Clinical trial NCT02507011
Conditions: Pulmonary Arterial Hypertension
Sponsor: University of Minnesota
Start date: 2016-01-31; Completion date: 2019-07-01
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The investigators will conduct a, randomized, phase 2, placebo-controlled, double-blinded, crossover trial of carvedilol in 26 PAH patients with World Health Organization functional class II or III symptoms and RV ejection fraction (EF) \< 45% for 6 months.

Detailed description:
Adult PAH patients on a stable dose of an approved PAH medication will undergo the following baseline assessments: cardiac magnetic resonance imaging (MRI), right heart catheterization (RHC), echocardiogram, 6-minute walk test (6-MWT), plasma NT-ProBNP (biomarkers of RV function) and serum catecholamine (measure of sympathetic activation), and quality of life. Patients will be randomized to carvedilol (3.125 mg bid and escalated to 9.375 mg bid, as tolerated, over 3 months) or placebo in a 1:1 fashion. After 6 months, testing is repeated and patients are crossed over to the alternate treatment. Testing is repeated at the end of the study (month 13).

Arms: arm 1: Crossover Design: Participants receive Carvedilol first and placebo second arm 2: Crossover Design: Participants receive placebo first and Carvedilol second
Interventions: intervention 1: Carvedilol intervention 2: Placebo
Intervention descriptions: intervention 1: Beta-adrenergic receptor blocker intervention 2: Placebo

Protocol documents:
Prot_SAP_001.pdf: 
1
Beta-blockers in Pulmonary Arterial Hypertension – A Phase 2 Double-Blind, Placebo-
Controlled, Crossover Study Evaluating the Efficacy,
and Safety of Carvedilol for Right Ventricular Dysfunction in Pulmonary Arterial 
Hypertension
Regulatory Sponsor:
Department of Medicine
Cardiovascular Division
420 Delaware Street SE
Minneapolis, MN
Phone: 612-624-8970 Fax: 612-626-4411
Study Product:
Carvedilol
IND Number:
Trial Registration:
Version / Date:
10.12.17
CONFIDENTIAL
This document is confidential and the property of the University of Minnesota.  No part of it 
may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor.
Statement of Compliance
This document is a protocol for a human research study.  This study will be conducted according 
to US and International standards of Good Clinical Practice, applicable government regulations 
and Institutional research policies and procedures.  
All individuals responsible for the design and conduct of this study have completed Human 
Subjects Protection Training and are qualified to be conducting this research prior to the 
enrollment of any subjects.  
As Principal Investigator, I agree to conduct this clinical study in accordance with the design and 
specific provisions of this protocol.  Modifications to the study are acceptable only with an 
approved protocol amendment.  I agree to obtain approval from the IRB and/or regulatory bodies 
of competent jurisdiction, for the protocol and informed consent before initiating the study, to 
obtain consent from subjects prior to their enrollment in the study, to collect and record data as 
required by this protocol and case report forms, to prepare adverse event and study reports as 
required by this protocol and to maintain study documentation for the period of time required.


2
Thenappan Thenappan
06/05/2015
________________________________________________ _________________
Print Name/Title of Principal Investigator
Date
As a Sub-Investigator, I agree to conduct this clinical study in accordance with the design and 
specific provisions of this protocol.  Modifications to the study are acceptable only with an 
approved protocol amendment.  I agree to obtain approval from the IRB and/or regulatory bodies 
of competent jurisdiction, for the protocol and informed consent before initiating the study, to 
obtain consent from subjects prior to their enrollment in the study, to collect and record data as 
required by this protocol and case report forms, to prepare adverse event and study reports as 
required by this protocol and to maintain study documentation for the period of time required.
Marc R Pritzker
06/05/2015
________________________________________________ _________________
Print Name/Title of Sub- Investigator
Date
Print Location if multi-site protocol
Rebecca Cogswell
06/05/2015
________________________________________________ _________________
Print Name/Title of Sub- Investigator
Date
Print Location if multi-site protocol


3
Version History
Version #
Approval 
Date
Significant Changes from Previous Version
Version   1
08.12.2015
Original Protocol Version
Version 2
10.08.2015

+/- 5 days window for all clinic visits

phone call at 4 weeks after completing the 13-
month visit to assess clinical safety
Version 3

Remove open-label access post study 
completion

Clarification of screening window


4
Table of Contents
Statement of Compliance
Version History
Study Summary
List of Abbreviations
1.
Study Contact Information
1.1
Sponsor Contact Information
1.2
PI Contact Information
1.3
Sub-Investigator Contact Information
1.4
Key Study Personnel
2.
Introduction / Background and Rationale
2.1
Relevant Pre-Clinical Data
2.2
Relevant Clinical Data
3.
Investigational Agent
3.1
Description / Indications
3.2
Placebo / Active Control Agent
3.3
Drug Accountability
3.3.1 Drug Receipt
3.3.2 Packaging
3.3.3 Storage
3.3.4 Blinding of Study Drug
3.3.5 Dispensing of Study Drug
3.3.6 Return or Destruction of Study Drug
4.
Study Objectives
4.1
Primary Objective
4.2
Secondary Objectives
5.
Study Design
5.1
Overview of Study Design
5.2
Anticipated Duration of the Clinical Investigation
5.3
Evaluation Criteria
5.3.1 Primary Clinical Endpoint
5.3.2 Secondary Clinical Endpoints
5.4
Study Population
5.4.1 Sample Size
5.4.2 Subject Recruitment
5.4.3 Subject Screening
5.4.4 Prior and Concomitant Therapy
5.4.5 Inclusion Criteria
5.4.6 Exclusion Criteria
5.4.7 Exit Criteria
6.
Study Procedures
6.1
Informed Consent
6.2
Randomization Scheme
6.3
Blinding
6.3.1 Blinding Procedure
6.3.2 Unblinding Procedures
6.4
Laboratory Testing Procedures
6.4.1 Specimen Preparation
6.4.2 Specimen Handling and Storage


5
6.4.3 Specimen Shipment
6.4.4 Laboratory Testing:  Normal Values/Reference Ranges
6.5
Clinical Procedures
6.5.1 Treatment Regimen
6.5.2 Preparation and Administration of Study Drug
6.6
Follow-Up Procedures and Therapy Transition
6.7
Study Timetable / Schedule of Events
6.8
Study Protocol Compliance / Treatment Adherence
6.9
Deviations from the Clinical Protocol
6.10
Protocol Amendments After Study Initiation
6.11
Subject Withdrawal
6.11.1
How to Withdraw Subjects
6.11.2
Data Collection and Follow-Up for Withdrawn Subjects
6.12
Subject Compensation
7.
Data Collection and Analysis
7.1
Subject Populations for Analysis
7.2
Statistical Methods
8.
Safety and Adverse Events
8.1
Definitions
8.2
Recording Adverse Events
8.3
Reporting Adverse Events
8.3.1 Study Sponsor Notification by Investigator
8.3.2 IRB Notification by Investigator
8.3.3 FDA Notification by Sponsor
8.3.4 UPIRTSO Events
8.4
Safety Monitoring Plan
8.4.1 Anticipated Risks / Risk Mitigation
8.4.2 Medical Monitoring for Participant Safety
8.4.3 Study Stopping Rules
8.4.4 Anticipated Adverse Events 
8.5
Data Safety Monitoring Board
9.
Data Handling and Record Keeping
9.1
Confidentiality
9.2
Source Documents
9.3
Case Report Forms
9.4
Clinical Reports
9.5
Records Retention
10.
Study Monitoring, Auditing, and Inspecting
10.1
Study Monitoring Plan
10.2
Quality Assurance Procedures
10.3
Auditing and Inspecting
11.
Administrative Study Information
11.1
Technical Support
11.2
Pre-Site Qualification
11.3
Materials Provided by Sponsor / Coordinating Center
12.
Ethical Considerations
13.
Study Finances
13.1
Funding Source
13.2
Conflicts of Interest


6
14.
Publications Plan
15.
References
16.
Appendices and Attachments


7
Study Summary
Title
A Phase 2 Double-Blind, Placebo-Controlled, Crossover 
Study Evaluating the Efficacy,
and Safety of Carvedilol for Right Ventricular 
Dysfunction in Pulmonary Arterial Hypertension
Short Title
Carvedilol PAH 
Protocol 
Numbers
Protocol identifiers
Study Sponsor
List the regulatory sponsor and/or IND holder
Phase
II
Principal 
Investigator
Thenappan Thenappan, MD
Study Design
Phase 2 Double-Blind, Placebo-Controlled, Crossover 
Study
Study Duration
1 year
Study Center(s)
University of Minnesota, 
420 Delaware Street SE,
MMC 508
Minneapolis, MN 55435
Objectives
Estimate the efficacy of chronic beta-adrenergic receptor 
blockade with carvedilol on RV function in patients with PAH.
Assess the safety and tolerability of chronic carvedilol 
therapy in patients with PAH
Number of 
Subjects
26
Main Inclusion 
Criteria
1. Age > 18 years
2. WHO category 1 pulmonary arterial hypertension (Dana 
Point 2008)
3. WHO functional class II-III
4. RVEF by cardiac MRI < 45%
5. Stable on PAH-specific therapy as defined by no change 
in PAH-specific treatment and functional class in the past 3 
months. Patient can be on either mono or combination 
PAH-specific therapy
Study Product, 
Dose , Route, 
Regimen
Carvedilol (generic) 
Dose: 3.125 mg bid to 12.5 mg bid as tolerated
Route: Oral 
Duration of 
Administration
13 months
Reference 
Therapy
Placebo
Endpoints
The primary efficacy outcome is the mean change in RVEF 
as measured by cardiac MRI before and after 6 months of 
carvedilol treatment compared to placebo


8
The primary safety outcome is the absence of adverse 
events associated with carvedilol
Statistical 
Methods
We will compare RVEF before and after therapy using 
paired t-tests or Wilcoxon signed-rank tests. The null 
hypothesis is that treatment with carvedilol has no effect on 
RVEF in patients with PAH with a two-sided alternative that 
carvedilol changes RVEF. Using a similar approach, we will 
also compare echo parameters of RV function, right heart 
hemodynamics, 6-minute walk distance, plasma NT-
ProBNP, plasma catecholamine level, and MLHF 
questionnaire before and after study drug therapy.
List of Abbreviations: 
AE
Adverse Event
CFR
Code of Federal Regulations
CRF
Case Report Form
CMRI
Cardiac Magnetic Resonance Imaging
DSMB
Data and Safety Monitoring Board
DSMP
Data and Safety Monitoring Plan
EF
Ejection fraction
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICH
International Conference on Harmonization
IDS
Investigational Drug Services
IRB
Institutional Review Board
PAH
Pulmonary arterial hypertension
PHI
Protected Health Information
RV
Right Ventricle
SAE
Serious Adverse Event


9
1.0 Study Contact Information
1.1 Principal Investigator Contact Information (Coordinating Center)
Thenappan Thenappan, MD
Center for Pulmonary Hypertension
Cardiovascular Division
University of Minnesota Medical School
420 Delaware Street SE,
MMC 508
Minneapolis, MN 55435
tthenapp@umn.edu
Phone: 612-624-8970; Fax: 612-626-4411 
1.2 Sub-Investigators Contact Information 
Marc R Pritzker, MD; E Kenneth Weir, MD
Center for Pulmonary Hypertension
Cardiovascular Division
University of Minnesota Medical School
420 Delaware Street SE,
MMC 508
Minneapolis, MN 55435
tthenapp@umn.edu
Phone: 612-624-8970; Fax: 612-626-4411 
1.3 Key Study Personnel
Clinical Coordinator: Gretchen Peichel, RN
Study Monitor: CTSI 
Medical Monitor: Thenappan Thenappan, MD
Statistician: Sue Duval, Ph.D. 


