Conditions: Single Ventricle Fontan
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 26
Healthy volunteers: no

Brief summary:
This study evaluates the effect of carvedilol in patients who have undergone a Fontan heart operation. All participants will receive carvedilol and placebo for 12 weeks. Exercise tests will be performed at the end of each 12 week period.

Detailed description:
Carvedilol is a well studied heart failure medication in adult heart failure that has been shown to improve outcomes. However, it has not been studied in patients who have had a Fontan heart operation. Study participants will receive either placebo or carvedilol for 12 weeks, at the end of the 12 weeks participants will perform an exercise test. Then study participants will receive treatment with placebo or carvedilol for 12 weeks (opposite of what participants go the first 12 weeks) and will again perform an exercise test.

Arms:
arm 1: Study participants will receive carvedilol for 12 weeks arm 2: Study participants will receive placebo (sugar pill) for 12 weeks

Interventions: intervention 1: Carvedilol intervention 2: Placebo
Intervention descriptions: intervention 1: Carvedilol will be given for 12 weeks and then an exercise test will be performed intervention 2: Placebo will be given for 12 weeks and then an exercise test will be performed

Protocol document:
Prot_SAP_000.pdf: 
 
 
1
 
 
 
 
Effect of Carvedilol on Exercise Performance in Fontan Patients 
 
 
 
 
 
2March2018 
 
 
 
 
 
 
 
 
 
 
 
Funded by the American Heart Association 
 
Award #: 16MCPRP313500009 
 
 
 
 
 
 


 
 
2
Effect of Carvedilol on Exercise Performance in Fontan Patients 
 
 
 
TABLE OF CONTENTS 
 
PROTOCOL OVERVIEW  (ABSTRACT) 
1-2 
 
A. SPECIFIC AIMS 
3-5 
1. Primary Aim 
3 
2. Secondary Aims 
3-5 
 
B.  BACKGROUND 
6-10 
1. Management and Outcomes of Single Ventricle Patients 
6-8 
2. Rationale for Trial 
8 
3. Rationale for Study Outcomes 
9-10 
4. Rationale for Study Drug 
10 
5. Rationale for Screening Laboratories 
11 
 
C.  STUDY DESIGN AND METHODS 
12-35 
1. Overview 
12 
2. Human Subject Consideration 
13-16 
3. Recruitment and Eligibility  Phases 
16-17 
4. Screening Phase 
17 
5. Treatment Phase 
17-21 
6. Potential Risks, Benefits, Adverse Events and Protections 
21-31 
7. Measurements 
31-35 
8. Statistical Analysis 
36 
 
D.  REFERENCES 
37-40 
 
 


 
 
1
 
EFFECT OF CARVEDILOL ON EXERCISE PERFORMANCE IN FONTAN PATIENTS 
 
OVERVIEW (ABSTRACT) 
Until the late 20th century patients with a diagnosis of a functional single ventricle (SV) 
circulation was uniformly fatal.  The development of staged surgical palliation including 
the initial neonatal procedure, Glenn shunt, and modified Fontan procedure, has 
dramatically improved survival.1-3  Despite advances in surgical techniques and medical 
care, these patients still suffer from lower quality of life, decreased exercise capacity, 
poorer neurodevelopmental outcomes, need for heart transplantation and other co-
morbidities.4-12  Although patients with SV circulation comprise a small portion of all 
congenital heart disease, 2-4% of congenital heart disease, they require a great deal of 
resource utilization.4,13-15 Improvements in management of this small population will 
have a large impact on patient and societal costs. 
 
Although carvedilol and other beta-blockers are well-established medications for adults 
with biventricular ventricular dysfunction, these agents are used less frequently in 
pediatric patients with heart failure, especially in patients with congenital heart disease. 
Similar to biventricular heart failure patients, circulating levels of norepinephrine are 
higher in Fontan patients with few or no signs and symptoms of heart failure compared 
to age-matched controls.16 Circulating levels of norepinephrine are associated with 
poorer outcomes in Fontan patients.16,17 Increased concentrations of circulating 
catecholamines are known to have deleterious effects on myocardial function, and 
blocking of this process reduces mortality in patients with biventricular heart failure. A 
multicenter randomized trial of carvedilol versus placebo in pediatric heart failure 
patients with multiple different etiologies including some with SV failed to show an 
improvement in the primary endpoint of improved functional state.18  However, a smaller 
non-blinded study indicated improvement in ventricular function in Fontan patients with 
carvedilol.19  Therefore, it is reasonable to hypothesize that beta blockers will improve 
functional status in Fontan patients. Carvedilol has α1 in addition to β1, β2, receptor–
blocking properties making this agent the preferred beta-blocker in patients with 


 
 
2
increased systemic vascular resistance.  Systemic vascular resistance is increased 
Fontan patients which may adversely affect function of the single ventricle. 20,21  
Therefore, carvedilol may provide more physiologic benefit than other more selective 
beta blockers.  
 
Potential participants in this study are patients with SV who have undergone Fontan 
palliation, who are now between the ages of 10 years and 35 years.  Participants will 
initially undergo a screening phase which will include an exercise test to determine if 
they can adequately perform a maximal exercise test (RER>1.0 at maximal exercise) 
and safety laboratories. Participants who are able to exercise as described and who 
have acceptable safety laboratories will be randomly assigned to receive either 
carvedilol or placebo for the first 12 week treatment period. After a 6 week washout 
period, all participants will cross over to the other treatment arm for 12 weeks. Exercise 
data will be collected at baseline and at 12, 19, and 30 weeks after randomization.  The 
primary aim of the study is to compare the effect of carvedilol therapy to that of placebo 
therapy on exercise performance as measured by peak oxygen consumption per 
kilogram.  Secondary endpoints include the following: peak heart rate during exercise, 
submaximal exercise capacity, ventilatory efficiency of carbon dioxide, and safety profile 
of carvedilol in Fontan patients.  The total sample size target of 30 participants will be 
recruited over approximately 24 months. 
 
There is a lack of controlled clinical trials that have systematically investigated whether 
carvedilol will benefit Fontan patients. The results of this study will provide preliminary 
efficacy data for carvedilol in Fontan patients and inform the design and sample size 
calculations necessary for a large multicenter trial. 


