Clinical trial NCT02053246
Conditions: Pulmonary Hypertension Diastolic Heart Failure Heart Failure With Preserved Ejection Fraction
Sponsor: University of Florida
Start date: 2014-01-01; Completion date: 2021-03-01
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Heart failure with preserved ejection fraction (HFpEF), is one of the leading causes of pulmonary hypertension (PH). Despite the severity of this disease, no established treatments exist for this class of PH. Nebivolol is a drug used in high blood pressure and heart failure, but not used in patients with PH. Due to some additional properties it possesses, the investigators believe nebivolol will improve disease severity in patients with PH associated with HFpEF. The hypothesis of this research study is that nebivolol improves PH severity in patients with HFpEF, as measured by hemodynamic and clinical parameters.

Detailed description:
This research study will be a prospective, open-label 18-week clinical study of nebivolol in patients with PH associated with HFpEF. Patients will be identified in clinic based on echocardiogram (TTE) and right heart catheterization (RHC) results (both part of standard clinical care) indicating PH and HFpEF.

Arms: arm 1: Participants will be started at 2.5 mg of nebivolol by mouth daily if on a beta-blocker the dose will start at 5mg, and titrated up to 10 mg daily, as tolerated.
Interventions: intervention 1: Nebivolol
Intervention descriptions: intervention 1: Nebivolol will be started at 2.5 mg by mouth daily if on a beta-blocker the dose will start at 5mg, and titrated up to 10 mg daily, as tolerated.

Protocol documents:
Prot_SAP_000.pdf: 
Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 1 of 8 
PROTOCOL 
 
Title: Improving treatment personalization of pulmonary hypertension associated with diastolic heart 
failure 
 
Protocol Version: 3 
10/08/2018 
 
Investigators: 
  
Julio Duarte, PharmD, PhD, Assistant Professor 
Department of Pharmacotherapy and Translational Research, UF 
 
Hassan Alnuaimat, MD, Associate Professor 
Division of Pulmonary, Critical Care and Sleep Medicine, UF 
 
Ali Ataya, MD, Assistant Professor 
Division of Pulmonary, Critical Care and Sleep Medicine, UF 
 
 
 


Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 2 of 8 
Study Hypothesis and Specific Aims  
The objective of this application is to evaluate nebivolol as a potential treatment for patients with 
pulmonary hypertension (PH) associated with diastolic heart failure, or heart failure with preserved 
ejection fraction (HFpEF).  Our central hypothesis is that nebivolol improves PH severity in patients 
with HFpEF, as measured by hemodynamic and clinical parameters.  The rationale for this research is 
that once we determine the extent to which nebivolol improves PH, it could be developed as a treatment 
for PH and HFpEF, especially if patients who respond best can be identified before treatment.  
We will test our central hypothesis and accomplish these objectives by pursuing the following 
specific aim:  
 
Define the clinical role of nebivolol as a potential treatment for PH associated with HFpEF using 
hemodynamic and functional status measurements. 
Our working hypothesis is that nebivolol, via its β1-antagontistic and β3-agonistic activities, as well as its 
anti-inflammatory, anti-proliferative, and endothelial NO-stimulating properties, will decrease 
pulmonary pressures and improve 6-minute walk distance and dyspnea scores in patients with HFpEF-
associated PH. 
 
