Food and Drug Administration (FDA) 
5. Why is this research study being done?  
The purpose of this research study is to compare the quality and effectiveness of two 
generic versions of a blood pressure lowering medication, called metoprolol 
succinate, to the brand name version of this medication (Toprol XL). The study will 
also look at the effect of genetic makeup on drug response.  Genetic makeup is what 
determines a person’s body traits, such as height and eye color. Genetic makeup 
differs from person to person, which is why one person’s body traits are different from 
another person’s. Genetic makeup can also determine how the body breaks down a 
drug. This can cause drug effects to differ from person to person.    
You are being asked to be in this research study because you are currently being 
treated for high blood pressure and/or you previously participated in the 
Pharmacogenomic Evaluation of Antihypertensive Responses trials (PEAR-1 or 
PEAR-2). 
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. 
 
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY? 
6.   What will be done as part of your normal clinical care (even if you did not 
participate in this research study)?  
Regular visits to your doctor for blood pressure checks and occasional blood work is 
part of your normal clinical care for your high blood pressure.  Checking your blood 
pressure at home may also be part of your normal care.  Your normal clinical care 
should continue.  Things will be done during your participation in this study that would 
not be considered part of normal clinical care. While you would normally have your 
blood pressure monitored by your doctor, we will monitor it in more ways.  We will 
also look at drug levels in your body and your heart rate during exercise.    
7.  What will be done only because you are in this research study?  
If you are18 years of age or older, and agree to participate in the study, it will involve 
a minimum of 7 study visits (possibly up to 15 visits) occurring over a 6-15 week 
period.  Three (3) of the visits will involve an overnight stay, and each overnight stay 
will take about 28 hours. Other study visits are expected to be 30 minutes to 1 hour.  
There will be 4 periods of drug treatment of various lengths of time.  You will be given 


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a study medication for your blood pressure called Toprol XL for periods 1 and 3.  You 
will be given a generic form of Toprol XL (Generic Drug A or Generic Drug B) for 
periods 2 and 4. During the time you are in the study, your metoprolol succinate 
treatment will be managed by the study physician and your other blood pressure 
medications may be adjusted to control you blood pressure. Any other medical 
conditions will continue to be managed with your primary care physician. 
The first visit (screening visit) and outpatient visits will occur at the Clinical Research 
Center (CRC) at the UF Health Clinical and Translational Research Building (CTRB) 
at 2004 Mowry Rd, Gainesville, FL 32610. The enrollment visit will occur in the UF 
Health Family Medicine - Hampton Oaks at 200 SW 62nd Blvd, Gainesville, FL 
32607.  Overnight visits will occur in the CRC at CTRB or at UF Health Shands 
Hospital at 1600 SW Archer Rd, Gainesville, FL 32608. 
Screening Visit 
If you agree to participate by signing this form, the study nurse will draw 3 
teaspoonfuls (15 mL) of blood from a vein in your arm. Two teaspoons (10 mL) will be 
drawn for basic blood work and one teaspoon (5 mL) will be drawn for genotyping. 
The study nurse will collect your medical history and the list of your current 
medication. The study nurse or the Clinical Research Center Nursing staff will check 
your vitals (blood pressure, heart rate, respiration rate, temperature) and height and 
weight. If you are a woman of childbearing potential, we will perform a urine 
pregnancy test. This will end the screening visit.  If you still qualify for the study after 
initial testing, the study nurse will call you to schedule the enrollment visit. 
Enrollment Visit 
The study nurse will check your vitals and the study physician, Dr. Siegfried Schmidt 
will perform a physical exam and discuss your medical history with you.  If you are 
eligible to participate you will be randomized to one of two groups like flipping a coin.  
You or the researcher cannot choose which group you will be assigned to:    
• Study Group A- start with Toprol XL, switch to Actavis metoprolol succinate, 
switch back to Toprol XL, then switch to Dr. Reddy metoprolol succinate. 
• Study Group B- start with Toprol XL, switch to Dr. Reddy metoprolol succinate, 
switch back to Toprol XL, then switch to Actavis metoprolol succinate. 
Each study group will consist of treatment with Toprol XL for 2 periods, treatment with 
Dr. Reddy metoprolol succinate for one period, and treatment with Actavis metoprolol 
succinate for one period.  The generic drug periods will be in a different order for each 
study group. After the enrollment visit, you will be provided up to a 2-week supply of 
study drug to begin the first of four treatment periods. 
Period 1 
You will be provided with the blood pressure medication called Toprol XL (metoprolol 
succinate). You will take this study medication for 7-28 days. The length of time you 
take the medication will depend on your blood pressure level and when you are able 