 
 
3
A.  SPECIFIC AIMS 
There is an unmet need for a better understanding of the effects of traditional heart 
failure medications in patients with Fontan circulation.  It is now standard practice in 
developed nations for patients with a functional single ventricle (SV) circulation to 
undergo a three-stage surgical palliation.  Survival to stage III palliation, the Fontan 
procedure, has greatly improved in recent decades.5  Despite complete physiologic 
palliation, Fontan subjects suffer from lower exercise capacity than their peers and have 
a poorer quality of life.6,8  The emphasis of SV care has evolved from preventing 
mortality to improving quality of life.  The utility of traditional heart failure medications 
the SV population is not completely understood. Exercise testing is a frequently used 
measure of cardiovascular health, as it allows insight into cardiac and pulmonary 
responses to exercise and is a robust tool for predicting poorer cardiovascular 
outcomes in heart failure, including patients with Fontan circulation. The specific aims of 
this research are as follows.  
 
Primary Aim 1: To compare the effect of carvedilol to that of placebo on peak exercise 
capacity. 
Rationale: Peak exercise capacity is directly related to cardiovascular health and has 
been shown to be predictive of outcomes in patients with cardiovascular disease.  
Primary and Secondary Measures: Peak volume of oxygen consumption indexed to 
patient weight (peak VO2) is the primary outcome measure. Secondary measures will 
include maximum watts performed, respiratory exchange ratio at peak exercise.  
Hypothesis: Carvedilol will increase peak exercise capacity. 
 
Secondary Aim 1: To compare the effect of carvedilol to that of placebo on 
chronotropy. 
Rationale: Beta-blockers are sometimes avoided in Fontan patients because of a 
theoretical concern of worsening chronotropic incompetence.  However, this has never 
been studied systematically. 


 
 
4
Measures: Primary outcome measure is peak heart rate during exercise. Secondary 
measures will be heart rate reserve (heart rate at peak exercise minus baseline heart 
rate) and chronotropy reserve (peak heart rate minus baseline heart rate divided by the 
difference of predicted peak heart rate and baseline heart rate). 
Hypothesis: Carvedilol will decrease peak heart rate 
 
Secondary Aim 2: To compare the effect of carvedilol to that of placebo on 
submaximal exercise capacity 
Rationale: Submaximal exercise capacity is directly related to cardiovascular health and 
has been shown to be prognostic of outcomes in cardiovascular disease. 
Measures: Primary outcome measure will be the volume of oxygen consumption at 
anaerobic threshold indexed to patient weight. Secondary measures will include watts 
and respiratory exchange ratio at anaerobic threshold. 
Hypothesis: Carvedilol will increase volume of oxygen consumption at anaerobic 
threshold.  
 
Secondary Aim 3: To compare the effect of carvedilol to that of placebo on ventilatory 
efficiency of carbon dioxide. 
Rationale: The ventilatory efficiency of carbon dioxide has prognostic value in patients 
with heart failure. 
Measures: Primary measures will be ventilatory equivalent of carbon dioxide at 
anaerobic threshold (VE/VCO2 at anaerobic threshold). Secondary measure will be 
slope of minute ventilation to volume of carbon dioxide production (VE/VCO2 slope).  
Hypothesis: Carvedilol will improve ventricular mechanics and therefore decrease 
ventilatory efficiency of carbon dioxide. 
 
Secondary Aim 4: To evaluate the safety of carvedilol in Fontan patients over an 
intermediate time period. 
Rationale: Limited data are available regarding the safety profile of carvedilol in the 
Fontan population has not been previously described. 


 
 
5
Measures: Laboratory data and the number of serious adverse events and adverse 
events reported during the two different treatment periods (carvedilol v. placebo).  
Hypothesis: Carvedilol will have a similar side effect profile compared to placebo. 
 
 
 
 
 


 
 
6
B.  BACKGROUND 
 
B.1 Management and Outcomes of Single Ventricle Patients  
B.1.1 Surgical Palliation of Single Ventricle Patients.   
A multitude of different congenital anatomical cardiac defects can result in single 
ventricle physiology.  The most common and well known is hypoplastic left heart 
syndrome, but others include double-inlet left ventricle, unbalanced atrioventricular 
canal, and tricuspid atresia.  Currently the management of these patients involves a 
three step staged surgical palliation. No anatomically corrective procedure other than 
heart transplantation exists for this population.   
 
Although the type of 1st stage palliation varies based upon anatomy, subsequent 
surgeries focus on creating surgical anastomoses enabling passive flow of systemic 
venous blood to the pulmonary circulation so that the functional SV pumps only to the 
systemic circulation. The third stage of palliation (modified Fontan procedure) typically is 
done between age 18 months to 6 years depending on institutional preference and 
patient characteristics.  The Fontan procedure, connects the inferior vena cava to the 
pulmonary arteries to create a complete total cavopulmonary anastomosis.   The Fontan 
circulation results in elevated central and peripheral venous pressures, which in turn, 
leads to an elevated systemic vascular resistance. 21-24 
 
B.1.2 Complications of Current Single Ventricle Palliation.  
Although the Fontan procedure is the goal for palliation for the patient with SV, this 
abnormal circulation results in multiple unique situations that may deleteriously affect 
the patient. Fontan patients often develop ventricular dysfunction leading to heart failure 
symptoms and heart transplantation.  Heart transplantation is a possible therapeutic 
option, however, patients with previous single ventricle palliation are at higher risk for 
complications (death, rejection and infection) after transplantation than patients with a 
biventricular circulation.9  Even without important signs or symptoms of heart failure, 
Fontan patients’ quality of life is lower than their peers, evidenced by decreased 


 
 
7
exercise capacity, lower neurodevelopmental quotients, and lower rates of medical 
insurance coverage.6-8,25-27  
 
Exercise performance is decreased in Fontan patients when compared to patients with 
a biventricular circulation.11,13 It has been hypothesized this is related to the inability to 
increase ventricular filling during exercise, however, the exact mechanism is not 
known.10 It is possible that only having passive blood flow to the pulmonary arteries, 
with no pulmonary pumping chamber, leads to a situation where the Fontan circulation 
cannot sufficiently augment ventricular filling to the systemic ventricle during exercise. 
However, chronically increased systemic vascular resistance likely contributes to 
impaired exercise capacity. Additionally, it has been well described that Fontan patients 
suffer from chronotropic incompetence.28  The degree of chronotropic incompetence 
has been associated with mortality in this population.29 
 
Although carvedilol and other beta-blockers are well-established medications for adults 
with biventricular ventricular dysfunction, these agents are used less frequently in 
pediatric patients with heart failure, especially in patients with congenital heart disease. 
Similar to biventricular heart failure patients, circulating levels of norepinephrine are 
higher in Fontan patients with no or few signs and symptoms of heart failure compared 
to age-matched controls.16 Circulating levels of norepinephrine are associated with 
poorer outcomes in Fontan patients.16,17 Increased concentrations of circulating 
catecholamines are known to have deleterious effects on myocardial function, and 
blocking of this process reduces mortality in patients with biventricular heart failure. A 
multicenter randomized trial of carvedilol versus placebo in pediatric heart failure 
patients with multiple different etiologies including some with SV failed to show an 
improvement in the primary endpoint of improved functional state.18  However, a smaller 
non-blinded study indicated improvement in ventricular function in Fontan patients with 
carvedilol.19  Therefore, it reasonable to hypothesize that beta blockers will improve 
functional status in Fontan patients.  Carvedilol has α1 in addition to β1, β2, receptor–
blocking properties making this agent the preferred beta-blocker in patients with 
increased systemic vascular resistance.  Systemic vascular resistance is increased in 


 
 
8
Fontan patients which may adversely affect function of the single ventricle. 20,21  
Therefore, carvedilol may provide more physiologic benefit than other more selective 
beta blockers.  
 