Background and Significance 
Clinically, PH is marked by increased pulmonary vascular resistance leading to right heart 
failure, and ultimately death.1  Thus, PH carries a poor prognosis, with a yearly mortality rate of 9%.2  
PH can include either pulmonary arterial hypertension (PAH) or pulmonary venous hypertension (PVH), 
which is often caused by left-sided heart failure.  Increased pulmonary artery pressure (PAP) in patients 
with PVH develops from backward transmission of increased left atrial pressure, and is the most 
common cause of PH, with studies estimating its presence in 60-90% of heart failure patients.3-6  
However, approximately half of these patients have PAPs that are disproportionally higher than 
expected from their left arterial pressure, with greatly increased peripheral vascular resistance.4  This 
increase in PAP is associated with significantly worse outcomes, with one study estimating that heart 
failure patients with very high PAP possess an increased the risk of death by greater than 2-fold 
compared to heart failure patients with normal PAP.7  Such poor outcomes are particularly troubling in 
patients with PH and HFpEF, where no established guidelines for treatment exist.8  Thus, development 
of treatments for this category of PH is greatly needed. 
Current approved treatment classes for PAH, such as endothelin receptor antagonists and 
prostacyclins have either been shown ineffective, or have been associated with increased mortality when 
used in heart failure patients.9,10  Nebivolol is a third generation β-blocker which has been shown to 
improve diastolic dysfunction in both rats and humans with HFpEF.11-13  In addition, this particular β-
blocker has a profile that should make it ideal for treatment HFpEF patients with PH.  Importantly, 
nebivolol has been shown in a clinical study to improve mean PAP and PCWP in HFpEF patients 
without PH.13  However, to what extent it improves these hemodynamic parameters in HFpEF patients, 
who also have PH, is unknown. 
This project will contribute toward determining whether these potentially beneficial properties of 
nebivolol, known to improve diastolic dysfunction, will also improve PH severity in patients with 
HFpEF. This contribution will be important because it could uncover a potential treatment for a disease 
category that currently has no accepted treatments.  If nebivolol significantly improves PH severity in 
patients with HFpEF, it can be further researched as a probable treatment.  Furthermore, this project 
should also advance knowledge of the hemodynamic effects of chronic nebivolol treatment in HFpEF 
patients, as very few clinical studies have measured hemodynamics by right heart catheterization both 
before and after chronic oral treatment.  
 
 


Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 3 of 8 
Methods 
This project will be a prospective, open-label four-month clinical pilot study of 40 patients with 
PH and HFpEF.  Patients will be started at 2.5 mg of nebivolol by mouth daily if they were not taking a 
beta-blocker at enrollment, and titrated up to 10 mg daily, as tolerated.  Patients who cannot tolerate a 
dose increase will continue on the maximum tolerated dose throughout the study.  Patients already on a 
beta-blocker at enrollment will begin on 5 mg and will be titrated to 10 mg daily. DNA and RNA will be 
collected for genomic studies of disease and drug response.  All study procedures will occur at either the 
UF Clinical Research Center (CRC) or Shands Hospital. 
 
 
 
Visit 1 (week 0):  
• Blood sample: 2x 8 mL PAXgene (RNA), 1x 10mL lavender top (plasma and PBMCs), 1x 3mL 
lavender top (CBC with diff), 2x 4mL Li Heparin (nt-proBNP, CMP), 1x2.7mL blue top (INR) 
• Vital signs: blood pressure, pulse, respirations, height, weight, etc. 
• Dyspnea index 
• 6-minute walk test 
• Medication history 
• EKG 
Table 1. Procedures for each interaction with subjects 
Test/Procedure 
Visit 1/1A  
(wk 0-1) 
Call 1 
(wk 1) 
Call 2 
(wk 2) 
Visit 2 
(wk 4) 
Call 3 
(wk 5) 
Visit 3 
(wk 8) 
Call 4 
(wk 9) 
Visit 4 
(wk 18) 
right heart 
catheterization 
X* 
 
 
 
 
 
 
X 
transthoracic echo 
X* 
 
 
 
 
 
 
X 
electrocardiogram 
X 
 
 
X 
 
X 
 
X 
6-minute walk 
distance 
X 
 
 
X 
 
X 
 
X 
vital signs 
X 
 
 
X 
 
X 
 
X 
dyspnea index 
X 
 
 
X 
 
X 
 
X 
complete blood 
count 
X 
 
 
X 
 
X 
 
X 
INR 
X 
 
 
 
 
X 
 
X 
liver function test 
X 
 
 
X 
 
X 
 
X 
basic metabolic 
panel 
X 
 
 
X 
 
X 
 
X 
nt-proBNP 
X 
 
 
 