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to come in for the first overnight study visit. If you are taking metoprolol succinate or a 
drug like metoprolol succinate before the study, it will be stopped.  You will be started 
on Toprol XL at a dose that should have the same effect on your blood pressure. 
Also, your dose of metoprolol succinate may be adjusted up or down to achieve or 
maintain your goal blood pressure.  If you are not taking metoprolol succinate or a 
drug like metoprolol succinate before the study, Toprol XL will be started at a low 
dose of 50 mg/day.  It may be necessary to reduce the dose or stop another blood 
pressure medicine so that you can safely take the study medication.  By signing this 
consent form, you are providing permission for Dr. Larisa Cavallari or Dr. Siegfried 
Schmidt to talk to your doctor before adjusting any of your medications. You may be 
asked to return for an outpatient visit once a week for up to 3 study visits for a blood 
pressure check and increase in the dose of your study medication. At least one 
titration visit, documenting BP < 140/90 mm Hg, will be required before scheduling the 
first overnight study visit. You will need to take your study medication each morning at 
9AM. Metoprolol succinate extended-release tablets should be swallowed whole and 
not chewed or crushed. 
You will be provided a home blood pressure monitor. The study nurse will show you 
how to use the monitor. You will be asked to take your blood pressure each morning 
when you wake up and each evening when you go to bed. If your systolic blood 
pressure (top number) is above 170 or below 100, diastolic blood pressure (bottom 
number) is above 110, or heart rate (pulse) is less than 50 for 2 measurements in a 
row taken about 5 minutes apart, you should contact the study nurse for a BP check 
visit as soon as possible. You should bring your home blood pressure monitor and 
study medication pill bottle with any leftover pills each time you come for a study visit. 
Your study nurse will provide you with the dates and times you will need to come in 
for each study visit.  
Overnight study visit 
After taking your study medication for 7- 28 days, you will be asked to come to the 
CRC or to UF Health Shands Hospital at 7:30AM for an overnight visit. You should 
bring comfortable clothing and shoes for the exercise treadmill test. The overnight 
visit will last approximately 28 hours. You should not consume caffeine or alcohol 
beginning at 8PM the night before your study visit and during the entire overnight 
study. You should not eat or drink anything except for water after 12 midnight the 
night before your study visit. We will ask you to stay on site until the following morning 
after completion of the study. If you leave before completion of the visit, you may be 
withdrawn from the study. You will not be allowed to shower during the overnight stay. 
At the beginning of the overnight visit, you will have a blood pressure cuff placed on 
your arm and electrodes (small, flat, sticky patches) placed on your chest.  The 
electrodes will be attached to a monitor that you may clip to your belt or wear around 
your neck to check your heart rate. The cuff will be attached to a monitor that can be 
worn on your waist.  The monitor will take your blood pressure at random times 4 
times per hour between 8 AM and 11PM, two times per hour between 11PM and 6 
AM, and 4 times per hour between 6AM and 8AM.  You will also have a catheter 
placed in a vein in your arm so that blood can be drawn. A little over 1 teaspoonful (6 