10
2.0 Introduction / Background and Rationale
Safety and Efficacy of Beta-blockers in Pulmonary Arterial Hypertension: Pulmonary arterial 
hypertension (PAH) is characterized by progressive narrowing of the resistance pulmonary arteries, 
ultimately leading to right ventricular (RV) failure and death. It is a debilitating disease, associated with 
significant morbidity and a 1-year mortality rate of 15-20%. Moreover, the economic burden of PAH is 
high; estimated PAH-related healthcare costs in the United States are ~ $ 29 billion dollars per year. As 
the disease progresses, the RV dilates due to maladaptive remodeling and eventually fails. Multiple 
studies have consistently shown that long-term outcomes in PAH are largely determined by RV 
function. Despite this, all approved therapies for PAH target the pulmonary vasculature and not the RV. 
Neurohormonal activation has been observed in isolated RV failure secondary to PAH. Although 
neurohormonal modulation with pharmacological blockade of the β-adrenergic receptors is one of the 
main treatment strategies in left ventricular systolic dysfunction, the efficacy and safety of this treatment 
approach in isolated RV failure secondary to PAH has not been determined. In fact, beta-blockers are 
considered not safe in PAH, as these patients are dependent on the heart rate to maintain cardiac 
output. However, increasing evidence from animal studies and early human experience suggest that 
chronic β-adrenergic receptor blockade indeed improves RV function in PAH. Thus, β-adrenergic 
receptor blockers, if proven safe and efficacious in humans, may offer an inexpensive therapy for 
improving RV function, the main determinant of long-term PAH outcomes.
The long-term goal of our research is to develop novel therapies that improve RV function and thereby 
improve outcomes in PAH. In this proposal, we will evaluate pharmacological blockade of the β-
adrenergic receptor as a potential therapeutic target for the treatment of RV failure resulting from PAH. 
Carvedilol is a non-selective α1/β1/β2-adrenergic receptor antagonist that causes reverse remodeling 
of the left ventricle and improves survival in patients with left ventricular systolic dysfunction. In animal 
models of PAH, carvedilol reverses RV remodeling and restores RV β-receptor signaling pathways, 
ultimately leading to improved RV function. Moreover, results from a retrospective, propensity score 
analysis published by our group and a recent small open label trial show that β-adrenergic receptor 
antagonists are safe in PAH patients. Based on these preliminary data, we hypothesize that by 
inhibiting neurohormonal activation, treatment with carvedilol will improve RV function as measured by 
cardiac magnetic resonance imaging (MRI), and will be safely tolerated, in PAH patients. 
Specific Aim: Determine the efficacy (improvement in RV function) and safety of long-term β-
adrenergic receptor blockade with carvedilol in patients with PAH. We will conduct a, randomized, 
phase 2, placebo-controlled, double-blinded, crossover trial of carvedilol in 26 PAH patients with World 
Health Organization functional class II or III symptoms and RV ejection fraction (EF) < 45% for 6 
months. 
Protocol: Adult PAH patients on a stable dose of an approved PAH medication will undergo the 
following baseline assessments: cardiac magnetic resonance imaging (MRI), right heart catheterization 
(RHC), echocardiogram, 6-minute walk test (6-MWT), plasma NT-ProBNP (biomarkers of RV function) 
and plasma catecholamine (measure of sympathetic activation), and quality of life. Patients will be 
randomized to carvedilol (3.25 mg bid and escalated to 12.5 mg bid, as tolerated, over 3 months) or 
placebo in a 1:1 fashion.  After 6 months, testing is repeated and patients are crossed over to the 
alternate treatment. Testing is repeated at the end of the study (month 13). Outcome measures will 
include the following:


11
1.1 Primary Efficacy Outcome: 6-month change in RVEF as measured by cardiac MRI. We 
hypothesize that carvedilol will increase RVEF. A 5-unit increase in RVEF will be considered 
meaningful, as this has been associated with improvement in survival.  
1.2 Secondary Efficacy Outcomes: 6-month change in RV function (as measured by echocardiogram 
and RHC), exercise endurance (6-MWT), serum NT-ProBNP, plasma catecholamine levels, and quality 
of life (MLHF quality of life survey). 
2. Primary Safety Outcome: Absence of hypotension (<90 mm Hg), bradycardia (<50 bpm or 
advanced atrioventricular nodal block), bronchospam, or acute decompensated right heart failure 
requiring hospitalization. We hypothesize that carvedilol will be safely tolerated by PAH patients.
These pilot data will enable us to implement a large phase III, placebo-controlled, randomized clinical 
trial. Carvedilol has great potential as a safe and effective therapy to improve long-term outcomes in 
PAH. Implementation and completion of this study will substantially enhance the applicant’s expertise in 
conducting investigator initiated clinical trials while providing important preliminary data for an R01 
application to further the goal of identifying targeted efficacious interventions for RV dysfunction in PAH.
A. Significance 
Significance of RV dysfunction in PAH: Despite progress in understanding the pathogenesis and 
treatment of PAH, it remains a fatal illness1. The Food and Drug Administration (FDA) has approved 11 
PAH-specific therapies. Most act on the pulmonary vasculature by inhibiting pulmonary 
vasoconstriction, while potentially decreasing pulmonary vascular smooth muscle proliferation and 
endothelial cellular proliferation. None have a proven direct effect on the RV except for 
phosphodiesterase-5-inhibitors, which may have a RV inotropic effect but this has not been confirmed 
in humans2. These therapies produce a modest improvement in functional capacity, and overall survival 
data are equivocal3,4.
Initial RV hypertrophy in PAH is an adaptive response to the increased afterload with preserved 
contractile function. As the disease progresses, the RV dilates due to maladaptive remodeling and 
eventually fails 5. The mechanisms that switch the adaptive, compensatory hypertrophy of the RV to 
maladaptive RV dilatation and ultimately RV failure are under investigation6 7. Observational PAH 
registries and clinical trial data have consistently shown that baseline RV function, including RV ejection 
fraction, cardiac output, and right atrial pressure, is the major predictor of long-term mortality in patients 
with PAH 1,8-11. A recent metaanalysis of prognostic factors in PAH reported that right atrial pressure 
was the most commonly reported parameters to be associated with mortality in patients with PAH. In 
fact, the RV response to therapy rather than the change in pulmonary vascular resistance (PVR) is the 
key determinant of clinical outcomes in PAH 12. Despite frequency of PAH patient death from RV 
failure, RV function has not been investigated as a potential additional treatment target. Thus, there is 
an unmet need for novel cardiac-specific therapies preventing or reversing RV dysfunction in 
PAH5.  
Neurohormonal Activation and RV Dysfunction in PAH: Neurohormonal activation has been 
proposed as a mechanism for the switch from adaptive to maladaptive RV remodeling in PAH (Figure 


12
1). Similar to left ventricular systolic dysfunction, neurohormonal activation has been observed in 
isolated RV failure due to PAH in both experimental animal models and human PAH13 6,14-17.  Over time, 
this high catecholamine-state leads to significant down-regulation and desensitization of the β-
adrenergic receptors in the failing RV in PAH through activation of G-receptor protein kinase 2 (GRK2) 
6,18. Eventually, this leads to many adverse consequences, including a reduction in RV contractility and 
reduced responsiveness to exogenous catecholamine stimuli 6. 
Pharmacological blockade of the β-adrenergic receptors is one of the main treatment strategies in left 
ventricular systolic dysfunction. Multiple, large, randomized, double-blind controlled trials have 
demonstrated that long-term beta-blockade therapy 
in left ventricular systolic dysfunction improves 
cardiac function and reduces maladaptive 
ventricular remodeling and sudden arrhythmias, 
ultimately leading to improved quality of life and 
survival19-22. By analogy, a β-adrenergic receptor 
inhibitor may have therapeutic benefit in RV failure 
due to PAH.
Inhibition of Neurohormonal Activation in 
Animal Models of PAH: Pre-clinical animal 
experiments demonstrate that inhibition of 
neurohormonal activation by chronic β-adrenergic 
receptor blockade improves RV function, reverses 
RV remodeling, and restores RV β-receptor 
signaling pathways 6,23-26. Chronic treatment with 
arotinolol (a pure α and β adrenergic receptor blocker) in a rat model of monocrotaline (MCT)-induced 
PAH prevented development of PAH and RV hypertrophy25. Galein, a small molecule inhibitor of GRK2, 
decreased GRK2 activation and improved RV function in two experimental models of PAH with RV 
failure6. Bisoprolol (a ß1-cardioselective blocker) improved RV function in MCT-induced PAH; this 
improvement in RV function was associated with reductions in RV fibrosis and inflammation, and 
restoration of RV β-adrenergic signaling24. In Sugen/hypoxia and MCT rat models of PAH, treatment 
with carvedilol (a non-selective α1/β1/β2-adrenergic receptor antagonist) reduced RV hypertrophy, 
improved RV function, and reversed RV remodeling, resulting in improved exercise endurance and 
survival23. The improvement in survival with carvedilol treatment was impressive: 50% of the vehicle-
treated rats died, whereas all rats in the carvedilol-treated group survived. The improvement in RV 
function was associated with reduction in RV fibrosis and capillary rarefaction, increased reactivation of 
fetal genes with a pronounced switch from α to β myocyte heavy chain, and normalization of calcium 
handling protein Serca2a. The improvement in RV function with carvedilol in this model was due to a 
direct effect of carvedilol on the RV as there was no change in the severity of the angioproliferative 
pulmonary vasculopathy. Metoprolol, a cardio-selective β-blocker with no α-blocking properties, had 
similar but less pronounced effects in the SU5416 and hypoxia model. This finding, along with the 
significant improvement in survival with carvedilol treatment, suggests that the α-blocking and the anti-
oxidant properties of carvedilol may have an additional beneficial role. 
Figure 1: Neurohormal Activation in PAH