 
X 
 
X 
RNA collection 
X 
 
 
X 
 
X 
 
X 
DNA collection 
 
 
 
X 
 
X 
 
 
serum collection 
X 
 
 
X 
 
X 
 
X 
change in 
nebivolol dose 
X 
 
X 
X 
 
 
 
X 
adverse effect 
assessment 
 
X 
X 
 
X 
 
X 
 
medication history 
X 
 
 
X 
 
X 
 
X 
* = if not done within previous 3 months as part of clinical care 


Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 4 of 8 
• Patients will be asked to take oral nebivolol 2.5 mg (or 5 mg) once daily until Visit 2 (if visit 1A 
is not needed).  Instruct patient to discontinue previous beta-blocker and begin nebivolol today 
if they have not taken any beta-blocker today, and tomorrow if they have already taken a beta-
blocker today. 
• Place note in medical record documenting name of study, responsible physician, procedures, and 
medication dose. 
• If possible, schedule Visit 1A or Visit 2. 
• Once complete, provide patient with compensation ($50). 
Visit 1A – IF NEEDED (week 0-1): 
• If the patient has not received a two-dimensional transthoracic echocardiogram (TTE) within 3 
months of enrollment, it will be done for research purposes, possibly on the same day as visit 1.   
• If the patient has not received a right heart catheterization (RHC) within 3 months of enrollment, 
it will be done for research purposes (Appendix 1). 
• Patients will be asked to take oral nebivolol 2.5 mg (or 5 mg) once daily until Visit 2. Instruct 
patient to discontinue previous beta-blocker and begin nebivolol today if they have not taken any 
beta-blocker today, and tomorrow if they have already taken a beta-blocker today. 
• Once complete, provide patient with compensation ($200). 
Phone Call 1 (week 1): 
• How does patient feel compared to before starting study drug?   
• Any perceived side effects? 
• If not done already, schedule Phone Call 2 
Phone Call 2 – IF NEEDED (week 2): 
• How does patient feel compared to before starting study drug?   
• Any perceived side effects? 
• If tolerated, increase nebivolol dose to 5 mg (after approval by study physician) 
• If not done already, schedule Visit 2. 
Visit 2 (week 4): 
• Blood sample: 1x 6 mL purple top (DNA), 1x 8 mL PAXgene (RNA), 1x 10mL lavender top 
(plasma and PBMCs), 1x 3mL lavender top (CBC with diff), 1x 4mL Li Heparin (CMP) 
• Vital signs: blood pressure, pulse, respirations, height, weight, etc. 
• Dyspnea index 
• 6-minute walk test 
• Medication history 
• EKG 
• If tolerated, increase nebivolol dose to 10 mg once daily. 
• Update medical record to reflect new dose. 
• If possible, schedule Visit 3. 
• Once complete, provide patient with compensation ($40). 
Phone Call 3 (week 5): 
• How does patient feel compared to before starting study drug?   
• Any perceived side effects? 
• Provide results of safety assessment (everything looks similar to baseline OR significant 
difference in ________; the study physician recommends you _________.) 


Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 5 of 8 
• If not done already, schedule Visit 3. 
Visit 3 (week 8): 
• Blood sample: 1x 6 mL purple top (DNA), 1x 8 mL PAXgene (RNA), 1x 10mL lavender top 
(plasma and PBMCs), 1x 3mL lavender top (CBC with diff), 2x 4mL Li Heparin (nt-proBNP, 
CMP), 1x2.7mL blue top (INR) 
• Vital signs: blood pressure, pulse, respirations, height, weight, etc. 
• Dyspnea index 
• Medication history 
• 6-minute walk test 
• EKG 
• If possible, schedule Visit 4. 
• Once complete, provide patient with compensation ($40). 
Phone Call 4 (week 9): 
• How does patient feel compared to before starting study drug?   
• Any perceived side effects? 
• Provide results of safety assessment (everything looks similar to baseline OR significant 
difference in ________; the study physician recommends you _________.) 
• If not done already, schedule Visit 4. 
Visit 4 (week 18):  
• Blood sample: 2x 8 mL PAXgene (RNA), 1x 10mL lavender top (plasma and PBMCs), 1x 3mL 
lavender top (CBC with diff), 2x 4mL Li Heparin (nt-proBNP, CMP), 1x2.7mL blue top (INR) 
• Vital signs: blood pressure, pulse, respirations, height, weight, etc. 
• Dyspnea index 
• Medication history 
• 6-minute walk test 
• EKG 
• Two-dimensional transthoracic echocardiogram (TTE) for research purposes 
• RHC for research purposes (Appendix 1).   
• Based on study physician recommendation, patients will be advised on how to proceed with 
beta-blocker treatment after the end of the study. 
• Update medical records to indicate patient has completed study.   
• Once complete, provide patient with final compensation ($250). 
 