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mL) will be drawn 12 times during the overnight visit for a total of about 1/3 cup or 5 
tablespoonfuls (72 mL).  The times of the blood draw are around 9 AM, 9:30 AM, 10 
AM, 11 AM, 12 PM, 1 PM, 3 PM, 5 PM, 9 PM, 1 AM, 5 AM, and 9 AM the following 
day. 
You will be provided with a "SmartBar®" (similar to a granola bar) to eat around 8:30 
AM. You will be asked to swallow a "SmartPill®" capsule with water right after you 
finish the SmartBar. The “SmartPill®" capsule is a blue and clear oblong pill that is 
little larger than a vitamin pill. Both the SmartBar and "SmartPill®" capsule are 
cleared by the Food and Drug Administration. You will be given a special recorder to 
chart the progress of the "SmartPill®" capsule as it moves through your body. The 
recorder will chart the pH (acidity) of your stomach and intestines. The recorder 
should remain within 2 feet of you and can be worn on a belt clip or lanyard (cord) 
around your neck.  Approximately at 9 AM, you will be given a dose of your study 
medication.  Actual times may vary depending on your time of arrival, blood draws, 
and/or intake of SmartPill. 
You will also be provided with a menu of meals to select from during your overnight 
stay. The menu includes a variety of meals including vegetarian options. The same 
food options you chose for the first overnight visit will be provided to you for the 
second and third overnight visits. 
The blood pressure monitor, heart rate monitor, and catheter in your arm will be 
removed around 9AM the following morning. You will be asked to take your next dose 
of study medication approximately at 9AM. You will be taken to the Shands Heart 
Center, located in the Shands hospital, for an exercise treadmill test around 11AM. 
The actual times may vary depending on a time of treadmill availability, but we will 
inform you as soon as we know. Small areas on your chest will be cleaned, and 
electrodes (small, flat, sticky patches) will be placed on these areas. The electrodes 
will be attached to an electrocardiograph monitor (ECG or EKG) that charts your 
heart's electrical activity. A blood pressure cuff will be placed around your arm. You 
will be asked to start walking on the treadmill. The speed and slope of the treadmill 
will be increased every 2 to 3 minutes. You may feel like you are walking uphill. The 
total exercise time will last between 7 and 12 minutes. Your heart's electrical activity, 
heart rate and blood pressure will be monitored before, during, and after the test. You 
will also be asked how you are feeling at regular intervals during the test. At the end 
of the test, you will be asked to walk slowly for a couple of minutes to cool down. Your 
heart's electrical activity, heart rate, and blood pressure will continue to be monitored 
until they return to pre-test levels. The electrodes will then be removed.  You will be 
provided with up to a 2-week supply of the next study drug to begin taking at 9 AM the 
next day.     
SmartPill® Capsule 
The "SmartPill®" capsule will naturally pass during a bowel movement within 3 to 5 
days. You can remove the recorder after you notice the "SmartPill®" capsule has 
passed in your stool or after 5 days. You will be able to resume most of your usual 
activities while wearing the recorder, but should avoid excessive exercise. The 