13
Based on the beneficial effects observed in preclinical animal experiments, we hypothesize that 
long-term pharmacological blockade of the β-adrenergic receptors with carvedilol will reverse 
RV remodeling and improve RV function in patients with PAH and RV dysfunction. By improving 
RV function, chronic treatment with carvedilol will improve functional capacity and survival in patients 
with PAH. To test this hypothesis, we propose a randomized, phase 2, placebo-controlled, double-
blinded, crossover trial of carvedilol in 26 PAH patients with World Health Organization functional 
class II or III symptoms and RVEF < 45% for 6 months. 
B. Innovation
Currently β-blockers are contraindicated in patients with PAH because of a theoretical concern that their 
negative inotropic properties will lead to worsening right ventricular function and ultimately failure. 
However, this is based on a small study demonstrating improved exercise capacity and hemodynamics 
after withdrawal of propranolol in 10 patients with porto-pulmonary hypertension27. In addition, this study 
lacked a sensitivity analysis with a long-term comparison between those who continued beta-blocker use 
and those who discontinued it. Moreover, 8 of the 10 patients in this study were receiving the first 
generation, non-selective beta-blocker propranolol that perhaps has a greater bronchial and myocardial 
depressive effect than the currently available selective beta-blockers. Chronic β-adrenergic receptor 
blockade with carvedilol would provide a novel strategy for treatment of RV dysfunction in PAH 
patients, the important determinant of long-term outcomes, and thereby fills an important deficit 
in the management of PAH. Carvedilol has been available in the market for treatment of left ventricular 
systolic dysfunction for the last two decades and it has been well tolerated. Should the proposed phase-2 
study confirm safety and suggest efficacy in PAH, carvedilol has the potential to move quickly to a Phase 
3 clinical trial. Such a therapy would address a major unmet need for this orphan disease: an inexpensive 
oral therapy, which improves the RV. 
One Phase 1/2 trial of β-blockers in patients with PAH was recently completed in the Netherlands 
(NCT01246037-PI Dr. A. Vonk Noordegraaf)28. This trial tested bisoprolol, a cardioselective β1-blocker. 
Although bisoprolol was safely tolerated, there was no significant improvement in RV function. Compared 
to bisoprolol, carvedilol has a superior profile with additional vasodilator and anti-oxidant properties29,30. 
Furthermore, carvedilol by acting as a “biased” ligand stimulates β-arrestin signaling in addition to 
antagonizing G-protein mediated signaling31. β-arrestin-dependent signaling is cardioprotective in the 
presence of chronic catecholamine stimulation32. Consistent with this, the beneficial effects observed with 
carvedilol in PAH animal experiments were impressive with a 50% reduction in mortality23. Furthermore, 
the Netherlands trial included patients with both normal and reduced RVEF. However, similar to left 
ventricular systolic dysfunction, it possible that beta-blockers are effective specifically in patients with 
reduced RVEF. Thus, we chose to study carvedilol in PAH patients with RVEF < 45%. Currently, there is 
another clinical trial studying the role of carvedilol in PAH (NCT01586156-PI Dr. Samara Farha). Our 
study differs from theirs critically in ours is a crossover design restricted to only patients with WHO 
category I PAH. This is important, as there is significant heterogeneity among patients with various WHO 
categories of pulmonary hypertension, which could potentially influence the results. We also have 
different end points (RVEF by cardiac MRI and invasive hemodynamics) and test different biomarkers 
(plasma catecholamines). These trials are complementary.  


14
C. Preliminary Work 
C.1. Beta-blocker therapy is not associated with adverse outcomes in PAH: a propensity score 
analysis: We recently showed that beta-blocker therapy is not associated with increased long-term 
outcomes in PAH using propensity score-matching analysis33. We studied patients in the Pulmonary 
Hypertension Connection (PHC) registry to assess the safety of β-blockers in patients with isolated RV 
failure due to PAH33. PHC, which was initiated in March 2004, enrolled all patients evaluated at a single 
United States practice over time at 3 different university hospitals between 1982 and 2014. 
Methods: Over the study period, 4 physicians acquired all the clinical data. 
Data were collected by chart review and entered with an Internet-based electronic data capture system. 
Patients were entered retrospectively from 1982 to February 2004 and prospectively from March 2004 
through 2013. From the PHC registry, we identified all adult patients (> 18 years of age) with PAH (n = 
564). Of the 564 
patients, 71 patients 
with PAH were on 
chronic β-blocker 
therapy at the time of 
presentation. We 
compared baseline 
clinical, 
echocardiographic, 
and hemodynamic 
characteristics, and 
long-term survival in 
PAH patients with 
(n=71) and without 
beta-blocker (n=493) 
use at baseline. 
Propensity score-
matching was used to 
match pairs of PAH 
patients with and 
without beta-blocker 
use (matched cohort). 
We compared all-
cause mortality 
between the groups 
in the total cohort and 
the matched cohort 
using bootstrap 
validation, Kaplan-
Meier, and Cox 
proportional hazard 
analyses.
Table 1: Baseline Characteristics by Beta-blocker Use
Characteristics
Total Cohort
Matched Cohort
Beta-Blocker
Beta-blocker
Yes
(N=71)
No
(N=493)
P-value
Yes
(N=63)
No
(N=51)
P-value
Age
59 ± 14
55 ± 14
0.02
58 ± 14
59 ± 15
0.63
Female
54 (76.1)
400 (81)
0.34
48 (76)
39 (77)
0.427
Etiology
0.01
0.91
Idiopathic 
23 (33)
227 (46)
21 (33)
15 (29)
CTD
24 (34)
155 (31)
23 (37)
17 (33)
CHD
6 (9)
36 (7)
5 (8)
7 (14)
Portopulmonary 
15 (21)
37 (8)
11 (17.5)
9 (18)
Anorexigen
1 (1)
20 (4)
1 (1.5)
0 (0)
Familial 
1 (1)
16 (3)
1 (1.5)
2 (4)
Others
1 (1)
2 (1)
1 (1.5)
1 (2)
WHO FC III/IV
58 (81.7)
428 (86.8)
0.24
53 (84.1)
43 (84.3)
0.97
Hypertension
48 (67.6)
141 (28.6)
<0.01
40 (63.5)
30 (58.8)
0.61
Diabetes
7 (9.9)
36 (7.3)
0.45
7 (11.1)
7 (13.7)
0.67
History of Obesity
27 (38.0)
87 (17.7)
<0.01
21 (33.3)
14 (27.5)
0.50
CAD
9 (12.7)
25 (5.1)
0.01
7 (11.1)
6 (11.8)
0.91
Medications
Di
i
4 (5 6)
79 (16 0)
0 02
4 (6 4)
3 (5 9)
0 62


15
Results: Comparison of Clinical, Echocardiographic, and Hemodynamic Characteristics (Table 1): PAH 
patients on chronic β-blocker therapy were older; more often had diabetes, coronary artery disease, 
and obesity; had worse renal function; were more often on diuretics, digoxin, and angiotensin 
converting enzyme inhibitors; and more frequently had left ventricular and RV hypertrophy than patients 
not taking β-blockers.  Baseline heart rate was lower in patients taking β-blockers. The severity of 
pulmonary hypertension and RV dysfunction was not different between those with and without beta-
blocker use. After propensity matching, 63 patients with beta-blocker use were compared to 51 patients 
without beta-blocker use.
Comparison of Long-term Outcomes: During a median follow-up time of 4.8 years, there were 339 
(60%) deaths in the total cohort and 70 deaths 
(61%) in the matched cohort. There was no 
difference in absolute mortality between those 
with and without beta-blockers (P=0.71). Beta-
blocker use was not associated with increased 
all cause-mortality in the total cohort after 
adjusting for propensity score (adjusted HR 1.0, 
95% CI 0.7-1.5) and in the matched cohort (HR 
1.2, 95% CI 0.8-2.0) (Figure 2).
Conclusion: There was no statistically 
significant difference in long-term mortality 
between propensity score-matched pairs of 
PAH patients with and without beta-blocker use. 
C.2. Safety and feasibility of carvedilol in PAH patients with RV dysfunction: In a recent small, 
open label trial of 6 patients with PAH, carvedilol was safely tolerated without major side effects34. The 
median dose tolerated was 18.75 mg bid with three patients reaching the maximum dose of 25 mg bid. 
None of the patients had to down titrate or discontinue carvedilol. In addition, carvedilol improved RVEF 
and RV stroke volume, due to a reduction in RV end-systolic volume and without changes in RV end-
diastolic volume. There was also a trend towards improvement in 6-MWD. 
We currently have an ongoing phase I/2 open label trial to assess the safety and feasibility of carvedilol 
therapy in patients with PAH and RV dysfunction (NCT02120339 –PI: Thenappan Thenappan, MD). 
This trial was initiated in August 2014 and we have enrolled 5 patients. DSBM reviewed the interim 
analysis of the first five patients and recommended enrolling more patients to see a definite signal for 
efficacy and safety of carvedilol for RV dysfunction in PAH.
C.3. Summary: These preliminary data suggest that beta-adrenergic blockade with carvedilol is safe 
and feasible in patients with PAH. This is also a testament for the feasibility of an investigator-initiated 
phase 1/2 trial by our team at University of Minnesota.
3.0 Investigational Agent(s)
Figure 2: Comparison of Survival by Beta-blocker 
Use in the Propensity Score (PS) Matched Cohort


16
3.1 Description / Indications
Carvedilol, a non-selective α1/β1/β2-adrenergic receptor antagonist, will be used in this trial to 
evaluate the effect of chronic beta-adrenergic receptor blockade in patients with PAH. Carvedilol 
is approved by the FDA, and it is currently used in the treatment of left ventricular systolic 
dysfunction and hypertension. It is well tolerated and has minimal side effects. Carvedilol will be 
used in this study in patients with right ventricular failure due to PAH, which is not a FDA 
approved indication. Investigational new drug application has been filled and permission has 
been already. Patients with PAH routinely take carvedilol for other indications and it is well 
tolerated. 
3.2 Placebo / Active Control Agent
This is a placebo controlled crossover trial. Hence, subjects will be randomized to carvedilol vs. 
placebo in a 1: 1 fashion. After 6 months, testing is repeated and patients are crossed over to the 
alternate treatment. 
3.3
Blinding of Study Drug 
The subjects, investigator team, and the treating physicians will be blinded to the study drug 
(carvedilol vs. placebo) until the analysis of the month 12 (primary endpoint) data is complete 
for all subjects. The investigational drug pharmacy at University of Minnesota will be employed 
to manage the conduct of the study. 
3.4 Drug Accountability
The investigation drug service (IDS) pharmacy will be used to maintain a central log documenting 
screening, implement stratification and randomization, assess current inventories of the study 
drug, initiate any necessary resupply of study drugs, and to document discontinuation of the 
study drug. 
The investigational pharmacy at University of Minnesota will provide adequate doses of the study 
drug in a double-blinded fashion (carvedilol vs. placebo) during each study visit. The study drug 
supply will be replenished at the baseline, 4 week, 8 week, 12 week, month 4 and month 5 study 
visits. The drug will be stored at room temperature, away from excess heat and moisture. The 
investigational pharmacy will assign bottle numbers and provide instructions for dispensing of 
blinded study drug. 
Study drug accountability: Accountability of the study drug is the responsibility of the principal 
investigator. The investigator will ensure that the study drug is used in accordance with the 
protocol. The investigator may choose to assign some of the drug accountability responsibilities 
to a pharmacist or other appropriate individual. Drug accountability records indicating the drug’s 