Eligibility Criteria 
Study Population. This study will include PH patients from Shands Hospital and UF Health 
pulmonary hypertension and cardiology clinics.  Patients must be diagnosed with PH by right heart 
catheterization (RHC).  This procedure is the gold-standard for PH diagnosis and is the most accurate 
way to measure the hemodynamics necessary to differentiate subtypes of PH.  Inclusion criteria for this 
study include:  
1. Adults (≥ 18 years of age) with World Health Organization Group 2 Pulmonary Hypertension:  
a. Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg,  
b. And pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg or left ventricular end 
diastolic pressure (LVEDP) ≥ 15 mmHg 


Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 6 of 8 
2. Evidence of either diastolic dysfunction on echocardiogram OR elevated filling pressures on 
invasive hemodynamic testing OR BNP>200 (NT-proBNP>220) pg/mL  
3. NYHA class II-IV symptoms  
4. Left ventricular ejection fraction (LVEF) ≥ 45% 
To assure any effect on hemodynamics are not due to other medications, patients must have no 
changes within one month to their cardiovascular medication regimen, including ACE-inhibitors, 
angiotensin receptor blockers, diuretics, and nitrates.  Exclusion criteria include:  
1. Other causes of heart failure other than diastolic dysfunction, such as restrictive cardiomyopathy 
or infiltrative cardiomyopathy 
2. Women who are pregnant or nursing 
3. Liver cirrhosis,  
4. primary valvular disease 
5. Acute coronary syndrome 
6. Causes of PH other than that of heart failure, such as: chronic thromboembolic PH, sickle-cell 
disease, or sarcoidosis 
7. Severe bradycardia or greater than 1st degree heart block 
8. Decompensated heart failure 
9. Current use of a third generation beta-blocker (nebivolol, carvedilol, or labetalol) or high dose of 
other beta-blockers (greater than 100 mg daily of metoprolol, or equivalent).  
 
Plans for subject selection, recruitment, and documentation of informed consent 
This study will include PH patients from Shands Hospital and UF Health pulmonary 
hypertension and cardiology clinics.  Eligibility will be reviewed and if requirements are met, patients 
will be approached to gauge interest.  If interested, patients will be asked to provide informed written 
consent. 
 
Description of Procedures 
 
Hemodynamic Measurements.  To confirm the diagnosis of PH associated with HFpEF and 
obtain baseline hemodynamic measurements, right heart catheterizations (RHCs) will be performed by 
UF cardiologists and pulmonologists using standard techniques. Any procedures done during 
catheterization beyond those mentioned will be at the discretion of the physician performing the for 
clinical indications.  
Transthoracic echocardiograms (TTEs) performed by UF Health technicians will also be used to 
obtain further hemodynamic parameters, including those that are indicative of diastolic dysfunction.  
TTEs will be read by a cardiologist as per American Society of Echocardiography guidelines.  Diastolic 
dysfunction will be determined by tissue Doppler imaging.  RV measurements including size, lateral 
tricuspid annular velocity, E wave, A wave, and isovolumic relaxation time will be performed. 
 
Functional Assessments. The 6-minute walk test will be performed in accordance with standard 
practice both at baseline and at completion of the study.  Briefly, subjects will be asked to walk for six 
minutes along a pre-measured path, with a practice walk being performed first.  Distance walked, 
oxygen saturation, and a Dyspnea Index will be determined. 
 