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recorder should be worn at all times except during bathing and sleeping.  The 
recorder should be kept within 2 feet of you when you are not wearing it.  Remove the 
recorder before bathing and place it somewhere nearby where it will not get wet. You 
may place the recorder under your pillow or on your nightstand while sleeping. You 
will be asked to return the recorder at your next study visit (next overnight study or 
outpatient visit depending which occurs first).  
Period 2 
You will be provided with generic drug A or B, depending on which Study Group you 
are in, at the end of the first overnight study visit.  The dose of the generic medication 
will be the same as the dose of Toprol XL you were taking at the end of period 1. You 
will take the generic study drug for 7 days. You will need to take your study 
medication each morning at 9AM. 
You will use the same home blood pressure monitor. You will take your blood 
pressure each morning when you wake up and each evening when you go to bed. If 
your systolic blood pressure (top number) is above 170 or below 100, diastolic blood 
pressure (bottom number) is above 110, or heart rate (pulse) is less than 50 for 2 
measurements in a row taken about 5 minutes apart, you should contact the study 
nurse for a BP check visit as soon as possible. You should bring your home blood 
pressure monitor and study medication pill bottle with any leftover pills with you for 
your next overnight stay.  
After 7 days on the generic blood pressure medication, you will again return to the 
CRC or to UF Health Shands Hospital for an overnight stay and repeat all of the tests 
described above during the overnight study visit. At the end of the overnight study 
visit, you will be provided with up to a 2-week supply of Toprol XL at the same dose 
as the generic product in Period 2 to begin at 9 AM the next day. 
You will again wear the data recorder until you notice the "SmartPill®" capsule has 
passed in your stool or for 5 days. You will be able to resume most of your usual 
activities while wearing the recorder, but should avoid excessive exercise. The 
recorder should be worn at all times except during bathing and sleeping. The recorder 
should be kept within 2 feet of you when you are not wearing it. Remove recorder 
before bathing and place it somewhere nearby where it will not get wet.  You may 
place it under your pillow or on your nightstand while sleeping. You will be asked to 
return the recorder at your next scheduled study visit.  
Period 3 
You will again take the brand name blood pressure medication Toprol XL at the same 
dose as the generic product in period 2. You will need to take your study medication 
each morning at 9AM. You will take this study medication for 7-28 days. The length of 
time is flexible to help you schedule the final overnight visit after period 4. There is no 
overnight study visit in period 3. If the blood pressure monitor and/or the heart rate 
monitor malfunctions during Visit 1, you may be asked to wear the blood pressure 
monitor and/or the heart rate monitor for a 24 hour period at your home during Period 
3.  You may choose not to take part in the Period 3 monitoring if you are asked to do 


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so, and not taking part in this additional monitoring during Period 3 will have no effect 
on your treatment or ability to complete Period 4 as scheduled. You will need to come 
to in for an outpatient visit each week during Period 3 for a blood pressure check and 
to pick up another 7 day supply of medication until you are ready to begin Period 4.  
You will use the same home blood pressure monitor. You will take your blood 
pressure each morning when you wake up and each evening when you go to bed. If 
your systolic blood pressure (top number) is above 170 or below 100, diastolic blood 
pressure (bottom number) is above 110, or heart rate (pulse) is less than 50 for 2 
measurements in a row taken about 5 minutes apart, you should contact the study 
nurse for a BP check visit as soon as possible. You should bring your home blood 
pressure monitor with you and study medication pill bottle with any leftover pills each 
time you come to the clinic. Your study nurse will provide you with the dates and 
times you will need to come to clinic. 
Period 4 
After completing 7-28 days with the brand name Toprol XL, you will be provided with 
the second generic blood pressure medication at the same dose as Toprol XL you 
took at the end of Period 3. You will take the second generic study medication for 7 
days.  You will need to take your study medication each morning at 9AM. 
You will use the same home blood pressure monitor. You will take your blood 
pressure each morning when you wake up and each evening when you go to bed. If 
your systolic blood pressure (top number) is above 170 or below 100, diastolic blood 
pressure (bottom number) is above 110, or heart rate (pulse) is less than 50 for 2 
measurements in a row taken about 5 minutes apart, you should contact the study 
nurse for a BP check visit as soon as possible.  You should bring your home blood 
pressure monitor and study medication bottle with any leftover pills with you for your 
final overnight stay. Your study nurse will provide you with the date for your overnight 
stay.   
After 7 days of taking the second generic blood pressure medicine, you will again 
return to the CRC or UF Health Shands Hospital for an overnight stay and repeat all 
of the tests described above during the overnight study visit.  You will be discharged 
from the research unit after the treadmill test is over.  If you were taking metoprolol or 
another β-blocker before the study, you will be placed back on your pre-study 
medication after the overnight visit.  You should start taking your pre-study medication 
the following day or as instructed by Dr. Cavallari or Dr. Schmidt.  If you were not on a 
β-blocker before the study, you will be given a lower dose of the study medication to 
take for one week. You should continue to check your blood pressure with your home 
monitor each morning and evening. If your systolic blood pressure (top number) is 
above 170 or below 100, diastolic blood pressure (bottom number) is above 110, or 
heart rate (pulse) is less than 50 for 2 measurements in a row taken about 5 minutes 
apart, you should contact the study nurse for a BP check visit as soon as possible.   
You will again wear the data recorder until you notice the "SmartPill®" capsule has 
passed in your stool or for 5 days. You will be able to resume most of your usual 
activities while wearing the recorder, but should avoid excessive exercise. The 