17
delivery date, use by each subject and end of study destruction and disposal of the drug will be 
maintained. These records will adequately document that the subjects were provided the doses 
as specified in the protocol.
4.0 Study Objectives
The goal of this study is to evaluate the effect of long-term inhibition of neurohormonal 
activation with carvedilol, a nonselective α1/β1/β2-adrenergic receptor antagonist, on RV 
reverse remodeling and function. In addition, we will determine the safety and tolerability of 
long-term carvedilol therapy in PAH patients.
General Hypothesis and Outcome Measures
By inhibiting neurohormonal activation, carvedilol, will cause reverse remodeling of the RV and 
improve its function as measured by Cardiac MRI in PAH patients.
Specific Aim: Estimate the efficacy and safety of long-term β-adrenergic receptor 
blockade using carvedilol on RV function in PAH patients 
4.1. Primary Objective: 
1. The primary efficacy outcome is the mean change in RVEF as measured by cardiac 
MRI before and after 6 months of treatment. An improvement of 5% will be considered 
to be clinically significant. Assessment of the RV is challenging due to its complex 
geometry.  Cardiac MRI offers the ability to acquire 3-dimensional datasets that do not 
require geometric modeling. In addition to being highly reproducible35, RVEF measured 
by cardiac MRI can be used to identify PAH patients that are likely to have clinical 
worsening8.  The prognostic ability of cardiac MRI-measurements of RVEF is similar to 
that as mean pulmonary artery pressure and exercise capacity.
2. The primary safety outcome is the absence of adverse events associated with carvedilol 
including hypotension (<90 mm Hg), bradycardia (<50 bpm or advanced atrioventricular 
nodal block), bronchospam, or acute decompensated right heart failure requiring 
hospitalization.
4.2. Secondary Objective: 
The following exploratory, secondary efficacy outcomes will be studied.
1. Mean change in tricuspid annular plane systolic excursion (TAPSE), a measure of RV 
function by transthoracic echocardiography36
2. Mean change in cardiac output and right-sided filling pressures measured by RHC
3. Mean change in exercise capacity assessed by 6-MWT
4. Mean change in plasma NT-ProBNP level, a biomarker of RV function in PAH37,38
5. Mean change in plasma catecholamine levels
6. Improvement in quality of life assessed by MLHF quality of life survey, which has been 
validated in PAH40,41


18
5.0 Study Design
5.1 Overview of Study Design
Study Type: Intervention
Study Design: Controlled, 
Allocation: Randomized
End Point Classification: Safety/Efficacy study
Intervention Model: Study drug vs. placebo
Masking: Double-blinded
Primary purpose:  Treatment
Intervention: The study drug (carvedilol vs. placebo) will be started in an escalating dose 
regimen as tolerated. Patients will be randomized to carvedilol (3.25 mg bid and escalated to 12.5 mg 
bid, as tolerated, over 3 months) or placebo in a 1:1 fashion.  Carvedilol will be started at 3.125 mg 
twice a day. The dose will be increased as tolerated to 6.25 mg twice a day at week 4, 9.375 
mg twice a day at week 8, and 12.5 mg twice a day at week 12 or the highest dose as 
tolerated by the patient. After 6 months, testing is repeated, study drug is weaned gradually over 2 
weeks and patients are crossed over to the alternate treatment after an additional wash out period of 2 
weeks. Testing is repeated at the end of the study (month 13).
Estimated number of patients: 26
5.2 Anticipated Duration of the Clinical Investigation
The anticipated duration of the study from enrollment of the first subject to completion of the final 
report to the IRB is approximately 3 years.  The anticipated accrual rate is approximately 1 
patient a month. 
5.3 Evaluation Criteria
5.3.1. Primary endpoint: 
1. The primary efficacy outcome is the mean change in RVEF as measured by cardiac 
MRI before and after 6 months of treatment. An improvement of 5% will be considered 
to be clinically significant. Assessment of the RV is challenging due to its complex 
geometry.  Cardiac MRI offers the ability to acquire 3-dimensional datasets that do not 
require geometric modeling. In addition to being highly reproducible35, RVEF measured 
by cardiac MRI can be used to identify PAH patients that are likely to have clinical 
worsening8.  The prognostic ability of cardiac MRI-measurements of RVEF is similar to 
that as mean pulmonary artery pressure and exercise capacity.
2. The primary safety outcome is the absence of adverse events associated with carvedilol 
including hypotension (<90 mm Hg), bradycardia (<50 bpm or advanced atrioventricular 
nodal block), bronchospam, or acute decompensated right heart failure requiring 
hospitalization.


19
5.3.2. Secondary endpoints:
The following exploratory, secondary efficacy outcomes will be studied.
1. Mean change in tricuspid annular plane systolic excursion (TAPSE), a measure of RV 
function by transthoracic echocardiography36
2. Mean change in cardiac output and right-sided filling pressures measured by RHC
3. Mean change in exercise capacity assessed by 6-MWT
4. Mean change in plasma NT-ProBNP level, a biomarker of RV function in PAH37,38
5. Mean change in plasma catecholamine levels
6. Improvement in quality of life assessed by Minnesota living with Heart Failure 
Questionnaire (MLHFQ), which has been previously used and validated in PAH40,41
5.4
Study Population
The study will enroll only patients with WHO category I PAH who meets the inclusion and 
exclusion criteria described below.
5.4.1 Sample Size
The effect of carvedilol therapy on RV function in patients with PAH is not well known. To date, no prior 
clinical trials have reported the effects of chronic β-blocker therapy on RV function secondary to PAH. 
Addetia et al showed that to detect a 5% difference in RVEF by cardiac MRI for 80% power and 
significance α<0.05 in PAH patients, the number of subjects needed is 2335. Assuming a 10% drop out 
rate, we are planning to enroll 26 subjects to obtain at least 23 completed studies. This is a proof-of-
concept trial, thus the goal of this study is to obtain data to estimate the variability of the outcome 
measures and obtain preliminary estimates of treatment effects in order to plan an appropriately 
powered, larger, phase 3, randomized, placebo-controlled trial. We will use the findings from the pilot 
study to refine our sample size calculation. We expect that a sample size of 26 will be sufficient to 
detect trends in echo parameters of RV function, hemodynamics, 6MWT, NT-ProBNP, plasma 
catecholamine, and MLHF score.
5.4.2 Subject Recruitment
Subjects will be recruited from the pulmonary hypertension clinic at the University of Minnesota 
who fulfill the inclusion and exclusion criteria. 
5.4.3 Subject Screening
The study consists of a screening visit and a treatment period. Potential participants will be 
screened using data collected at their routine outpatient appointment at the pulmonary 
hypertension clinic at University of Minnesota.  Eligible participants will complete the screening 
assessment including written consent, physical examination, medical history, electrocardiogram, 
blood to assess routine hematology, biochemistry, NT-ProBNP, 6 minute walk test 28 days prior 
to baseline, and transthoracic echocardiogram, cardiac MRI to assess baseline right ventricular 
function, and right heart catheterization (if none available within previous 3 months).  Potential 
drug interactions with carvedilol will also be assessed.  After completion of screening 


20
assessment and obtaining written consent, patients will proceed to the baseline (week 0) study 
visit.
5.4.4 Prior and Concomitant Therapy
At screening visit and subsequent visits concomitant medications will be assessed for potential 
drug interactions with carvedilol. Subjects have to be on stable PAH-specific therapies for at 
least 3 months before enrolling in this clinical trial. Subjects will continue to take PAH-specific 
therapies during this clinical trial. No increase in current background PAH medication dose (oral, 
inhaled, Intravenous, subcutaneous) or addition of a new PAH medication will be allowed during 
the study duration of 12 months. If a subject needs up titration of PAH specific therapy due to 
progression of underlying pulmonary vascular disease, subjects will exit the study.
5.4.5 Inclusion Criteria
1. Subjects will be eligible to participate in the study if all of the following conditions exist:
2. Age > 18 years
3. WHO category 1 pulmonary arterial hypertension (Nice 2013)
4. WHO functional class II-III
5. RVEF by cardiac MRI < 45%
6. Stable on PAH-specific therapy as defined by no change in PAH-specific treatment and 
functional class in the past 3 months. Patient can be on either mono or combination PAH-
specific therapy
5.4.6 Exclusion Criteria
Subjects will be excluded from participation in the study if any of the following conditions exist:
1. Significant persistent bradycardia (resting heart rate < 60 bpm) without a permanent 
pacemaker
2. Second or third degree AV block without a permanent pacemaker
3. Significant sinus tachycardia (resting heart rate > 110 bpm)
4. Use of anti-arrhythmic drugs
5. Hypotension defined as systolic blood pressure < 100 mmHg at the time of enrollment
6. Significant illness in the past 30 days requiring hospitalization
7. Acute decompensated right heart failure within past 30 days
8. Known allergy or intolerance to carvedilol or other β blockers
9. Cardiac index < 2 l/min/m2 or right atrial pressure > 15 mm Hg by right heart 
catheterization within last 3 months
10.Clinically significant severe asthma
11.Positive pregnancy test in patients of child bearing-potential
5.4.7 Exit/Discontinuation Criteria
Subjects will be discontinued from the study for the following reasons:
1. The subject no longer wishes to participate
2. Development of intolerable side-effects related to carvedilol


21
3. Development of significant hypotension (reduction in blood pressure associated with 
dizziness or syncope or SBP less than 100 mm Hg despite dose reduction)
4. Development of significant bradycardia despite dose reduction (HR < 50 bpm without a 
permanent pacemaker or reduction in heart rate associated with dizziness or syncope)
5. Development of decompensated right heart failure requiring hospitalization
6. Subject is a female of child-bearing potential who becomes pregnant
7. Subject death
8. Subject completes the protocol.
9. Subject is non-compliant with the protocol (See Section 6.8 for definition of non-
compliance)
10.Subject’s well-being, in the opinion of the Investigator would be compromised by study 
continuation.
11.DSMB and/or IRB recommendation
Patients who discontinue or wish to drop out early from the study will undergo final assessment 
at the time discontinuation.
6.0
Study Procedures
6.1
Consent Process
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  The consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  The subject or legally 
acceptable surrogate must sign this consent form, and the investigator-designated research 
professional obtaining the consent.  A blank copy of the IRB-approved form must be kept on-
site and by the sponsor-investigator.  
6.2
Randomization Scheme
Subjects will complete the randomization visit within 4 weeks of the screening visit. After review 
of the inclusion and the exclusion criteria to confirm continued eligibility, subjects will be 
randomized to study drug in a 1:1 fashion to placebo vs. carvedilol administered twice daily. 
Randomization will be done by the investigational pharmacy at University of Minnesota either in 
a sealed envelope or using block randomization scheme. The IDS pharmacy will maintain the 
randomization code until the completion of the study.
6.3 Blinding 
6.3.1 Blinding procedure
The subjects, investigator team, and the treating physicians will be blinded to the study drug 
(carvedilol vs. placebo) until the analysis of the month 12 (primary endpoint) data is complete 
for all subjects. The investigational drug pharmacy at University of Minnesota will be employed 
to manage the conduct of the study.


22
6.3.2 Unblinding procedure 
In the event of a medical emergency where breaking the blind is required to provide medical 
care to the subjects, the investigators may obtain the treatment assignment directly from the 
investigational drug service pharmacy for that subject. Treatment assignment should remain 
blinded unless that knowledge is necessary to determine subject emergency medical care. The 
rationale for unblinding must be clearly explained in source documentation and on case report 
forms along with the data on which the treatment assignment was obtained. 
6.4
Clinical Procedures
We propose a randomized, phase 2, placebo-controlled, double-blinded, crossover study to determine 
the safety and efficacy of carvedilol in in stable PAH patients with WHO functional class II or III 
symptoms and RVEF < 45% (Figure 3). Potential patients will be identified from our pulmonary 
hypertension clinic at the University of Minnesota. 