Statistical Methods 
Planned statistical analysis: Student’s t-test for paired samples will be used to determine 
differences between hemodynamic measurements taken before and after six months of nebivolol 


Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 7 of 8 
treatment. Thus, each patient will serve as their own control. The two primary efficacy phenotypes to be 
measured are mPAP and PCWP.  In secondary analyses, mitral valve Doppler flow velocity pattern, CO, 
PVR, CI and TPR will also be analyzed in an attempt to better characterize the mechanisms by which 
nebivolol affects the hemodynamic profile.  In addition, Student’s t-test for paired samples will be used 
to determine differences in 6-minute walk time before and after nebivolol treatment.  Fisher’s Exact Test 
will be used to compare dyspnea scores before and after six months of nebivolol treatment.  In all 
analyses, P ≤ 0.05 in a two-tailed distribution will be considered statistically significant. Statistical 
analyses will be performed using SAS 9.2 (SAS Institute, Cary, NC). 
 
Rationale for selection of subject 
Sample Size Calculation. Change in mean pulmonary artery pressure was used to estimate the 
sample size required to achieve satisfactory statistical power for this study. We calculated our sample 
size to be well-powered to detect a 15% decrease in mean mPAP (a clinically significant change).  This 
would be approximately 4 mmHg at our minimum mPAP cut-off of 25 mmHg.  We assumed a standard 
deviation of 5.5 derived from previous HFpEF treatment studies.13  Thus, with a power of 0.95, and a 
two-sided α of 0.05, we would require a sample size of 27 patients.  Because of the length of the study, 
we estimate an additional 30% will be needed to offset study attrition, thus a total sample size up to 40 
patients will be enrolled. 
 
Safety Monitoring and Assessment  
Patients will be called 1 week after each dose change.  BP and HR will be measured at each visit, 
as well as BMP, ECG, and LFT will be performed as safety assessments.  Accumulated safety data will 
be reviewed by a study physician every six months to assess overall safety of nebivolol treatment. 
 
Data Management  
Patient data will be initially recorded using the patient data collection form and RHC data 
collection form. Patient data will then be transferred and stored using a custom-built REDCap database.  
REDCap is a secure, web-based application for building and managing online databases for the 
collection and entry of research data.  Consents and other paper documentation will be kept in a locked 
cabinet in Dr. Duarte’s locked, private office. 
 
Risks and Benefits 
Patients may not directly benefit.  There is a potential benefit from improvements in progression 
of their PH.  The potential risks include: 
• Nebivolol:  Risk of side effects such as: large decrease in blood pressure (less likely), headache 
(less likely), dizziness (less likely), nausea (rare), fatigue (rare), diarrhea (rare), difficulty 
breathing (very rare), and slow heart rate (very rare).   
• Blood draws: discomfort at needle site (less likely), bruising at needle site (less likely), pain at 
site (less likely), swelling of vein (rare), fainting (rare), and infection (rare). 
• Echocardiogram: no risks associated with this procedure 
• Right heart catheterization: pain (less likely) or infection at catheterization sight (rare), 
vascular/valve damage (very rare), edema (rare), bruising (less likely), internal bleeding (very 
rare), blood clots (very rare), excessive fluid around the heart (very rare), and irregular heart 
rhythms (very rare). 
• 6-minute walk distance: fatigue during walk (less likely) 
• Accidental disclosure of PHI (rare) 
 


Personalized Treatment of PH with DD Protocol, Version 3, 10/08/18 
Page 8 of 8 
Relevant Literature 
 