B.1.3  Animal Models of Single Ventricle Heart Disease  
There are no animal models of SV and therefore preliminary data for this population 
using such models is not available.  Therefore, this highly vulnerable population is not 
significantly studied. 
 
B.1.4  Carvedilol treatment of patients with SV 
Carvedilol has proven safe and effective for the treatment of congestive heart failure 
and hypertension in adults.  A study by Albers et al. showed that carvedilol 
pharmacokinetics in adolescents was similar to that of adults.30.  Ishibashi and 
colleagues described using carvedilol in patients with SV with an age range of 1 month 
to 35 years (mean 10 years).  The average maximum dose of carvedilol was 0.42mg/kg 
± 0.29.  In this study, only one patient out of 51 discontinued carvedilol because of an 
adverse side effect.19 
 
B.2  Rationale for this Trial 
Despite the major advances that have been made in the medical and surgical 
management of SV, morbidity and early mortality persist.  Moreover, medical therapies 
often used in patients with Fontan without good data regarding safety and efficacy in 
this population.  Existing medical therapies are used because they have been shown to 
be effective in other patient populations. Furthermore, we are only beginning to 
appreciate the "new" natural history of Fontan patients who are now surviving into 
young adulthood.  There is emerging knowledge that these patients show a chronic 
inability to provide adequate preload the systemic ventricle, significantly lowered 
maximal heart rates and chronically elevated systemic vascular resistance, combined 
with elevated levels of catecholamines and activation of the renin-angiotensin system.  
Therefore, this study aims to systematically study the effects of a commonly available 
and often used medication in patients with Fontan physiology.   


 
 
9
 
B.3  Rationale for Selection of Outcome Measures    
B.3.1  Peak Oxygen Consumption per Kilogram  
Exercise testing with metabolic cart analysis has been proven one of the best 
prognostic tests in heart failure and pulmonary hypertension, often superior to other 
traditional cardiovascular tests.31,32 Reports have confirmed that prognostic capability of 
exercise testing with metabolic cart applies to Fontan population.29,33  Specifically, peak 
oxygen uptake per kilogram has been shown to be associated with significant outcomes 
in Fontan patients.33  Also, normative equations for predicted peak oxygen uptake have 
been developed and validated.34 
 
B.3.2  Effect of Carvedilol on Chronotropy 
Carvedilol is a beta blocker and therefore reduces the augmentation of heart rate as a 
result to released circulating catecholamines concentrations. Peak heart rate during 
exercise is associated with outcomes in patients with CHD.35  Therefore, congenital 
heart disease cardiologists are concerned about starting beta blockers in the SV 
population.  However, the chronotropic incompetence seen in SVs is similar to the 
chronotropic incompetence seen in adults with heart failure.  In that population, the 
discontinuing carvedilol was not associated with improvements in chronotropic 
competence.36  Therefore, it is possible that carvedilol will not have a negative impact 
on chronotropic incompetence which would eliminate a significant barrier to its use in 
the SV population.  
 
B.3.3  Submaximal Exercise 
Submaximal exercise is measured by the oxygen uptake at anaerobic threshold.  
Anaerobic threshold is the point where carbon dioxide production increases at a rate 
faster than oxygen consumption indicating the point in which a patient begins to 
produce measurable amounts of lactic acid.  This time point in exercise testing may 
reflect more usual activities of daily living and has been associated with outcomes in the 
Fontan population.35 
 


 
 
10
B.3.4 Ventilatory Efficiency of Carbon Dioxide 
The ventilatory efficiency of carbon dioxide has been shown to have a prognostic value 
in adult heart failure, independent of other exercise testing variables. 37 The ventilatory 
efficiency of carbon dioxide is measured by the ratio of minute ventilation of to carbon 
dioxide production at anaerobic threshold.  Ventilatory efficiency of carbon dioxide is 
also measured by calculating the slope of the regression line created by plotting minute 
ventilation to carbon dioxide production throughout the exercise test. In a recent study, 
the ventilatory efficiency of carbon dioxide was associated with unscheduled 
hospitalization and mortality in Fontan patients.38 
 
B.3.5 Safety Profile of carvedilol 
Carvedilol is a commonly used medication in heart failure.  Due to efficacy studies in 
different populations, cardiologists often use carvedilol in the Fontan population.  
However, there is a lack of data regarding the safety profile of carvedilol specific to the 
Fontan population.  Adverse events will be recorded.  While hepatic and renal 
dysfunction are rare adverse events (<1%) of carvedilol, they are of severe 
consequence in the Fontan population.  Possible hepatic or renal dysfunction 
associated with carvedilol in Fontan patients has not been previously described. 
Therefore a comprehensive metabolic panel will be monitored throughout the study.  
B-type natriuretic peptide (BNP) is a seromarker of heart failure that is associated with 
important outcomes in the Fontan population.  Therefore, BNP will be measured during 
the study to assess the effect carvedilol has on serum BNP in Fontan patients.  
 
B.4 Rationale for Study Drug 
Carvedilol is a well studied non-selective beta blocker with alpha-1 blocker activity as 
well.  In adult heart failure trials it has been proven superior to other form of beta-
blockers in preventing mortality and hospitalizations.  Given it’s superiority in treating 
heart failure, carvedilol was chosen as the beta blocker for this study.   
 
 
B.5 Rationale for Screening Laboratories 


 
 
11
B.5.1 B-type natriuretic peptide (BNP)  
BNP is a seromarker made in response to ventricular or atrial myocardial stretch.  It is a 
well-studied seromarker shown to be associated with heart failure in multiple different 
populations. Decreases in BNP have been associated with improved outcomes in the 
SV population.40 A BNP >300pg/mL has been associated with a significant increase in 
chances of needing heart transplant, heart failure admission or death.44 BNP will be 
used in the screening phase to determine eligibility for randomization as outlined below. 
 