Screening and Randomization: Following initial evaluation and consent, 26 patients 
meeting inclusion and exclusion criteria will be randomized to carvedilol or placebo in a 1: 1 
ratio as the initial therapy in this 6-month crossover trial.

Dose escalation phase (D1 and D2): Study drug (carvedilol or placebo) dose will be 
gradually escalated as tolerated every 4 weeks over a 3-month period. Carvedilol will be 
started on day 0 at 3.125 mg twice a day. The dose will be increased as tolerated to 6.25 
mg twice a day at week 4, 9.375 mg twice a day at week 8, and 12.5 mg twice a day at 
week 12 as tolerated. Dose escalation will be stopped and the dose decreased to the 
previous dose (50% reduction) if the patient develops: 1. Systolic blood pressure < 100 mm 
Hg, 2. Heart rate < 55 bpm, or 3. Fluid retention requiring intravenous diuretics. 

Maintenance phase (M1 and M2): Patients will be continued on a stable dose of the study 
drug (maximum tolerated dose of carvedilol or placebo) for additional 3 months. 

Washout and Cross-over: After 6 months of treatment, the study drug will be tapered down 
over two weeks and after additional two weeks of washout period,  patients will be crossed 
over to the alternative treatment for 6 months.
 Figure 3: Study Design


23

Completion phase: The study drug dose (carvedilol or placebo) will be tapered down slowly 
over a 2-week period. All patients will have a follow up phone call at 4 weeks after 
completing the study to assess clinical stability.
Visit and assessment schedule: 
Screening
Screening should be performed no more than 28 days prior to the baseline visit (TTE, cMRI 
and RHC within the previous 3 months). After going through the consent process and obtaining 
written consent, participant eligibility will be determined using data collected during their 
routine outpatient visit.  These include the following:

Obtain written consent

Demographics

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class

6 minute walk test

Transthoracic echocardiogram

Blood samples for routine hematology, blood chemistry and NT-ProBNP

Cardiac MRI for assessment of right ventricular function (right ventricular size, volumes, 
and ejection fraction)

Right heart catheterization
Baseline visit (Week 0)
The following will be obtained during baseline visit. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

Plasma catecholamine levels

Quality of life assessment with MLHF questionnaire

Pregnancy test if subject is a female of child-bearing potential
After obtaining above procedures subject will be randomized 1: 1 to placebo vs. carvedilol 
3.125 mg orally twice a day. 


24
Week 2
The following assessments will be done as an outpatient. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class
Week 4
The following assessments will be done as an outpatient. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class 

If patient is tolerating the study drug, dose will be increased to 2 pills (placebo or 
carvedilol 3.125 mg) twice a day
Week 6
The following assessments will be done as an outpatient. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class
Week 8
The following assessments will be done as an outpatient. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class


25

If patient is tolerating the study drug, dose will be increased to 3 pills (placebo or 
carvedilol 3.125 mg) twice a day
Week 10
The following assessments will be done as an outpatient. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class
Week 12
The following assessments will be done as an outpatient. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class

6 minute walk test

Blood samples for routine hematology, blood chemistry and NT-ProBNP

If patient is tolerating the study drug, dose will be increased to 1 pill (placebo or 
carvedilol 12.5 mg) twice a day
Month 4
The following assessments will be done as an outpatient. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class
Month 5
The following assessments will be done as an outpatient. 

Medical history

Physical examination


26

Concomitant medications

Vital signs

EKG

WHO functional class
Month 6
The following will be obtained during baseline visit. 

Medical history

Physical examination

Concomitant medications

Vital signs

EKG

WHO functional class

6 minute walk test

Transthoracic echocardiogram

Blood samples for routine hematology, blood chemistry and NT-ProBNP

Cardiac MRI for assessment of right ventricular function (right ventricular size, volumes, 
and ejection fraction)

Right heart catheterization

Quality of life assessment with MLHF questionnaire

Plasma catecholamine levels
6 months of treatment, the study drug will be tapered down over two weeks and after additional 
two weeks of washout period, patients will be crossed over to the alternative treatment for 6 
months. 
All study clinic visits will be scheduled within ± 5 days of the actual expected calendar date as 
per the protocol. 
6.4
Follow-Up Procedures 
Study Assessments: 
Physical examination and medical history:
Physical examination will be performed to ensure suitability according to the inclusion and 
exclusion criteria at screening and to document the health status at the time points specified in 
the schedule of events.  The physical examination comprises measurement of height and body 
weight and a routine medical examination. 
A detailed medical history will be recorded at screening and brief history will be taken at other 
visits. The medical history will elicit information concerning existing medical conditions, major 
illnesses, and related surgical procedures. Any prescribed or over the counter medications that 
the subject received within the past 30 days should be recorded. Subjects will be instructed to 
notify the study doctor before beginning new prescribed or over the counter medications. 


27
EKG: Electrocardiogram will be formed during each study visit to exclude bradyarrythmias
RV Function by Cardiac MRI: Cardiac MRI will be performed on a Siemens 1.5 T Sonata 
scanner (Siemens Medical Solutions, Erlangen, Germany) with simultaneous EKG recording 
according to a protocol described previously. Short-axis cine images of the heart from apex to 
base will be acquired, covering the whole RV. The endo- and epicardial contours of the RV will 
be delineated manually by a blinded observer and processed using specialized software to 
obtain RV mass, end-systolic, and end-diastolic volume. Three measurements of RV wall 
thickness will be obtained for the RV free wall at the mid-ventricular level and the mean value 
will be calculated. Stroke volume will be determined from the flow in the main pulmonary artery 
in an image plane positioned perpendicular to the main pulmonary artery using a two-
dimensional, spoiled gradient-echo pulse sequence, and one-dimensional velocity-encoding 
signal parallel to the flow in the pulmonary artery. Cardiac output will be determined by 
multiplying stroke volume by heart rate. Parameters are indexed by correcting for body surface 
area. RV ejection fraction will be determined by dividing stroke volume by RV end-diastolic 
volume.
RV Function by Echocardiography: Echocardiograms will be performed according to standard 
American Society of Echocardiography criteria using commercially available ultrasound 
machines. Cardiac chamber sizes will be assessed from multiple views. RV outflow tract flow 
will be assessed with the sample volume positioned immediately below the pulmonic valve in 
the parasternal short-axis view with pulse wave and continuous wave Doppler. Analysis of the 
pulsed wave Doppler signal in the RV outflow tract will allow for measurement of the velocity 
time integral (surrogate of stroke volume), time to peak velocity (acceleration time) and for 
categorization of the basic morphology of the Doppler signal (no notch, late systolic notch, mid-
systolic notch). Color Doppler will be used to assess the degree of tricuspid regurgitation in 
multiple views. The highest right atrial to RV gradient from continuous wave Doppler will be 
used as an estimate of RV systolic pressure. Tricuspid annular plane systolic excursion will be 
measured using either M-mode imaging or two-dimensional imaging from the apical four-
chamber view. Tissue Doppler imaging will be used for assessment of RV systolic and diastolic 
performance. 
Right heart catheterization (RHC): Patients will undergo RHC using standard techniques. With 
the patient supine, the pressure transducers will be leveled at the mid-thorax. Mild sedation will 
be administered per patient request. The RHC will utilize a balloon flow-directed thermodilution 
catheter that will be placed in the PA.  The catheter will be advanced to the pulmonary wedge 
position and validated by hemodynamic tracings, fluoroscopy, and blood sampling for oxygen 
saturation if needed. Measurements of mean right atrial pressure, pulmonary artery systolic, 
diastolic and mean pressure, and pulmonary wedge pressure will be recorded on paper for 5 
seconds and measured at end-expiration. Thermodilution cardiac output will be measured in 
triplicate and averaged. O2 saturation will be measured from the pulmonary artery with a co-
oximeter. Systemic blood pressure will be determined by cuff manometry and systemic oxygen 
saturation by pulse oximetry.


28
6MWT: The 6MWT will be performed according to American Thoracic society guidelines42. 
Briefly, the 6MWT is performed in an enclosed, level, measured corridor. Subjects will be 
instructed to walk at their own pace but to cover as much ground as possible in 6 minutes. The 
supervising study personnel accompanies the subject and encourages them with the 
standardized statements, “You are doing well” or “Keep up the good work,” but avoids other 
phrases of encouragement.
Plasma Catecholamine levels: plasma catecholamine levels will be measured on blood 
samples as a send out test at ARUP Reference Labs in Utah.
Plasma NT-ProBNP: Plasma NT-proBNP testing will be performed at the University of 
Minnesota Medical Center laboratory.  
Quality of Life: We will use the Minnesota Living with Heart Failure Questionnaire for assessing 
quality of life. Minnesota Living with Heart Failure survey has been used in previous PAH 
clinical trials and has also been validated as a reliable measure of quality of life in PAH 
patients40,41.
6.7
Study Timetable / Schedule of Events
        
6.8
Study Protocol Compliance / Treatment Adherence
We will do pill counts at each clinic visit as a measure of compliance. If a subject is non-compliant 
with taking his study drug for more than 2 weeks continuously, that subject will be excluded from 
the study. The subject will undergo final assessment including cardiac MRI and right heart 
catheterization at the time of exclusion from the study. 
6.9
Deviations from the Clinical Protocol
When a deviation from the protocol is necessary for an individual subject, the investigator must 
complete a description of the deviation from the protocol and justification on the Protocol 
Deviation Form.  
6.10
Protocol Amendments After Study Initiation


29
Should changes in the study plan or protocol become necessary in the course of the clinical trial, 
those specific changes will be discussed and agreed upon by the Sponsor, its acting 
representative if appropriate, Investigator, and appropriate IRB approval obtained before the 
changes are implemented.  All changes must be documented as protocol amendments.  For 
studies conducted under an IND, FDA approval and/or notification may be required in addition 
to the IRB approval.
6.11
Subject Withdrawal
6.11.1 How to Withdraw Subjects
Subjects will be discontinued from the study for the following reasons:
1. The subject no longer wishes to participate
2. Development of intolerable side-effects related to carvedilol
3. Development of significant hypotension despite dose reduction (reduction in blood 
pressure associated with dizziness or syncope or SBP less than 90 mm Hg)
4. Development of significant bradycardia despite dose reduction (HR < 50 bpm without a 
permanent pacemaker or reduction in heart rate associated with dizziness or syncope)
5. Development of decompensated right heart failure requiring intravenous diuretics or 
hospitalization
Patients who discontinue or wish to drop out early from the study will undergo final assessment 
at the time discontinuation. Carvedilol will be gradually tapered of over 4 weeks period unless 
the patient is having a serious adverse event.
6.11.2 Data Collection and Follow Up for Withdrawn Subjects
Patients who discontinue or wish to drop out early from the study will undergo final assessment 
at the time discontinuation including cardiac MRI and right heart catheterization. A subject will 
be considered lost to follow up if we are unable to reach the patient despite 5 phone calls to 
the subject or to the next-of-kin and 3 certified letters. 
6.12
Subject Compensation
Subjects will receive a $25 gift card at the completion of the 6 month and 13-month visit. 
7.0
Data Collection and Analysis
7.1
Subject Population(s) for Analysis
All-treated population:  Any subject randomized into the study that received at least one 
exposure to study drug will be subjected to the study analysis – both for the primary analysis 
and any applicable secondary analyses. 
7.2
Statistical Methods
The primary objective of this study is to determine the effect of carvedilol therapy on RV function 
in PAH patients. We will measure the mean change in RVEF before and after carvedilol therapy. 
We will compare this variable before and after carvedilol therapy using paired t-tests or Wilcoxon 