1. 
D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results 
from a national prospective registry. Annals of internal medicine. Sep 1 1991;115(5):343-349. 
2. 
Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: 
insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease 
Management (REVEAL). Circulation. Jul 13 2010;122(2):164-172. 
3. 
Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart 
failure with preserved ejection fraction: a community-based study. Journal of the American College of 
Cardiology. Mar 31 2009;53(13):1119-1126. 
4. 
Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA, Borlaug BA. Effects of vasodilation 
in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on 
response to therapy. Journal of the American College of Cardiology. Jan 31 2012;59(5):442-451. 
5. 
Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular 
systolic function and pulmonary artery pressure in patients with chronic heart failure. Journal of the 
American College of Cardiology. Jan 2001;37(1):183-188. 
6. 
Willens HJ, Kessler KM. Severe pulmonary hypertension associated with diastolic left ventricular 
dysfunction. Chest. Jun 1993;103(6):1877-1883. 
7. 
Bursi F, McNallan SM, Redfield MM, et al. Pulmonary pressures and death in heart failure: a community 
study. Journal of the American College of Cardiology. Jan 17 2012;59(3):222-231. 
8. 
McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary 
hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus 
Documents and the American Heart Association developed in collaboration with the American College of 
Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. Journal 
of the American College of Cardiology. Apr 28 2009;53(17):1573-1619. 
9. 
Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for 
severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). American 
heart journal. Jul 1997;134(1):44-54. 
10. 
Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with 
bosentan in patients with severe chronic heart failure: results of a pilot study. Journal of cardiac failure. 
Feb 2005;11(1):12-20. 
11. 
Zhou X, Ma L, Habibi J, et al. Nebivolol improves diastolic dysfunction and myocardial remodeling 
through reductions in oxidative stress in the Zucker obese rat. Hypertension. Apr 2010;55(4):880-888. 
12. 
Ma L, Gul R, Habibi J, et al. Nebivolol improves diastolic dysfunction and myocardial remodeling through 
reductions in oxidative stress in the transgenic (mRen2) rat. American journal of physiology. Heart and 
circulatory physiology. Jun 1 2012;302(11):H2341-2351. 
13. 
Nodari S, Metra M, Dei Cas L. Beta-blocker treatment of patients with diastolic heart failure and arterial 
hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. 
European journal of heart failure. Oct 2003;5(5):621-627. 
 
 

ICF_001.pdf: 
IRB Project #: 201501144
Page 1 of 13
IRB Version: 10/1/2018
PI Version: 12/06/2018
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 
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?
Improving Treatment Personalization of Pulmonary Hypertension Associated with 
Diastolic Heart Failure
Study ID:IRB201501144   Date Approved: 3/6/2019


IRB Project #: 201501144
Page 2 of 13
IRB Version: 10/1/2018
PI Version: 12/06/2018
3.
Who do you call if you have questions about this research study?
Principal Investigator: 
Julio Duarte, Pharm.D., Ph.D.
Assistant Professor, UF College of Pharmacy
352-273-8132
juliod@cop.ufl.edu
Other research staff:  
Evan Waters
Clinical Research Coordinator
352-294-5885
waterse@ufl.edu
4.  Who is paying for this research study? 
The sponsor of this study is the United States National Institutes of Health.
5.  In general, what do you need to know about this Research Study?
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
to which you are entitled. 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.    
a) In general, what is the purpose of the research, how long will you be involved?
This study is testing a new treatment for pulmonary hypertension associated with a 
specific type of heart failure (left diastolic heart failure).
b) What is involved with your participation, and what are the procedures to be 
followed in the research? 
Participation in this study will involve taking an oral nebivolol tablet once daily for 
four months, and at least four study visits to test your response and check for any 
potential adverse effects using vital signs, laboratory tests, electrocardiogram, 
cardiac catheterization and echocardiogram.
c) What are the likely risks or discomforts to you? 
While not common, risks could include adverse effects from the study medication 
or study procedures.
d) What are the likely benefits to you or to others from the research?
You many not benefit directly from this research, but if nebivolol benefits patients 
with this type of pulmonary hypertension, it may be studied further as a potential 
treatment for this disease.
Study ID:IRB201501144   Date Approved: 3/6/2019