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recorder should be worn at all times except during bathing and sleeping.  The 
recorder should be kept within 2 feet of you when you are not wearing it. Remove 
recorder before bathing and place it somewhere nearby where it will not get wet.  You 
may place the recorder under your pillow or on your nightstand while sleeping. You 
will be asked to return the recorder at your next study visit.  
Follow up study visits after study completion or withdrawal 
You will be asked to return for an outpatient visit one week after the final overnight 
study visit to return the data recorder and get a blood pressure check.  You may be 
asked to return weekly for up to 2 more visits or until you have been safely removed 
from the study medication and are back on your pre-study medication.  You should 
bring your blood pressure monitor and study medication pill bottle with any leftover 
pills with you to each visit.  The study nurse will call you around 30 days after the final 
overnight stay for a final follow up to make sure you are back on your pre-study 
medications and to ask you about your blood pressure readings. 
If you have any questions now or at any time during the study, please contact one of 
the research team members listed in question 3 of this form. 
8. How long will you be in this research study? 
You will be in this research study for 6-15 weeks. 
9. How many people are expected to take part in this research study? 
50 
 
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND  
WHAT ARE YOUR OPTIONS? 
10. What are the possible discomforts and risks from taking part in this research 
study? 
There is a risk that your blood pressure will become too low which may cause you to 
feel light headed or dizzy or to feel tightness or pressure in your chest. Your blood 
pressure may be elevated if it does not respond well to the blood pressure 
medications you are given, which might cause you to have a headache or feel 
pressure in your head. This might also cause you to feel pressure in your chest. 
There is also a risk with elevated blood pressure of heart attack or stroke. If you 
experience any of these symptoms you should measure your blood pressure with 
your home monitor and you should call your study nurse or doctor immediately to 
report your blood pressure and your symptoms. 
The study medication is a beta blocker, and may cause you to experience a slow 
heartbeat, dizziness, light-headedness, drowsiness, fatigue, depression, diarrhea, 


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nausea or vomiting, shortness of breath and wheezing. If you experience any of these 
symptoms you should report them immediately to the study nurse listed in section 3. 
The study medication may also involve risks to the embryo or fetus if you are 
pregnant or become pregnant while taking the medication.  
The risks of placing a catheter in your arm for drawing blood include discomfort at the 
site of puncture; possible bruising and swelling around the puncture site; rarely an 
infection; and uncommonly, faintness from the procedure. The total amount of blood 
drawn during the entire study is about 15 tablespoons (about 1/2 pint). 
The risks with the "SmartPill®" capsule include the capsule staying in the body longer 
than expected and/or accidentally inhaling the capsule. If you experience any unusual 
symptoms, you should report them immediately. There is a risk of damage to the 
stomach or intestines if the "SmartPill®" capsule is in the body during an MRI test.  
Side effects of the exercise treadmill test can include shortness of breath, light 
headedness, drop in blood pressure, or abnormal heart rhythm. In rare cases, these 
side effects can be serious or life-threatening. Medical staff trained in emergency 
response will be present for the studies.  Also possible are direct injuries such as 
bruises, sprains, and strains and indirect problems such as worsening of pain from 
arthritis.  
The risks of genetic testing include those related to confidentiality surrounding the            
genetic information, and the chance that the genetic information could in some way 
expose you  to increased risk regarding employment or that future life, health, 
disability or long term care insurance providers could potentially use this genetic 
information to deny, limit or raise rates for insurance coverage. To protect you from 
this risk, your DNA will not be stored with any of your identifying information and the 
results of your genetic testing will not be given to you and it will not become part of 
your medical record. If you signed a separate consent form for banking, your left over 
DNA and study records will be stored for future unknown research in the Center for 
Pharmacogenomcis Tissue and Data Bank.  If you do not sign the consent form for 
banking, your leftover DNA and study records will be used until the end of this study 
and then destroyed.  None of your personal health information or any identifying 
information will be stored with your DNA and study records.  If your DNA or study 
recorders are shared with other researchers, none of your personal identifying 
information will be shared. 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), makes it 
illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information.  Additional information 
can be obtained at: http://irb.ufl.edu/gina.html or call 1-800-669-3362.  If you think this 
law has been violated, it will be up to you to pursue any compensation from the 
offending insurance company and/or employer. 
Researchers will take appropriate steps to protect any information they collect about 
you.  However, there is a slight risk that information about you could be revealed 
inappropriately or accidentally.  Depending on the nature of the information, such a 
release could upset or embarrass you, or possibly affect your insurability or 