B.5.2 Complete Blood Count (CBC)  
CBC will be obtained to measure hematocrit and hemoglobin.  Significant anemia 
(hemoglobin <7gm/dL) or polycythemia (hemoglobin >18gm/dL) affects oxygen 
consumption during the exercise test. Therefore significantly abnormal hemoglobin 
(>18gm/dL or <7gm/dL) will introduce significant bias in the results.  Therefore,, anemia 
(hemoglobin <7gm/dL) and polycythemia (hemoglobin >18gm/dL) is an exclusion 
criteria as later outlined reduce confounding factors in comparisons of oxygen 
consumptions.  
 
B.5.3 Comprehensive Metabolic Panel (CMP) 
CMP will give the study investigators valuable information.  Serum albumin will be used 
to assess if patients meet exclusion criteria #17 (serum albumin <2.0g/dL).  AST/ALT 
will be used to assess for the presence of hepatic dysfunction as described in exclusion 
criteria #8.  Serum creatinine will be used to assess for renal dysfunction (creatinine 
>2.0mg/dL) as later outlined, and is an exclusion criteria (#7). 
 
B.5.4 Pregnancy Test   
Carvedilol is classified as pregnancy class C.  Rat models have shown increased 
chance of skeletal developmental delay.  However, this occurred only when rats were 
given 50 times the current recommended dose.  There are currently no adequate 
studies assessing safety during pregnancy and therefore pregnant patients will be 
excluded. 
C.  STUDY DESIGN AND METHODS 


 
 
12
C.1  Overview 
A randomized crossover trial of carvedilol vs. placebo in individuals with single ventricle  
physiology who have undergone a Fontan procedure (Figure. 1). 
Fontan Patient
Age = 10-35 yrs
Eligibility screening & consent
Screening exercise test & labs
RER > 1.0?
Acceptable Labs ?
Randomized
Treatment Period 1
Week 0-3: Up titration of study drug
Week 4-12: Maintenance of Study Drug 
Study Drug = carvedilol or placebo
Not randomized
Week 12 Exercise Testing
Week 13-18 
Week 13 Study drug dose decreased to off
Week 14-18 Washout Period (no study drug)
Treatment Period 2
Week 19-22 Up titration of study drug
Week 23-30 Maintenance of study drug
Study drug = drug not used in treatment period 1
Week 30 Exercise testing
Week 31- study drug dose reduced to off
No
Yes
 
 
 
C.2  Human Subjects Considerations 
This section includes information on the human subjects aspects of the research design 
and methods.  
 
 
 
 
 
C.2.1  Human Subjects Involvement and Characteristics 


 
 
13
Children and young adults will be enrolled for this trial from among patients followed by 
cardiologists at UT Southwestern Medical Center or local pediatric cardiologists in 
Dallas who have a Fontan circulation.  
 
C.2.1.a  Inclusion Criteria Screening Phase 
To be eligible for this trial the subjects must meet all of the following inclusion 
criteria at the time of enrollment: 
1) Informed consent of parent(s) or legal guardian; informed consent or 
assent of subject as applicable. 
2) Male or female children between the ages of 10 and 35 years with 
congenital heart disease that has been palliated with a Fontan circulation. 
 
C.2.1.b  Inclusion Criteria Treatment  Phase 
To proceed to randomization and treatment phase of the trial the subjects must 
meet the following criteria after the screening phase: 
1) Ability of perform a maximal exercise test as defined by a respiratory 
exchange ratio (RER) greater than 1.0 at the time of maximal exercise 
 
C.2.1.c  Exclusion Criteria Screening Phase 
To be eligible for this trial, the subjects must meet none of the following exclusion 
criteria at the time of enrollment: 
1) The use of beta blockers within 2 months of randomization 
2) Patients actively listed for transplantation at time of entry into the study 
or anticipated to undergo heart transplantation, interventional 
catheterization, or corrective cardiac surgery during the 7 months 
following entry into the study 
3) Sustained or symptomatic ventricular dysrhythmias uncontrolled by 
drug therapy or the use of an implantable defibrillator, and/or significant 
cardiac conduction defects, e.g., 2nd degree or 3rd degree AV block, or 
sick sinus syndrome, unless a functioning pacemaker is in place 


 
 
14
4) Uncorrected obstructive or severe regurgitant valve disease, nondilated 
cardiomyopathy, or significant systemic ventricular outflow obstruction 
5) Known renovascular hypertension or evidence of pulmonary 
hypertension (pulmonary vascular resistance > 6 Wood units) 
unresponsive to vasodilator agents such as oxygen, nitroprusside, or 
nitric oxide  
6) History or current clinical evidence of moderate-to-severe fixed 
obstructive pulmonary disease or severe reactive airway diseases (e.g., 
asthma) requiring hospitalization within the past 2 years or patient 
currently using long-term inhaled bronchodilators 
7) Renal, hepatic, gastrointestinal, or biliary disorder that could impair 
absorption, metabolism or excretion of orally administered medication 
8) Concurrent terminal illness or other severe disease (e.g., active 
neoplasm) or other significant laboratory value(s) which, in the opinion of 
the investigator, could preclude participation or survival  
9) Endocrine disorders such as primary aldosteronism, 
pheochromocytoma, hyper- or hypothyroidism, insulin-dependent 
diabetes mellitus 
10) Unwillingness or inability to cooperate, or for the parents or guardians to 
give consent, or for the child to give assent, or any condition of 
sufficient severity to impair cooperation in the study 
11) Pregnancy or possible pregnancy at time of randomization, or female of 
child bearing potential who are lactating, or sexually active and not 
taking adequate contraceptive precautions (e.g., intrauterine device or 
oral contraceptives for 3 months prior to entry into the study) 
12) Use of an investigational drug within 30 days of randomization, or within 
5 half-lives of the investigational drug (the longer period will apply) 
13) History of drug sensitivity or allergic reaction to -blockers or ß-blockers  
14) Use of any of the following medications within two weeks of 
randomization: MAO inhibitors, Calcium channel blockers, alpha 


 
 
15
blockers, beta blockers, disopyramide, flecainide, encainide, moricizine, 
propafenone, sotalol, or beta adrenergic agonists 
15) Hospital admission for protein losing enteropathy or plastic bronchitis 
within 3 months of randomization 
16) Active and/or chronic protein losing enteropathy or plastic bronchitis (on 
inhaled medication to control the plastic bronchitis). 
 