IRB Project #: 201501144
Page 3 of 13
IRB Version: 10/1/2018
PI Version: 12/06/2018
e) What are the appropriate alternative procedures or courses of treatment, if any, 
that might be helpful to you?  
There are no established treatments for this type of pulmonary hypertension, so 
your physician will continue to treat your heart failure and monitor your disease.
Additional and more detailed information is provided within the remainder of this 
Informed Consent form, please read before deciding if you wish to participate in this 
study.
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)? 
No treatments exist for this disease. Your doctor will continue to treat your heart 
failure and monitor your pulmonary hypertension. 
7.  What will be done only because you are in this research study? 
You will have approximately 3 tablespoons of blood taken at each study visit, a total 
of 4 times. The blood will be taken from your arm. The total amount of blood taken for 
the whole study will be about 12 tablespoons.  The blood will be used to test your liver 
function, your genetics, your blood cell counts, proteins that are associated with heart 
failure, and to check electrolytes in your blood.
Visit 1: You will be asked to provide a blood sample and a brief medical history, 
including questions about certain medications you take. Vital signs (such as blood 
pressure, pulse, temperature, and breathing rate) will be measured, an electronic 
tracing of your heart (EKG) will be done, and you will be given a breathing 
questionnaire and a 6-minute walk test. You will then be asked to take oral nebivolol 
2.5 mg once daily for one month (or 5 mg if you are already on a similar heart 
medication). If you are currently taking a similar heart medication, you will stop that 
medication the day before you start nebivolol.
Visit 1A (if needed): Either the same day as visit 1 or within a few days, you will be 
asked to undergo a transthoracic echocardiogram (measurement using sound waves 
to look at the heart) and a right heart catheterization (pressure measurements of your 
heart done with a catheter inserted into your arm or leg vein until it reaches your 
heart) for research purposes if you have not undergone one within 3 months of 
enrollment.  These measurements are needed to assess the degree of your heart 
failure and pulmonary hypertension.  
One week after your visit, you will be called to check for any potential problems.
Study ID:IRB201501144   Date Approved: 3/6/2019