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employability.  Questions 17-21 in this form discuss what information about you will 
be collected, used, protected, and shared. 
The results of the following tests are being done for research purposes only and might 
not be evaluated or used to diagnose/ treat the participant’s medical problems. The 
results might not be entered into the participant’s medical record. These tests may 
need to be repeated by the participant’s primary care doctor if required for the 
participant’s medical care in the future: 
1. All testing performed by CRC 
This study may include risks that are unknown at this time. 
Participation in more than one research study or project may further increase the risks 
to you.  If you are already enrolled in another research study, please inform one of the 
research team members listed in question 3 of this form or the person reviewing this 
consent with you before enrolling in this or any other research study or project. 
Throughout the study, the researchers will notify you of new information that may 
become available and might affect your decision to remain in the study.  
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the research team members listed in question 
3 in this form. 
11a. What are the potential benefits to you for taking part in this research study? 
 There may be no direct benefit for you for participating in the study. 
11b. How could others possibly benefit from this study? 
Others with high blood pressure may benefit from this research if the study results 
lead to higher quality generic blood pressure medications.   
11c. How could the researchers benefit from this study? 
In general, presenting research results helps the career of a scientist. Therefore, the 
Principal Investigator listed in question 3 of this form may benefit if the results of this 
study are presented at scientific meetings or in scientific journals. 
12. What other choices do you have if you do not want to be in this study?  
If you do not want to participate in this study, you can receive a blood pressure 
lowering medication via a prescription from your doctor, and you can obtain a blood 
pressure monitor from your local drug store to monitor your blood pressure at home. 
You should talk to your doctor about what medications might be most appropriate for 
you. 


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13a. Can you withdraw from this study? 
You are free to withdraw your consent and to stop participating in this study at any 
time.  If you do withdraw your consent, you will not be penalized in any way and you 
will not lose any benefits to which you are entitled.   
If you decide to withdraw your consent to participate in this study for any reason, 
please contact one of the research team members listed in question 3 of this form .  
They will tell you how to stop your participation safely. 
If you have any questions regarding your rights as a research subject, please call the 
Institutional Review Board (IRB) office at (352) 273-9600. 
13b. If you withdraw, can information about you still be used and/or collected? 
If you discontinue participation in the study (withdraw), the information about you 
collected up until the time you withdraw can still be used.      
13c. Can the Principal Investigator withdraw you from this study?  
You may be withdrawn from the study without your consent for the following reasons: 
• At the discretion of the principal investigator or study physician based on what 
is best for your health and safety.   
 
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE? 
14. If you choose to take part in this research study, will it cost you anything? 
Study Drugs and Devices 
Toprol XL, Dr. Reddy’s metoprolol succinate, Activas metoprolol succinate, 
SmartBar, SmartPill® and recorder, and home blood pressure monitor will be 
provided at no cost to you while you are participating in this study. 
Study Services  
The Sponsor will pay for all medical services required as part of your participation in 
this study as described above in the question “What Will Be Done Only Because You 
Are In This Research Study”. If you receive a bill for these services, please contact 
Dr. Larisa Cavallari at (352) 273-8245. 
Items/Services Not Paid for by the Sponsor 
Any other medical services provided to you that are not directly required by this study 
will be billed to you or your insurance company in the usual manner. 