30
signed-rank tests. The null hypothesis is that treatment with carvedilol has no effect on RVEF in 
patients with PAH with a two-sided alternative that carvedilol changes RVEF. Using a similar 
approach, we will also compare echo parameters of RV function, right heart hemodynamics, 6-
minute walk distance, plasma NT-ProBNP, plasma catecholamine level, and MLHF 
questionnaire before and after carvedilol therapy.
8.0
Safety and Adverse Events
8.1
Definitions
Adverse Event (AE)
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries will be regarded as 
adverse events.  Abnormal results of laboratory or diagnostic procedures are considered to be 
adverse events if the abnormality:

Results in study withdrawal

Is associated with a serious adverse event

Is associated with clinical signs or symptoms

Leads to additional treatment or to further diagnostic tests

Is considered by the Investigator to be of clinical significance.
Adverse Reaction
An adverse reaction is any adverse event caused by a drug.  Adverse reactions are a subset of 
suspected adverse reactions.
Suspected Adverse Reaction
A suspected adverse reaction is an adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.
Serious Adverse Event (SAE)
A serious adverse event (SAE) is any adverse event that is:

Fatal

Life-threatening

Requires or prolongs a hospital stay

Results in persistent or significant disability or incapacity

A congenital anomaly or birth defect
Important medical events are events that may not be immediately life threatening, but are clearly 
of major clinical significance and may be SAEs.  They may jeopardize the subject, and may 
require intervention to prevent one or the other serious outcomes noted above.  
Hospitalization 
Hospitalization shall include any initial admission (even if less than 24 hours) to a healthcare 
facility as a result of a precipitating clinical adverse effect; to include transfer within the hospital 
to an intensive care unit.  Hospitalization or prolongation of hospitalization in the absence of a 
precipitating, clinical adverse effect (e.g., for a preexisting condition not associated with a new 
adverse effect or with a worsening of the preexisting condition; admission for a protocol-specified 
procedure) is not, in itself, a serious adverse effect.


31
Expected Adverse Event
Expected adverse events are those that are known to be associated with or have the potential 
to arise as a consequence of participation in the study.
Unexpected Adverse Event
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the Investigator Brochure or Protocol at the specificity or severity that has been observed.
Unanticipated Problems Involving Risk To Subjects or Others (UPIRTSO)
An adverse event that in the opinion of the Principal Investigator is unexpected, related to the 
drug, and serious.
8.2
Recording of Adverse Events
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded in the source document, though should be 
grouped under one diagnosis.
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period must be followed up to determine the final outcome.  Any 
serious adverse event that occurs after the study period and is considered to be possibly related 
to the study treatment or study participation should be recorded and reported immediately.
8.3
Reporting of Serious Adverse Events
8.3.1 IRB Notification by Investigators
Reports of all serious adverse events (including follow-up information) must be submitted to the 
IRB within 5 working days if it falls under the UPIRTSO guidelines.  Copies of each report and 
documentation of IRB notification and receipt will be kept in the Clinical Investigator’s binder.
8.3.2 UPIRTSO Events
Investigators are required to submit a report of UPIRTSO events to the IRB within 5 working 
days of first learning of the event. 
8.4
Safety Monitoring Plan
Subjects will be evaluated at the University of Minnesota PH clinic every 2 weeks initially for 3 
months and then monthly for additional 3 months in each of the 6 month segments One of the 
PH team providers (Drs. Pritzker, Thenappan, Rebecca Cogswell) will evaluate subject for signs 
of right heart failure, bradycardia, and hypotension. Patients will also get electrocardiogram 
during each clinic visit to rule out bradyarrythmias including sinus bradycardia, atrioventricular 
nodal block, and new bundle branch block.
8.4.1 Anticipated Risks / Risk Mitigation


32
Risk associated with study procedures: Most of the procedures performed in this study are 
mostly part of the routine patient care. There is no risk associated with EKG, echocardiogram, 
cardiac MRI, and six-minute walk distance. The risk associated with right heart catheterization 
includes pain, infection, bleeding, pneumothorax, arrhythmias, pulmonary artery rupture, and 
death. Based on prospective and retrospective analyses, the rate of overall serious adverse 
events is around 1.1%. To minimize the risk of adverse events, an experience heart failure 
cardiologist or interventional cardiologist in the catheterization laboratory will perform the 
procedure using ultrasound and fluoroscopy guidance. The risk associated with phlebotomy 
includes discomfort, bleeding, or rarely, infection. 
Risk associated with Carvedilol: The most serious adverse effects of carvedilol are hypotension, 
significant bradyarrythmias including advanced atrioventricular block, and worsening right heart 
failure due to negative inotropic effect. To mitigate these risks, we will exclude patients with 
resting heart rate < 60 beats per minute, second or third degree atrioventricular block, systolic 
blood pressure < 100 mm Hg, sinus tachycardia with a resting hear rate > 100 bpm, or if they 
have NYHA class IV symptoms or decompensated right heart failure. During the dose escalation 
and maintenance phase, subjects will be evaluated at the University of Minnesota PH clinic by 
one of the PH team providers (Drs. Pritzker, Thenappan, Cogswell) every 2 weeks initially for 3 
months and then monthly for additional 3 months. We will decrease the carvedilol dose to the 
next lowest dose (50% reduction) if the heart rate is < 55 or systolic blood pressure is < 100 mm 
Hg. Subjects will be withdrawn if they develop advanced atriovenricular block or worsening right 
heart failure requiring hospitalization or intravenous diuretics. Subjects will be screened during 
each clinic visit with an EKG to detect asymptomatic bradyarrythmias. We will check serum NT-
ProBNP, a marker of heart failure, every 3 months to screen for worsening right ventricular 
failure.
There is also the risk of loss of privacy, which will be minimized as follows. All the paper 
documents, including consent forms, will be stored in a locked drawer in a securely locked room. 
The database will be password protected and access will be granted only to approved 
investigators. For the analysis phase, the data will be de-identified prior to exporting it. 
Written consent will be obtained in the patient’s native language and the risks, benefits, and 
alternatives to participating in the study will be reviewed. Patients will be required to demonstrate 
adequate reasoning faculties and an understanding of the facts before consent is obtained.   
8.4.2 Medical Monitoring for Participant Safety 
       
The Principal Investigator will oversee the safety of the study, including careful assessment and 
appropriate reporting of adverse events as outlined in Section 7.4.  Medical monitoring will 
include a regular assessment of the number and type of serious adverse events.  
8.4.3 Study Stopping Rules
Study Procedure
Anticipated Risks
Risk Mitigation
RHC
Pain, infection, bleeding, 
pneumothorax, 
arrhythmias, 
pulmonary 
artery rupture, and death
Experienced heart failure cardiologist will perform the 
procedure under ultrasound guidance
Phlebotomy
Discomfort, bleeding, or 
rarely, infection
Experienced phlebotomist will do the blood draw


33
The study will be stopped if one of the following endpoints are reached: 
A statistically significant treatment effect is demonstrated with regard to the primary outcome for 
any treatment arm relative to the others.
A statistically significant treatment effect cannot be achieved with regard to the primary outcome 
for the treatment arm relative to the others (analysis for futility).
Voluntary subject withdrawal in any arm of the study is significantly greater than expected, such 
that the statistical validity of the comparisons between arms is compromised.
The rate of severe adverse events in any arm of the study is such that continued participation 
would compromise subject safety.  
8.4.4 Anticipated Adverse Events
The anticipated adverse effects of carvedilol are listed below:
Common adverse effects:

Cardiovascular: Bradyarrhythmia (3%-10%), Hypotension (1.8% to 20.2%), Peripheral 
edema (1% to 7%). 

Endocrine metabolic: Abnormal weight gain (10% to 12%), Hyperglycemia (5% to 12%). 
Gastrointestinal: Diarrhea (2% to 12%). 

Neurologic: Dizziness (6% to 33%)
 
Serious Adverse Effects:

Cardiovascular: Atrioventricular block (1% to 3%) 

Dermatologic: Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal 
necrolysis 

Hematologic: Aplastic anemia 

Respiratory: Asthma with status asthmaticus (rare) 
8.5
Data Safety Monitoring Board
          
A data safety monitoring board consisting of Drs. Gary S Francis, Stephen L. Archer, Harm 
Boggard and Stuart Rich will review all serious events that occur during the course of the study, 
regardless of the treatment received by the subject and relationship to the drug.  This board will 
review all data and safety. An interim analysis after 5, 10, and 15 patients have been enrolled 
will be performed and reports submitted per IRB safety monitoring guidelines.
A serious adverse event will be reported to the DSMB by the investigator by telephone, email, 
or fax within 24 hours of the event.  A Serious Adverse Event (SAE) form must be completed by 
the investigator and either emailed or faxed to the DSMB within 24 hours.  The investigator will 


34
keep a copy of this SAE form on file at the study site.  Report serious adverse events by phone 
and facsimile to:
Thenappan Thenappan, MD
Assistant Professor of Medicine
Cardiology Division
University of Minnesota
420 Delaware Street, SE MMC 508
Minneapolis, MN 55455
Phone: 612 624 8970
Fax: 612 626 4411
At the time of the initial report, the following information should be provided:

Study identifier

Subject number

A description of the event

Date of onset

Current status

Whether study treatment was discontinued

The reason why the event is classified as serious

Investigator assessment of the association between the event and study treatment
Within the following 48 hours, the investigator must provide further information on the serious 
adverse event in the form of a written narrative.  This should include a copy of the completed 
Serious Adverse Event form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing serious adverse events will 
be provided promptly to the IRB and DSMB.
9.0
Data Handling and Record Keeping
9.1
Confidentiality
      


35
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following: 

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period.
9.2
Source Documents
Source Data are the clinical findings and observations, laboratory and test data, and other 
information contained in Source Documents.  Source Documents are the original records (and 
certified copies of original records); including, but not limited to, hospital medical records, 
physician or office charts, physician or nursing notes, subject diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, x-rays, etc.  When 
applicable, information recorded on the CRF shall match the Source Data recorded on the 
Source Documents.  
9.3
Case Report Forms
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it.
A Case Report Form will be completed for each subject enrolled into the clinical study.  The 
investigator will review, approve and sign/date each completed CRF; the investigator’s signature 
serving as attestation of the investigator’s responsibility for ensuring that all clinical and 
laboratory data entered on the CRF are complete, accurate and authentic.  
9.4
Clinical Reports
An annual progress report will be submitted to the IRB.  Investigators will submit a final report of 
the clinical study to the reviewing IRB within 3 months of termination or completion of the clinical 
study or the Investigator’s part of the clinical study.
9.5
Records Retention
The investigator will retain the specified records and reports for up to 2 years from completion 
of IRB related work and 6 years for HIPAA.   