C.2.1.d  Exclusion Criteria Treatment Phase 
To proceed to randomization and treatment phase of the trial the subjects must 
meet none of the following criteria after the screening phase: 
1) Hypoalbuminemia defined as serum albumin <2.0g/dL 
2) Renal dysfunction defined as serum creatinine >2.0mg/dL 
3) Hepatic dysfunction defined as serum AST and/or ALT> 3 times upper limit 
of normal (approximately 120 IU/L however, will vary depending on age),  
4) Significant anemia or polycythemia defined as hemoglobin >18gm/dL or 
hemoglobin <7gm/dL 
5) Severely elevated serum BNP defined as BNP>300pg/ml 
 
 
C.2.1.e  Subject Availability   
The estimated number of patients who meet trial eligibility criteria is approximately 150.  
Fontan patients are seen on an annual basis.  Therefore, assuming a consent rate of 
20%, the required 30 subjects can be enrolled within the two year timeframe.   
 
C.3. Recruitment and Eligibility Phases 
The Principal Investigator or designee at Children’s Medical Center and the study 
coordinator will be responsible for case finding and subject recruitment. 
 
For patients who meet inclusion criteria for the eligibility phase, the patient’s cardiologist 
will be approached.  Then potential study participants (if over 18 years of age) or the 
parent(s) or legal guardian of potential participants, will be approached about 
participation. At this time, a final determination about eligibility for the screening phase 


 
 
16
of the study will be made, and eligible patients or parents will be asked to participate in 
the study.  
 
A cardiologist experienced in the treatment of patients with Fontan circulation will be 
involved in obtaining consent.  Data (demographic, eligibility criteria and informed 
consent status) will be recorded on a screening form for all patients with Fontan 
circulation, regardless of their inclusion in the study, for definition of the study 
population.  The screening data will be obtained and stored in a confidential manner, in 
compliance with HIPAA requirements and local national regulations.   
 
Each subject enrolled in the trial will be assigned a study identification (ID) number so 
that study information will be confidential.  The link between subject name and ID 
number will be stored only in an encrypted password protected database at Children’s 
Medical Center and will only be accessible to the PI, study investigators and research 
coordinators.  Data that will be obtained on study participants includes demographic 
data and family history, information about their past and current medical care, 
echocardiographic imaging data, and information on adverse drug reactions and 
adverse events.  The stress test data will be interpreted at Children’s Medical Center by 
a study investigator and will contain the patient’s name.  The consent form will state this 
clearly.  All study procedures are conducted in accordance with local and HIPAA 
requirements and regulations.  
 
C.3.1. Gender and Minority Inclusion 
Based on current rosters of patients with Fontan circulation at Children’s Medical Center 
of Dallas, it is estimated that 50% of patients will be female and 15-35% of the patients 
will be of minority race/ethnicity.  Race, gender and other patient characteristics will not 
be considered when targeting enrollment. 
 
C.4  Screening Phase 
A screening exercise test and safety laboratories will be performed. If the study 
participant meets inclusion criteria for the treatment phase (RER>1.0 at maximal 


 
 
17
exercise test) and does not meet exclusion criteria for the treatment phase (serum 
albumin <2.0g/dL, hemoglobin <7gm/dL or hemoglobin >18gm/dL, AST and/or ALT > 3 
times upper limit of normal, BNP>300pg/ml, or serum creatinine greater than 2.0mg/dL) 
s/he enter the treatment phase of the study within 14 days from screening testing. Study 
participation will be terminated for all subjects who do not enter the treatment phase of 
the study.  
 
C.5  Treatment Phase 
C.5.1  Masking of Treatment Group Assignment 
The primary endpoint and most of the secondary endpoints will be measured by the 
study investigator, who will be unaware of each subject’s treatment group assignment.  
Randomization to treatment arm (carvedilol first versus placebo first) will be determined 
by Children’s Medical Center investigational drug pharmacy. 
 
No one else including subjects, their families, and primary care providers will be 
informed of the subject’s treatment assignment.     
 
The Data Safety and Monitoring Board (DSMB) will determine their preference for 
receipt of blinded or unblinded trial results prior to the interim look.  No clinical 
investigators will review trial outcomes, by arm or in aggregate, until the end of the trial. 
 
C.5.2  Randomization 
After eligibility has been confirmed as described above in C.2.1.a-d and the trial consent 
has been signed, subjects will be randomly assigned in a 1:1 ratio to receive carvedilol 
or placebo first using randomly permuted blocks.  All eligibility criteria must be 
confirmed, and written informed consent obtained, before randomization.  
Randomization will be accomplished by Children’s Medical Center of Dallas 
Investigation Drug Pharmacy.  
 
C.5.3  Study Drugs 
C.5.3.1  Uptitration Period 


 
 
18
After the baseline clinical evaluation, all subjects will be entered into the uptitration 
period, during which they will receive carvedilol or placebo in addition to their usual 
medications.  The goal of the uptitration period is to reach the effective dose (defined 
below) that will then be continued throughout the maintenance phase.  Based upon the 
subject’s body weight, the pharmacist will determine the appropriate initial dose of 
carvedilol.  Starting doses and the up-titration are shown in Table 1.  Dose ranges are 
provided but actual doses will be rounded up or down according to the available pill 
sizes (3.125mg increments). Each drug will be administered twice a day, at about the 
same time of day.  
  
Table 1. Uptitration Schedule (all dose ranges in mg/kg/dose) 
Weight 
Classification 
  
Initial Dose 
Uptitration 1 
Uptitration 2 
20-<30kg 
Absolute Dose 
1.56 mg 
3.125 mg 
6.25 mg 
  
Dose Range  
(0.06-0.08) 
(0.10-0.16) 
(0.20-0.32) 
30kg-<40kg 
Absolute Dose 
3.125 mg 
6.25 mg 
9.375mg 
  
Dose Range  
(0..08-0.10) 
(0.16-0.2) 
(0.23-0.31) 
40kg-60kg 
Absolute Dose 
3.125 mg 
6.25 mg 
12.5 mg 
  
Dose Range  
(0.05-0.08) 
(0.10-0.16) 
(0.20-0.32) 
>40kg 
Absolute Dose 
6.25 mg 
12.5 mg 
25 mg 
 
C.5.3.2. Down-titration of Study Drug 
During the washout period, after treatment period 2 (Table 5) or if it is necessary for a 
subject to stop the study drug, the subject should optimally be weaned off the drug as 
follows. Per manufacturer’s guidelines, carvedilol will be down-titrated over one week: 
 
Day 1:  
50% of previous dose 
Day 3-5: 
25 % of regular dose 
Day 7-10: 
Stop drug 
 
In the event of severe clinical instability or inability to take the study drug (i.e., severe 
vomiting), weaning may need to occur over a shorter period of time, at the discretion of 
the study physician and care providers. Reinitiation of study drug will be considered 


 
 
19
after the PI has consulted with the study participant (or legal guardians) and attending 
cardiologist. 
 