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15. Will you be paid for taking part in this study? 
You will receive up to $850.00 in VISA gift cards depending on how many study visits 
you attend.  A $10.00 VISA gift card will be given to you after your enrollment visit, 
screening visit, and each outpatient study required to adjust your medication or to 
repeat monitoring during Period 3. A $250 VISA gift card after will be given to you 
after each overnight study visit that you complete. If you leave the overnight study 
visit on your own before completing the 24-hour studies (before 9 AM the following 
day) or are withdrawn by study investigators before completing the 24-hour studies 
(before 9 AM the following day) study, you will receive $75.  If you complete the 24-
hour studies but leave the visit on your own or are withdrawn before the exercise 
treadmill test, you will receive $200. 
If you are paid more than $75 for taking part in this study, your name and social 
security number will be reported to the appropriate University employees for purposes 
of making and recording the payment as required by law. You are responsible for 
paying income taxes on any payments provided by the study. If the payments total 
$600 or more or you are a nonresident alien, payment will be processed through the 
University of Florida Accounts Payable department and the University must report the 
amount you received to the Internal Revenue Service (IRS). The IRS is not provided 
with the study name or its purpose. If you have questions about the collection and use 
of your Social Security Number, please visit: http://privacy.ufl.edu/SSNPrivacy.html. 
Your payment for participation in this research study is handled through the University 
of Florida’s Human Subject Payment (HSP) Program.  Your information which will 
include your name, address, date of birth, and SSN (depending on amount of money 
you are paid) is protected.  Access to the (HSP) Program site is limited to certain staff 
with the assigned security role.  You will be randomly assigned a specific identification 
(ID) number to protect your identity. 
The study team will provide you with an informational form called the Prepaid Card 
Facts document.  If you have any problems regarding your payment call the HSP 
Office (352) 392-9057. 
16. What if you are injured because of the study?   
If you are injured as a direct result of your participation in this study, only the 
professional services that you receive from any University of Florida Health Science 
Center healthcare provider will be provided without charge. These healthcare 
providers include physicians, physician assistants, nurse practitioners, dentists or 
psychologists. Any other expenses, including Shands hospital expenses, will be 
billed to you or your insurance provider.  
You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
research-related injuries. Please contact your insurance company for additional 
information.  


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The Principal Investigator will determine whether your injury is related to your 
participation in this study.  
No additional compensation is offered. The Principal Investigator and others 
involved in this study may be University of Florida employees. As employees of the 
University, they are protected under state law, which limits financial recovery for 
negligence.  
Please contact one of the research team members listed in question 3 of this form if 
you experience an injury or have questions about any discomforts that you 
experience while participating in this study.   
17. How will your health information be collected, used and shared? 
If you agree to participate in this study, the Principal Investigator will create, collect, 
and use private information about you and your health. This information is called 
protected health information or PHI. In order to do this, the Principal Investigator 
needs your authorization  The following section describes what PHI will be collected, 
used and shared, how it will be collected, used, and shared, who will collect, use or 
share it, who will have access to it, how it will be secured, and what your rights are to 
revoke this authorization.  
Your protected health information may be collected, used, and shared with others to 
determine if you can participate in the study, and then as part of your participation in 
the study.  This information can be gathered from you or your past, current or future 
health records, from procedures such as physical examinations, x-rays, blood or urine 
tests or from other procedures or tests.  This information will be created by receiving 
study treatments or participating in study procedures, or from your study visits and 
telephone calls.  More specifically, the following information may be collected, used, 
and shared with others:  
• Complete past medical history to determine eligibility criteria 
• Records of physical exams 
• Results of all study related tests and measures 
• Name, phone number, address, and email address  
• Social Security Number for the purpose of payment    
This information will be stored in locked filing cabinets or on computer servers with       
secure passwords, or encrypted electronic storage devices.  
Some of the information collected could be included in a "limited data set" to be used 
for other research purposes.  If so, the limited data set will only include information 
that does not directly identify you.  For example, the limited data set cannot include 
your name, address, telephone number, social security number, photographs, or 
other codes that link you to the information in the limited data set.  If limited data sets 
are created and used, agreements between the parties creating and receiving the 