36
10.0
Study Monitoring, Auditing, and Inspecting
This study will be monitored according to FDA/GCP guidelines.  The Investigator will allocate 
adequate time for such monitoring activities.  The Investigator will also ensure that the monitor 
or other compliance or quality assurance reviewer is given access to all study-related documents 
and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space 
to conduct the monitoring visit.
10.1
Study Monitoring Plan
Independent monitoring of the clinical study for clinical protocol and IDE application compliance 
will be conducted periodically (i.e., at a minimum of annually) by qualified staff of the University 
of Minnesota’s Clinical and Translational Science Institute (CTSI) in accordance with the 
attached monitoring plan.
10.2
Quality Assurance Procedures
Weekly meetings of the study's principal investigator and staff will be held to discuss matters 
related to the safety of protocol participants, validity and integrity of the data, enrollment rate, 
retention of participants, adherence to protocol, and data completeness.
10.3
Auditing and Inspection
   
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for inspections 
of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices.
11.0
Administrative Study Information
11.1
Pre-Study Site Qualification
This is an investigator-initiated single center study.
11.2
Materials Provided by Sponsor / Coordinating Center
This is an investigator-initiated single center study.
12.0
Ethical Considerations
This study is to be conducted according to US and international standards of Good Clinical 
Practice (21 CFR 312 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures.
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval 
of the study conduct.  The decision of the IRB concerning the conduct of the study will be made 
in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  
13.0
Study Finances 


37
13.1
Funding Source
This study is financed through American Heart Association Scientist Development Grant: 
15SDG25560048 awarded to the PI – Dr. Thenappan Thenappan
13.2
Conflicts of Interest
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must refer to the 
Regents Policies on Individual Conflict of Interest Policy or Institutional Conflict of Interest Policy. 
These policies require University Faculty and staff to report external professional activities and 
business and significant financial interests related to his or her University activities by submitting 
a REPA (Report of External Professional Activities) at least once per year. Faculty and staff 
should also file a REPA when substantial changes in business or financial interests occur, when 
an activity that presents a potential conflict of interest is anticipated, or when submitting an 
application for research support or technology transfer, submitting research protocols to the IRB, 
or receiving financial contributions. All University of Minnesota investigators will follow the 
University conflict of interest policy.
14.0
Publications Plan
The principal Investigator, Dr. Thenappan, holds the primary responsibility for publication of any 
results of the study. Neither the complete nor any part of the results of the study carried out 
under this protocol, nor any of the information provided by the principal investigator for the 
purposes of performing the study, will be published or passed on to any third party without the 
consent of the principal investigator.  Any investigator involved with this study is obligated to 
provide the principal investigator with complete test results and all data derived from the study.


38
15.0
References:
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Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Contemporary 
survival in patients with pulmonary arterial hypertension: a Reappraisal of the National 
Institutes of Health Risk Stratification Equation. Eur Respir J. Dec 23 2009.
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Nagendran J, Archer SL, Soliman D, et al. Phosphodiesterase type 5 is highly expressed 
in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 
5 improves contractility. Circulation. Jul 17 2007;116(3):238-248.
3.
Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of 
randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. Feb 
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4.
Macchia A, Marchioli R, Tognoni G, et al. Systematic review of trials using vasodilators in 
pulmonary arterial hypertension: why a new approach is needed. Am Heart J. Feb 
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Rich S. Right ventricular adaptation and maladaptation in chronic pulmonary arterial 
hypertension. Cardiol Clin. May 2012;30(2):257-269.
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Piao L, Fang YH, Parikh KS, et al. GRK2-mediated inhibition of adrenergic and 
dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in 
pulmonary hypertension. Circulation. Dec 11 2012;126(24):2859-2869.
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Drake JI, Gomez-Arroyo J, Dumur CI, et al. Chronic carvedilol treatment partially reverses 
the right ventricular failure transcriptional profile in experimental pulmonary hypertension. 
Physiol Genomics. Jun 17 2013;45(12):449-461.
8.
van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, 
volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. May 
2007;28(10):1250-1257.
9.
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;122(2):164-172.
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D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary 
hypertension: results from a national prospective registry. Ann Intern Med. Sep 01 
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Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and 
anorexigen-associated pulmonary arterial hypertension in the modern management era. 
Circulation. Jul 13;122(2):156-163.
12.
van de Veerdonk MC, Kind T, Marcus JT, et al. Progressive right ventricular dysfunction in 
patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol. 
Dec 6;58(24):2511-2519.
13.
Bristow MR, Minobe W, Rasmussen R, et al. Beta-adrenergic neuroeffector abnormalities 
in the failing human heart are produced by local rather than systemic mechanisms. The 
Journal of clinical investigation. Mar 1992;89(3):803-815.


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14.
Nootens M, Kaufmann E, Rector T, et al. Neurohormonal activation in patients with right 
ventricular failure from pulmonary hypertension: relation to hemodynamic variables and 
endothelin levels. J Am Coll Cardiol. Dec 1995;26(7):1581-1585.
15.
Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P. Increased 
sympathetic nerve activity in pulmonary artery hypertension. Circulation. Sep 7 
2004;110(10):1308-1312.
16.
Wensel R, Jilek C, Dorr M, et al. Impaired cardiac autonomic control relates to disease 
severity in pulmonary hypertension. Eur Respir J. Oct 2009;34(4):895-901.
17.
Usui S, Yao A, Hatano M, et al. Upregulated neurohumoral factors are associated with left 
ventricular remodeling and poor prognosis in rats with monocrotaline-induced pulmonary 
arterial hypertension. Circulation journal : official journal of the Japanese Circulation 
Society. Sep 2006;70(9):1208-1215.
18.
Morimitsu T, Miyahara Y, Sinboku H, et al. Iodine-123-metaiodobenzylguanidine 
myocardial imaging in patients with right ventricular pressure overload. Journal of nuclear 
medicine : official publication, Society of Nuclear Medicine. Aug 1996;37(8):1343-1346.
19.
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. Jan 2 
1999;353(9146):9-13.
20.
Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on 
total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol 
CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF 
Study Group. JAMA : the journal of the American Medical Association. Mar 8 
2000;283(10):1295-1302.
21.
Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic 
heart failure. N Engl J Med. May 31 2001;344(22):1651-1658.
22.
Reiter MJ, Reiffel JA. Importance of beta blockade in the therapy of serious ventricular 
arrhythmias. Am J Cardiol. Aug 20 1998;82(4A):9I-19I.
23.
Bogaard HJ, Natarajan R, Mizuno S, et al. Adrenergic receptor blockade reverses right 
heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care 
Med. Sep 1 2010;182(5):652-660.
24.
de Man FS, Handoko ML, van Ballegoij JJ, et al. Bisoprolol delays progression towards 
right heart failure in experimental pulmonary hypertension. Circ Heart Fail. Jan 
2012;5(1):97-105.
25.
Ishikawa M, Sato N, Asai K, Takano T, Mizuno K. Effects of a pure alpha/beta-adrenergic 
receptor blocker on monocrotaline-induced pulmonary arterial hypertension with right 
ventricular hypertrophy in rats. Circulation journal : official journal of the Japanese 
Circulation Society. Dec 2009;73(12):2337-2341.
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Wenzel D, Knies R, Matthey M, et al. beta(2)-adrenoceptor antagonist ICI 118,551 decreases 
pulmonary vascular tone in mice via a G(i/o) protein/nitric oxide-coupled pathway. 
Hypertension. Jul 2009;54(1):157-163.


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27.
Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise 
capacity 
and 
hemodynamics 
in 
patients 
with 
portopulmonary 
hypertension. 
Gastroenterology. Jan 2006;130(1):120-126.
28.
Jasmijn SJAVC, Karin De B, Martha W, et al. Beta-Blocker Therapy In Patients With 
Idiopathic Pulmonary Arterial Hypertension: A Randomized Controlled Trial. A19. LATE 
BREAKING ABSTRACTS IN CLINICAL TRIALS: American Thoracic Society; 2014:A6569-
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Ma XL, Yue TL, Lopez BL, et al. Carvedilol, a new beta adrenoreceptor blocker and free 
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hypercholesterolemic rabbits. J Pharmacol Exp Ther. Apr 1996;277(1):128-136.
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Mochizuki M, Yano M, Oda T, et al. Scavenging free radicals by low-dose carvedilol 
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J Am Coll Cardiol. Apr 24 2007;49(16):1722-1732.
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Wisler JW, DeWire SM, Whalen EJ, et al. A unique mechanism of beta-blocker action: 
carvedilol stimulates beta-arrestin signaling. Proceedings of the National Academy of 
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receptor transactivation of the EGFR confers cardioprotection. The Journal of clinical 
investigation. Sep 2007;117(9):2445-2458.
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Thenappan T, Roy SS, Duval S, Glassner-Kolmin C, Gomberg-Maitland M. beta-Blocker 
Therapy Is Not Associated With Adverse Outcomes in Patients With Pulmonary Arterial 
Hypertension: A Propensity Score Analysis. Circ Heart Fail. Nov 2014;7(6):903-910.
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hypertension with carvedilol is safe. Am J Respir Crit Care Med. Jun 15 2014;189(12):1562-
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41
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Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a 
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ICF_000.pdf: 
Approved for use by UMN IRB
Effective on 12/22/2017
IRB Study Number: 1507M75642
UNIVERSITY OF MINNESOTA
HSC# 1507M75642
Version Date: 10.12.2017
Page 1 of 14
CONSENT TO BE IN A RESEARCH STUDY
Study Title:
Beta-blockers in Pulmonary Arterial Hypertension – A Phase 2 Double-Blind, 
Placebo-Controlled, Crossover Study Evaluating the Efficacy and Safety of 
Carvedilol for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension
Investigator: Thenappan Thenappan, M.D.
 