C.5.3.3  Protocol Deviations in Treatment 
All deviations from the above schedules will be noted and described on a study report 
form.  In addition, for all non-study drugs, the dosage, treatment period, and reason for 
use will be recorded.  For modified and interrupted therapy, the length of and reason for 
the modification/interruption will be recorded.  Every attempt will be made to keep 
protocol deviations and non-protocol treatment to a minimum. 
 
C.5.3.4  Dispensing of Study Drug and Compliance Monitoring 
All study drugs (placebo and carvedilol) will be dispensed through the investigational 
drug pharmacy at Children’s Medical Center of Dallas. 
 
Pill Dispensing:  The family will receive a medication bottle.  Study drug in the form of 
pills will be dispensed by the pharmacy at visits 1, 2, 3, 4, 7, 8, 9, and 10.  
 
Unused study drug will be returned to the pharmacy to monitor compliance.  Study drug 
compliance will be assessed by comparing the expected to the measured number of 
doses in pill form of study drug returned.   
 
Once measurement the pill count by the pharmacy is complete, the pharmacy will 
destroy the returned study medication according to standard operating procedure. 
 
 
 
C.5.3.5  Subject Monitoring 
Subjects will be monitored for adverse events at each study visit.  If, during the study, 
the study investigator determines that the subject has developed an adverse reaction, 
further monitoring will be performed as clinically indicated. 
 


 
 
20
C.5.4  Indications for Permanent Discontinuation of Study Drug 
● Intolerance to study drug 
● Continued administration of study drug felt to be not indicated by the attending 
cardiologist or study investigator  
● Pregnancy or planned pregnancy 
● Other adverse events that require discontinuation of study drug in the judgment 
of the study investigator 
The reason and the circumstances for permanent discontinuation of study drug will be 
documented.  If study drug is permanently discontinued, the subject will continue to be 
followed and undergo expected tests and measurements through the planned 
completion date (31 weeks after randomization), unless an indication for withdrawal 
from trial is met. 
 
C.5.5  Indications for Withdrawal from the Trial 
● Subject/guardian refusal to continue in the trial, including refusal of the 
subject to sign the adult informed consent form upon reaching the age of 
consent 
● Subject failure to return for scheduled appointments 
The reason for withdrawal and the circumstances of withdrawal will be documented for 
all subjects withdrawn from the study.  
 
C.5.6  Trial Completion 
Subjects will be considered to have completed the study if they have completed the 
assessment scheduled for 31  2 weeks post-randomization.  Down-titration of the 
study drug will be performed as described in C.5.3.2.  
 
 
C.5.7  Other Treatments/Interventions 
Subjects will receive non-study medical care as recommended by their cardiologist and 
other care providers.  The need for additional procedures and all prescription 
medications will be recorded on study forms 
 


 
 
21
C.6. Potential Risks, Benefits, Adverse Events and Protections 
C.6.1. Potential Risks 
The possible risks or discomforts to the subjects include those listed below. 
1. Treatment with carvedilol may rarely induce adverse drug reactions including 
symptomatic bradycardia, dizziness, postural hypotension, fatigue, lethargy, 
mental depression, headache, nausea, diarrhea, sleep disturbances, and 
asthma exacerbation. 
3. Self-limited exercise tests pose very small risks of syncope, arrhythmias, 
hypotension, emesis, dizziness, leg or other muscle cramping. 
4. Risks associated with drawing blood from a vein include momentary 
discomfort and/or bruising.  Infection, excess bleeding, clotting, and fainting 
are also possible, although unlikely.  Less than 5 ml of blood is needed for the 
3 safety laboratories (CBC, CMP, and BMP).  
5. Study investigators from UT Southwestern and Children’s Health will have 
access to the medical record for 5 years after each subject completes the 
study to review the results of follow-up clinical course, surgical intervention, 
and other relevant studies. 
 
C 6.2  Protection Against Risks 
Protection of study subjects is implicit in all studies at UT Southwestern and Children’s 
Medical Center of Dallas, and is achieved through sound study design, patient 
education, strict adherence to informed consent principles, careful monitoring of 
subjects, and compliance with International Conference on Harmonisation (ICH) Good 
Clinical Practices, including HIPAA regulations or local national laws and regulations. 
 
C.6.2.a  Informed Consent   
Consent will be obtained from the parent(s) or legal guardian and consent or assent, as 
applicable, will be obtained from the subject.  This will be facilitated by IRB-approved 
study brochures, and information about the trial that will be placed on the clinical trials 
Web site, www.clinicaltrials.gov.  The site study investigators, study coordinators, or 
assigned designees will obtain consents, documented by the subject, parent(s) or legal 


 
 
22
guardian’s witnessed signature on an informed consent document that is compliant with 
HIPAA regulations and local and national laws and regulations.  The potential study 
participant will be informed of possible adverse effects from carvedilol some of which 
are transient, including: fatigue (20%), bradycardia (9%), hypotension (9%), syncope 
(3%), dizziness (6%), chest pain (2%), nausea (9%), vomiting (6%), cough (8%), 
insomnia (3%), headache (8%). If potential subjects or parents decline to participate, 
their or their child’s medical care will not be adversely affected in any way.  If they agree 
to participate, they are free to withdraw from the study at any time.  Additionally, 
subjects who reach the age of consent during their participation in the trial will be re-
consented with the adult informed consent form.   
 
C.6.2.b  Protection Against Risks 
To minimize the potential risks listed in Section C.6.1 the following steps will be taken: 
1. The starting doses of carvedilol will be low and will be up-titrated carefully (see 
Table 1).  
2. Subjects with known renal dysfunction will be excluded from the study. 
3. Blood draws, to the extent possible, will be performed after the application of a 
topical anesthetic cream.   
4. Serum creatinine, BNP, hemoglobin, hematocrit, AST and ALT will be measured 
as during the screening phase. Serum creatinine, BNP, AST and ALT will be 
measured during the treatment phase (Table 5).   
5. Pregnancy or a planned pregnancy during the trial are exclusion criteria. A urine 
pregnancy test will be obtained during the screening phase.  A statement 
regarding the potential risk of one of the study drugs will be given to female 
subjects of child-bearing potential and to the parents of female subjects less than 
18 years of age.  They will be asked questions about the subject’s sexual activity.  
In addition, this risk is listed in the consent and the assent.  Written 
documentation of birth control measures will be required for female subjects who 
are sexually active. 
6. The study sponsor will pay for all testing that is not part of routine care.  
 