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limited data set are required in order to protect your identity and confidentiality and 
privacy. 
18. For what study-related purposes will your protected health information be 
collected, used, and shared with others? 
Your PHI may be collected, used, and shared with others to make sure you can 
participate in the research, through your participation in the research, and to evaluate 
the results of the research study.  More specifically, your PHI may be collected, used, 
and shared with others for the following study-related purpose(s): 
• To determine the effectiveness of the study drugs 
• To determine if your genetic makeup affects response study medications     
Once this information is collected, it becomes part of the research record for this 
study.   
19. Who will be allowed to collect, use, and share your protected health 
information? 
Only certain people have the legal right to collect, use and share your research 
records, and they will protect the privacy and security of these records to the extent 
the law allows. These people include: 
• the study Principal Investigator (listed in question 3 of this form) and research 
staff associated with this project. 
• other professionals at the University of Florida or Shands Hospital that provide 
study-related treatment or procedures. 
• the University of Florida Institutional Review Board (IRB; an IRB is a group of 
people who are responsible for looking after the rights and welfare of people 
taking part in research).   
20. Once collected or used, who may your protected health information be shared 
with? 
Your PHI may be shared with: 
• the study sponsor (listed in Question 4 of this form). 
• United States governmental agencies who are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health 
and Human Services, and the Office of Human Research Protections. 
• Government agencies who are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments. 
Otherwise, your research records will not be released without your permission unless 
required by law or a court order. It is possible that once this information is shared with 


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authorized persons, it could be shared by the persons or agencies who receive it and 
it would no longer be protected by the federal medical privacy law.   
21. If you agree to take part in this research study, how long will your protected 
health information be used and shared with others? 
 
Your PHI will be used and shared with others until the end of the study. 
You are not required to sign this consent and authorization or allow researchers to 
collect, use and share your PHI. Your refusal to sign will not affect your treatment, 
payment, enrollment, or eligibility for any benefits outside this research study. 
However, you cannot participate in this research unless you allow the collection, use 
and sharing of your protected health information by signing this consent and 
authorization. 
You have the right to review and copy your protected health information.  However, 
we can make this available only after the study is finished. 
You can revoke your authorization at any time before, during, or after your 
participation in this study.  If you revoke it, no new information will be collected about 
you.  However, information that was already collected may still be used and shared 
with others if the researchers have relied on it to complete the research.  You can 
revoke your authorization by giving a written request with your signature on it to the 
Principal Investigator. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SIGNATURES 
As an investigator or the investigator’s representative, I have explained to the participant 
the purpose, the procedures, the possible benefits, and the risks of this research study; 
the alternative to being in the study; and how the participant’s protected health 
information will be collected, used, and shared with others:  
 
 
 
 
 
 
 
Signature of Person Obtaining Consent and 
Authorization 
 
Date 
 
 
 
You have been informed about this study’s purpose, procedures, possible benefits, and 
risks; the alternatives to being in the study; and how your protected health information will 
be collected, used and shared with others.  You have received a copy of this Form.  You 
have been given the opportunity to ask questions before you sign, and you have been told 
that you can ask   questions at any time.   
 
You voluntarily agree to participate in this study. You hereby authorize the collection, use 
and sharing of your protected health information as described in sections 17-21 above.  By 
signing this form, you are not waiving any of your legal rights. 
 
 
 
 
 
 
 
Signature of Person Consenting and Authorizing 
 
Date