University of Minnesota – Division of Cardiology
Sponsor:
This is an investigator-initiated study completely funded by the American Heart 
Association. The Investigational Drug Services at University of Minnesota will 
provide the study drug. The manufacture of carvedilol has no role in this study.
INTRODUCTION AND PARTICIPANT SELECTION
This study is being conducted by researchers from the University of Minnesota.  
You are invited to participate in a research study of beta-blockers as a potential therapeutic 
approach for the treatment of right heart failure due to Pulmonary Arterial Hypertension (PAH).  
You were selected as a possible participant because you are a patient at the Pulmonary 
Hypertension clinic at the University of Minnesota.
We ask that you read this form and ask any questions you may have before agreeing to be in the 
study.
STUDY PURPOSE
The purpose of the study is to see if carvedilol can be used as a treatment of right heart failure due 
to Pulmonary Arterial Hypertension (PAH).  Carvedilol is approved by FDA for treating several 
cardiovascular conditions including high blood pressure and left heart failure, but for this study it is 
being used off label in an experimental way.  
STUDY SIZE
This study will be conducted at the University of Minnesota.  A total of 26 people will participate in 
this research study.
STUDY PROCEDURES
This is a cross over study. Subjects will be randomly assigned to placebo or study drug initially for 
6 months and later will switch to the opposite group for additional 6 months. 
If you agree to participate in this study, we would ask you to do the following:


Approved for use by UMN IRB
Effective on 12/22/2017
IRB Study Number: 1507M75642
UNIVERSITY OF MINNESOTA
HSC# 1507M75642
Version Date: 10.12.2017
Page 1 of 14
Screening, Baseline, and Randomization Visit:
We will carefully monitor your progress by watching the standard clinical tests you have done to 
manage your condition. These include:

Obtain written consent

Medical history

Physical examination

Concomitant medications

Vital signs

Electrocardiogram

6 minute walk test

Heart Ultrasound

Blood samples (less than 2 teaspoons) for routine hematology, blood chemistry and brain 
natriuretic peptide (a measure of heart function)

Pregnancy test for female of childbearing potential   

Cardiac magnetic resonance imaging for assessment of right ventricular function (right 
ventricular size, volumes, and ejection fraction)

Right heart catheterization
In addition, so that we can learn more about your condition, the following tests will be done for the 
purposes of research and will not be billed to you or your insurance:

Quality of life assessment with Minnesota living with the heart Failure (MLHF) 
questionnaire

Blood samples (2 teaspoons) for measuring catecholamine levels (a measure of activation of 
autonomic nervous system).  This sample will be sent to an outside reference lab for testing.
After obtaining the above procedure, you will be randomly assigned to receive either carvedilol or 
placebo.  Randomization means you will be randomly assigned to a treatment based on chance, like 
a flip of a coin. Neither you nor the researcher chooses your assigned group. You will have an equal 
chance of being in either group. You be will be initiated on carvedilol or placebo 3.125 mg orally 
twice a day. If feasible, the screening and baseline visits will be done together.
Subsequently, you will be evaluated at the University of Minnesota pulmonary hypertension clinic 
by one of the pulmonary hypertension providers every 2 weeks initially for 3 months and then 
monthly for additional 3 months. Carvedilol or placebo dose will be increased gradually to 6.25 mg 
twice a day, 9.375 mg twice a day, and 12.5 mg twice a day at week 4, 8, and 12 as tolerated.
To monitor your progress, the following tests will be done for the purposes of research and will 
not be billed to you or your insurance at Week 2, week 4, week 6, week 8, week 10, month 4, and 
month 5:

Medical history

Physical examination

Concomitant medications

Vital signs


Approved for use by UMN IRB
Effective on 12/22/2017
IRB Study Number: 1507M75642
UNIVERSITY OF MINNESOTA
HSC# 1507M75642
Version Date: 10.12.2017
Page 1 of 14

Electrocardiogram

Functional class
Week 12
We will carefully monitor your progress by watching the standard clinical tests you have done to 
manage your condition. These include:

Medical history

Physical examination

Concomitant medications

Vital signs

Electrocardiogram

Functional class

Blood samples (less than 2 teaspoons) for routine hematology, blood chemistry and brain 
natriuretic peptide. 
The following tests will be done for the purposes of research and will not be billed to you or your 
insurance: 

6 Minute walk distance
Month 6
We will carefully monitor your progress by watching the standard clinical tests you have done to 
manage your condition. These include:

Medical history

Physical examination

Concomitant medications

Vital signs

Functional class

Electrocardiogram

Heart Ultrasound
Blood samples (less than 2 teaspoons) for routine hematology, blood chemistry and brain 
natriuretic peptide.
The following tests will be done for the purposes of research and will not be billed to you or your 
insurance:

6 minute walk test

Cardiac MRI for assessment of right ventricular function (right ventricular size, volumes, 
and ejection fraction)

Quality of life assessment with Minnesota Living with Heart Failure questionnaire

Right heart catheterization

Blood samples (an additional 2 teaspoons) for measuring catecholamine levels (a measure of 
activation of autonomic nervous system).  This sample will be sent to an outside reference 
lab for testing.


Approved for use by UMN IRB
Effective on 12/22/2017
IRB Study Number: 1507M75642
UNIVERSITY OF MINNESOTA
HSC# 1507M75642
Version Date: 10.12.2017
Page 1 of 14
After 6 months of treatment, the study drug will be tapered down over two weeks and you will be 
crossed over to the alternative treatment for 6 additional months with the same schedule described 
above.  Throughout the study, you will be evaluated at the University of Minnesota PH clinic by 
one of the PH team providers every 2 weeks initially for 3 months and then monthly for additional 3 
months in both of the 6-month segments.
STUDY DURATION
Your participation in this study will last 13 months.
At the conclusion of the study at 13-months, all patients will wean off the drug over a 2-week 
period. 
RISKS AND DISCOMFORTS
Most of the procedures performed in this study are part of the routine patient care. The risk 
associated with right heart catheterization includes: pain, bleeding, pneumothorax (an abnormal 
collection of air or gas in the pleural space that separates the lung from the chest wall), arrhythmias 
(a condition in which the heart beats with an irregular or abnormal rhythm), pulmonary artery 
rupture (a tear in the pulmonary artery due to catheter use), and death. Based on prospective and 
retrospective analyses, the rate of overall serious adverse events is around 1.1%. To minimize the 
risk of adverse events, an experienced heart failure cardiologist or interventional cardiologist in the 
catheterization laboratory will perform the procedure using ultrasound and fluoroscopy guidance. 
The risk associated with blood draws includes discomfort, bleeding, or rarely, infection. 
The risk associated with carvedilol according to frequency and severity: 
Common: Low heart rate, low blood pressure, fluid retention, weakness and fatigue particularly at 
the start of treatment, dizziness, diarrhea, weight gain, hair loss, and worsening control of blood 
glucose in patients with pre-existing diabetes mellitus.
Less common and serious: Very rarely fainting, heart block, heart failure during up-titration, low 
blood platelet count, low white blood cell count, attenuate or mask early symptoms and signs of low 
blood sugar in patients with pre-exisiting diabetes mellitus, and skin reactions.
Carvedilol should not be discontinued abruptly unless it is associated with serious adverse event as 
this may lead to an abrut increase in heart rate and blood pressure. Carvedilol should be tapered 
gradually over 2-4 weeks duration.
There is no adequate clinical experience with carvedilol in pregnant women. Hence, pregnant 
women are excluded from participating in this trial. Animal studies demonstrated that carvedilol or 
its metabolites are excreted in breast milk. It is not known whether carvedilol is excreted in human 
mi1k.  Breast-feeding is therefore not recommended during administration of carvedilol.
 
To lessen the risks associated with carvedilol, we will exclude patients with resting heart rate < 60 
beats per minute without a pacemaker, advanced heart block without a pacemaker, systolic blood 


Approved for use by UMN IRB
Effective on 12/22/2017
IRB Study Number: 1507M75642
UNIVERSITY OF MINNESOTA
HSC# 1507M75642
Version Date: 10.12.2017
Page 1 of 14
pressure < 100 mm Hg, resting hear rate > 110 bpm, or if they have functional class IV symptoms 
or decompensated right heart failure. Subjects with diabetes mellitus will be instructed to watch for 
early symptoms and signs of hypoglycemia. You will be closely monitored every 2 weeks initially 
for 3 months and once a month for the next 3 months. If it is determined that the you are not 
tolerating the dose well, the study doctor will decrease the dose.  If at any time in the study you 
have a serious adverse event or reaction to the study medication, the study drug will stopped. You 
will be screened for pregnancy at the time of enrollement. If you become pregnant during the study, 
the study drug will be stopped and  you will be exited from the study. Carvedilol will not be stopped 
abruptly unless you are having a serious adverse event related to the study drug. Otherwise it  will 
be tapered gradually over 2 weeks. 
Carvedilol has been availabe in the market for the last two decades and is commonly used to treat 
hypertension and left ventricular systolic dysfunction. 
As part of this study you will undergo three heart imaging procedures (right heart catheterizations).  
These procedures involve exposure to ionizing radiation.  This radiation exposure is not necessary 
for your medical care and is for research purposes only.  The average amount of radiation that the 
average person would receive from all of these procedures is approximately seven times that 
received from natural sources of radiation by a Minnesota resident in one year (3 mSv).  This 
exposure involves minimal risk and is necessary to obtain the research information desired
Risks associated with Placebo
There is no risk associated with taking the placebo treatment during the study as you will be 
continuing to take the standard FDA approved therapy for your pulmonary hypertension.
BENEFITS
There is no guarantee of direct benefit for participating in this research study.
ALTERNATIVES TO PARTICIPATING IN THIS STUDY
You can choose not to participate in this research study and receive your standard clinical care for 
the treatment of your pulmonary hypertension.
STUDY COSTS/COMPENSATION
There are no anticipated additional costs for participating in this research study.  You will receive a 
$25 gift at your 6 month visit and 13 month visit as a token of our appreciation for your 
participation in this research study.  We will provide parking voucher for your study visits.
RESEARCH RELATED INJURY
In the event that this research activity results in an injury, treatment will be available, including first 
aid, emergency treatment and follow-up care as needed. Care for such injuries will be billed in the 
ordinary manner to you or your insurance company. If you think that you have suffered a research 
related injury, let the study physicians know right away.


Approved for use by UMN IRB
Effective on 12/22/2017
IRB Study Number: 1507M75642
UNIVERSITY OF MINNESOTA
HSC# 1507M75642
Version Date: 10.12.2017
Page 1 of 14
CONFIDENTIALITY
The records of this study will be kept private. In any publications or presentations, we will not 
include any information that will make it possible to identify you as a subject.  Due to the nature of 
clinical trial oversight, some funding and regulatory agencies may have the right to review the 
records of this study.  These include: the study sponsor – The American Heart Association, Food 
and Drug Administration (FDA), The Office of Human Research Protections (OHRP), and 
Departments at the University of Minnesota with appropriate regulatory oversight.  To these 
extents, confidentiality is not absolute.  Study data will be encrypted according to current University 
policy for protection of confidentiality. 
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 could identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
PROTECTED HEALTH INFORMATION (PHI)
Your PHI created or received for the purposes of this study is protected under the federal regulation 
known as HIPAA.  Refer to the attached HIPAA authorization for details concerning the use of this 
information. 
VOLUNTARY PARTICIPATION
Participation in this study is voluntary. Your decision whether or not to participate in this study will 
not affect your current or future relations with the University of Minnesota, the University of 
Minnesota Medical Center-Fairview, or other Fairview Hospitals & Clinics.  If you decide to 
participate, you are free to withdraw at any time without affecting those relationships.  
CONTACTS AND QUESTIONS
The researcher conducting this study is Dr. Thenappan Thenappan.  You may ask any questions you 
have now, or if you have questions later, you are encouraged to contact him at 612-626-1991. 
You may also call the study coordinator, Gretchen Peichel, RN, at 612-626-6237.
If you have any questions or concerns regarding the study and would like to talk to someone other 
than the researcher(s), you are encouraged to contact the Fairview Research Helpline at telephone 
number 612-672-7692 or toll free at 866-508-6961.  You may also contact this office in writing or 
in person at Fairview Research Administration, 2344 Energy Park Drive, St. Paul, MN  55108.
You will be given a copy of this form to keep for your records.
Statement of Consent


Approved for use by UMN IRB
Effective on 12/22/2017
IRB Study Number: 1507M75642
UNIVERSITY OF MINNESOTA
HSC# 1507M75642
Version Date: 10.12.2017
Page 1 of 14
I have read the above information.  I have asked questions and have received answers.  I consent to 
participate in the study.
Printed Name_______________________________________
Signature of Subject__________________________________  
Date: _________________________________________
Printed Name of Person Obtaining Consent_______________________________________
Signature of Person Obtaining Consent___________________________________________ 
Date:  ________________________________________________________________