 
 
23
C.6.3  Potential Benefits of the Proposed Research 
The possible benefits of participation in the proposed study to the subject are:  
1. The subject’s family, primary care provider, and cardiologist will receive extensive 
information regarding the subject’s cardiac status.  
 
C.6.4  Risk/Benefit Ratio 
The risk/benefit ratio of the study is favorable.  The risk of adverse drug reactions is low, 
and most are relatively minor in nature and reversible with a decrease in the dose of 
study drug or cessation of therapy. There is a small risk of privacy being compromised 
in this study.  Subject identities will be coded to insure confidentiality and all data will be 
stored and communicated according to the code to protect against loss of privacy. 
There will be some unavoidable inconvenience to subjects and families because of 
study visits and blood draws.  However, subjects and families will be compensated 
within the limits of the study budget and local IRB guidelines for travel and related 
expenses for study visits.  All study costs not related to standard clinical care will be 
paid for. Given the anticipated benefits to subjects and others with the Fontan 
circulation, the risks are reasonable. 
 
C.6.5  Importance of Knowledge to be Gained 
Current data are very limited to support or refute the utility of carvedilol in this 
population. The variable practices in the use of carvedilol in management of SV patients 
underscore the need for further research. Data collected in the proposed study will 
provide important information regarding safety profile, as well as efficacy data crucial to 
the development of multicenter trials of carvedilol in Fontan patients. 
 
C.6.6  Data and Safety Monitoring Plan 
Throughout the performance of this study and during the performance of all procedures, 
subjects will be carefully monitored in accordance with current medical practices. 
Treatment with carvedilol as proposed in this study has had few if any reported side 
effects.   Based upon the extensive experience with all aspects of the study protocol 
procedures, it is anticipated that that the risk of adverse events associated with the 


 
 
24
study will be acceptably low and therefore will be monitored by the PI, the DSMB (see 
below), and the IRB. Maximum efforts will be undertaken to ensure the safety of all 
study participants. All personnel involved in performance of the study and its procedures 
will be fully trained and extensively experienced. All serious adverse events will be 
required to be reported to the IRB within 24 hours of it being brought to the attention of 
the attending physician of the subject as well as the principal investigator of the study. 
The DSMB will oversee progress and safety of the project and will consist of a 
congenital heart disease specialist, pediatric pharmacist and statistician. The DSMB will 
meet every 6 months to review the study. Non severe adverse events will be reported 
according to IRB protocol. 
 
A major component of safety monitoring is ascertainment and reporting of adverse 
events, including adverse drug reactions.  The approach to these activities for this trial 
is summarized in the sections that follow. 
 
C.6.6.a  Definition of Adverse Event and Adverse Drug Reaction 
International Conference on Harmonisation Good Clinical Practice guidelines define an 
adverse event as any untoward medical occurrence experienced by a subject 
administered a pharmaceutical product, regardless of its causal relationship to the study 
treatment.  An event can be any unfavorable and unintended sign, symptom, laboratory 
abnormality, or disease temporally associated with the use of the product.  An adverse 
drug reaction is a response to a drug that is noxious and unintended, and that occurs at 
doses normally used in humans for prophylaxis, diagnosis, or therapy of disease or for 
modification of physiological function.   
 
C.6.6.b  Classification of Adverse Events  
Monitoring adverse events requires that they be classified as to seriousness, 
expectedness, and potential relationship to the study drugs, all of which drive the 
reporting process. 
 
Seriousness 


 
 
25
A serious adverse event is one that: 
(a) Results in death, 
(b) Is life-threatening (the subject was, in the view of the Principal Investigator, in 
immediate danger of death from the event as it occurred), 
(c) Requires inpatient hospitalization or prolongation of existing hospitalization,  
(d) Results in persistent or significant disability/incapacity, or 
(e) Is a congenital anomaly/birth defect in the offspring of a participant. 
 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 
(http://ctep.cancer.gov) provides a grading system that is used to categorize the severity 
of adverse events, as follows: 
(a) Grade 1 Mild:  transient, requires no special treatment or intervention, does not 
interfere with daily activities 
(b) Grade 2 Moderate:  alleviated with simple treatments, may limit daily activities 
(c) Grade 3 Severe:  requires therapeutic intervention and interrupts daily activities 
(d) Grade 4 Life-threatening or disabling 
(e) Grade 5 Death. 
A serious adverse event, as defined above, encompasses CTCAE grades 4 and 5, and 
any Grade 3 event that requires or prolongs hospitalization, or that is disabling.   
 
Expectedness  
The purpose of reporting is to provide new, important information on serious reactions 
or events previously unobserved or undocumented.  Therefore, all adverse events will 
be evaluated as to whether their occurrence was unexpected.  
1.  Unexpected:  An unexpected adverse event or adverse drug reaction is one for 
which the nature or severity is not consistent with information in the protocol, consent 
form, or product brochure.   
2.  Expected:  An event is considered expected if it is known to be associated with the 
study drugs.  For this protocol, expected events include the following: 
a. 
Bradycardia 
b. 
Dizziness 


 
 
26
c. 
Syncope 
d. 
Hypotension 
e. 
Palpitations 
f. 
Fatigue 
g. 
Lethargy 
h. 
Mood changes 
i. 
Behavior changes 
j. 
Sleep disturbances 
k. 
Nightmares 
l. 
Headache 
m. 
Nasal congestion 
n. 
Gastrointestinal pain 
o. 
Dysgeusia 
p. 
Nausea 
q. 
Emesis 
r. 
Diarrhea 
s. 
Constipation 
t. 
Myalgias 
u. 
Back pain 
v. 
Peripheral edema 
w. 
Wheezing 
x. 
Shortness of breath 
y. 
Cough 
z. 
Chest pain 
aa. 
Renal dysfunction 
bb. 
Anemia 
cc. 
Hepatic dysfunction 
 
Causality 


 
 
27
Causality assessment is required in clinical investigations to help determine which 
events require expedited reporting.  The following criteria will be used to determine 
causality: 
1.  Not Related:  The event is clearly related to other factors, such as the subject’s 
clinical state, or non-study drugs or interventions. 
2.  Possibly Related:  The event follows a compatible temporal sequence from the time 
of administration of the study drug, but could have been produced by other factors such 
as the subject’s clinical state or non-study drugs or interventions. 
3.  Probably Related:  The event follows a reasonable temporal sequence from the time 
of drug administration, and cannot be reasonably explained by other factors such as the 
subject’s clinical state, or non-study drugs or interventions. 
 