IRB Project #: 201501144
Page 4 of 13
IRB Version: 10/1/2018
PI Version: 12/06/2018
If you were started on 2.5 mg of nebivolol, you will be called to check for any potential 
problems or side effects two weeks after your visit.  If you have no problems, and a 
study physician decides you are tolerating the medication well, you will be asked to 
increase your nebivolol dose to 5 mg. If you were already taking 5 mg, this call will not 
be needed.
Visit 2 (4 weeks): Your vital signs will be checked, a blood sample will be obtained, 
and an EKG will be performed to check for unwanted side effects.  If a study 
physician decides that you tolerate the study medication well, you will receive a dose 
increase to 5 mg daily for another 2 weeks (or 10 mg if you were previously taking 5 
mg).
One week after your visit, you will be called to check for any potential problems.
Visit 3 (8 weeks): Your vital signs will be checked, a blood sample will be obtained, 
and an EKG will be performed to check for unwanted side effects.   If a study 
physician decides that you tolerate the study medication well, you will receive a dose 
increase to 10 mg daily for the remaining 12 weeks, if you were not already taking 10 
mg. If any dose increase is not tolerated, you will be asked to revert to your previously 
tolerated dose.
One week after your visit, you will be called to check for any potential problems.
Visit 4 (18 weeks): Your vital signs will be checked, a blood sample will be obtained, 
and an EKG will be performed to check for unwanted side effects. (EKG) You will also 
be asked to undergo another right heart catheterization, heart ultrasound, breathing 
questionnaire, and a 6-minute walk test.  After the final measurements are taken, it 
will be up to your physician if you will continue nebivolol.  The right heart 
catheterization can occur either the same day or within a few days of your study visit.
Tests done only for research purposes will not be evaluated or used to diagnose or 
treat any of your medical problems. This/these test(s) may need to be repeated if 
required for your medical care in the future.
Once this research study is completed, any information that could identify you will be 
removed from any identifiable private information or identifiable biospecimens collected 
and that, after such removal, the information or biospecimens could be used for future 
research studies or distributed to another investigator for future research studies 
without additional informed consent from you or your legally authorized representative
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?
Completion of the research study will take approximately 4 months.
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9.
How many people are expected to take part in this research study?
Up to 60 subjects may be involved in this research.
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?
Risk of side effects from nebivolol include headache, nausea, fatigue, diarrhea, very 
slow heart rate, difficulty breathing, decrease in blood pressure, and dizziness.  
Please keep the study drug out of the reach of children or others who may not be able 
to read or understand the directions on the label.  Do not let anyone else take the 
study drug besides you.
The risks of taking blood include pain, a bruise at the point where the blood is taken, 
redness and swelling of the vein, and a rare risk of fainting and infection. 
Transthoracic echocardiogram: There are no risks associated with this procedure. 
Right heart catheterization (you may have this procedure done once or twice): pain, 
bruising, swelling, and rare risk of:  infection, blood vessel or heart valve damage, 
internal bleeding, lung collapse, blood clots, irregular heart rhythms, and excessive 
fluid surrounding the heart.
6-minute walk distance: You may experience fatigue during walk.
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 UF Center 
for Pharmacogenomics 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 
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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 
employability.  Questions 17-21 in this form discuss what information about you will 
be collected, used, protected, and shared.
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.
To help us protect your privacy, we have obtained a Certificate of Confidentiality from 
the National Institutes of Health. With this Certificate, the researchers cannot be 
forced to disclose information that may identify you, even by a court subpoena, in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings. 
The researchers will use the Certificate to resist any demands for information that 
would identify you, except as explained below.
The Certificate cannot be used to resist a demand for information from personnel of 
the United States Government that is used for auditing or evaluation of federally 
funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA).
You have been informed that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If 
an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate to withhold that 
information.  That is, if you give written consent for the release of information, we 
cannot withhold that information and we cannot hold responsibility for how that person 
may use your information. 
The Certificate of Confidentiality does not prevent the researchers from disclosing 
voluntarily, without your consent, information that would identify you as a participant in 
the research project under the following circumstances. If we learn about child abuse, 
elder abuse, or intent to harm yourself or others, we will report that information to 
appropriate authorities.
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11a. What are the potential benefits to you for taking part in this research study?
You may not directly benefit from participating in this study.  Based on experience 
with nebivolol in patients with similar conditions, researchers believe it may be of 
benefit to subjects with your condition by reducing blood pressure in your lungs and 
improving your heart function.  However, because individuals respond differently to 
therapy, no one can know in advance if it will be helpful in your particular case.
11b. How could others possibly benefit from this study?
If this study shows that nebivolol benefits patients with your condition, it may be 
studied further as a treatment for this disease.
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? 
Participation in this study is voluntary.  Your doctor will continue to monitor you and try 
to optimize your heart failure medications, as there are no other accepted treatments 
for this disease.
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:

You no longer meet study eligibility criteria

You do not follow the study procedures
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
You experience a severe side effect from the study medication or any study 
procedures

The study investigators believe it is in your best interest
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 Drug
Nebivolol, the study drug, 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. Julio Duarte at (352) 273-8132.
Items/Services Not Paid for by the Sponsor
All other medical services you receive would have been provided to you even if you 
were not in this study. These services will be billed to you or your insurance company 
in the usual manner. You will be responsible for paying any deductible, co-insurance, 
co-payments, for those services, and for any non-covered or out-of-network services. 
15. Will you be paid for taking part in this study?
You will receive cash in the amount below for completion of each study event as 
follows:  
Visit 1 = $50
1st right heart catheterization (if needed) = $200
Visit 2 = $40
Visit 3 = $40
2nd right heart catheterization = $200
Visit 4 = $50
TOTAL = $580 
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 
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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. 
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 
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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: 

Demographic information

Medical information and measurements as they relate to your heart and lungs

Genetic information

Medical and laboratory information as they relate to your response to nebivolol

Social Security Number for participant payment purposes
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 
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):

Research involving nebivolol response and heart or lung diseases
Once this information is collected, it becomes part of the research record for this 
study.  
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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 
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 completion 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.
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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
 
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