C.6.6.c Identification of and Data Collection Procedures for Adverse Events 
In this trial, a primary safety concern as well as one of the secondary end points is to 
capture and compare adverse drug reactions between carvedilol versus placebo.  In 
addition, following standard clinical trial procedures, information on other adverse 
events will be collected.   
 
Adverse drug reactions will be assessed at baseline, at the end of up-titration, and at 
each study visit through a standardized questionnaire that will be administered by the 
study coordinators or investigators. The assessment at baseline will be obtained while 
the subject is not taking any study drug and is essential to accurate assessment of drug 
effects.  Adverse events that are not considered adverse drug reactions will be identified 
when they are reported to the clinical center or during scheduled study visits by study 
coordinators and investigators.  Subjects and families will be encouraged to report any 
serious event to study personnel as soon as the event occurs, rather than waiting for 
scheduled visits.   
 
C.6.6.d  Reporting Procedures (Table 2) 
1.  Fatal or life-threatening adverse events are to be reported to the IRB within three 
working days after knowledge of the event.  Those that are unexpected and considered 


 
 
28
possibly or probably related to the study drug will be reported, by the PI to the DSMB 
Chair but no later than 7 calendar days after first knowledge of the event, followed by a 
complete report within 15 calendar days.  All other fatal or life threatening events will be 
reported to the DSMB within 15 days,  
 
2.  All other serious (i.e., non-fatal or not life-threatening) adverse events that are 
unexpected and considered possibly or probably related to the study drug will be 
reported to the IRB within 7 days of learning of the event.  The PI will report the event to 
the DSMB within 15 calendar days after first knowledge of the event.   
 
3.  All other adverse events not meeting the criteria for expedited reporting will be 
reported quarterly to the DSMB.   
 
4.  The following events do NOT need to be reported:   
● Planned hospitalizations for non-cardiovascular surgical, diagnostic, or other 
procedures. 
● Planned cardiac catheterization. 
● Social admissions in the setting of foster care or other similar circumstances. 
● Otitis media 
● Streptococcal pharyngitis 
● Allergic rhinitis 
● Uncomplicated upper respiratory infections 
● Short-term (<36 hours) fever with no other symptoms after immunizations 
● Uncomplicated gastroenteritis  
● Uncomplicated urinary tract infections 
● Hospitalizations or emergency room care for trauma, including broken bones, 
evaluation after motor vehicle accident, or similar incident. 
The site investigator or designee will report all serious adverse events to the IRB 
according to IRB policies. 
 
 


 
 
29
Table 2. Reporting of Adverse Events 
Seriousness 
Relatedness 
Expectedness 
Reporting Timeframe 
Fatal or life threatening 
 
Related or 
Unrelated 
 
Expected or 
Unexpected 
 
Within 3 days of 
learning of the event 
 
Serious, but not fatal or 
life threatening 
 
Related 
 
Unexpected 
 
Within 7 days of 
learning of the event 
 
All other 
 
At least quarterly 
 
C.6.6.e  Reporting Adverse Events to the Institutional Review Board  
After each DSMB meeting, a Summary Report of Adverse Events will be prepared and 
submitted at the continuing review to the IRB.  The Summary Report will contain the 
following information: 
● A statement that a DSMB review of outcome data, adverse events, and 
information relating to study performance took place on a given date 
● A statement as to whether or not the frequency of adverse events exceeded what 
was expected and indicated in the informed consent 
● A statement that a review of recent literature relevant to the research took place 
● The DSMB’s recommendation with respect to progress or need for modification of 
the protocol or informed consent.  If the DSMB recommends changes to the 
protocols or informed consent, the rationale for such changes and any relevant 
data will be provided 
● A statement that if safety concerns are identified, the NHLBI Program Official will 
communicate these promptly to the investigators.   
 
C.6.6.f  Post-Study Procedures for Adverse Events 
All adverse events unresolved at the time of the subject's termination from the study will 
be followed by the investigators until the events are resolved, the subject is lost to 
follow-up, or the adverse event is otherwise explained or has stabilized.  At the last 
scheduled contact, the investigator will instruct each subject or parent/guardian to report 
any subsequent event(s) occurring in the next 30 days that the subject, parent, or the 
subject's personal physician believes might reasonably be related to the study drugs.  


 
 
30
Any death or other clinically serious adverse event that may be related to the study 
drugs and that occurs at any time after a subject has discontinued study drug or 
terminated study participation will be reported.    
 
C.7  Measurements  
C.7.1. Study Data and Measurements are outlined in Table 4 and 5 
 
Table 4.  Screening Measures 
Screening Phase 
Visit 0 (week -2-0) 
Exercise Test 
x 
Pregnancy Test 
  x* 
BNP, CBC, CMP 
x 
*to be performed on females of child bearing age only (12 years of age or older) 
 
 
 


 
 
31
Table 5. Treatment Phase Measures 
  
Treatment Period 1 (week 0-12) 
  
Visit 1 
Visit 2 
Visit 3 
Visit 4  
Visit 5** 
Visit 6 
  
(week 0) 
(week 1) 
(week 2) 
(week 3) 
(week 8) 
week 12 
Duration (hrs) 
1-1.5 
<1 
<1 
<1 
<1 
2 
Vital signs 
x 
x 
x 
x 
x 
NYHA HF Classifications 
x 
x 
x 
x 
x 
Adverse Drug Effect 
x 
x 
x 
x 
x 
x 
Compliance Check 
x 
x 
x 
x 
x 
Safety Labs (CMP, BNP, 
CBC) 
X 
x 
Exercise Test 
x* 
x 
Study Drug Medication 
X_initiate 
X-
uptitration 
1 
X-
uptitration 
2 
X-no 
change 
X-after visit 
stop study 
medication*** 
  
Washout Period (Week 13-18) 
  
Treatment Period 2 (week 19-30) 
  
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11** 
Visit 12 
  
(week 19) 
(week 20) 
(week 21) 
(week 22) 
(week 26) 
(week 30) 
Duration (hrs) 
2 
<1 
<1 
<1 
<1 
2 
Vital Signs 
x 
x 
x 
x 
x 
NYHA HF Classifications 
x 
x 
x 
x 
x 
Adverse Drug Effect 
x 
x 
x 
x 
x 
x 
Compliance Check 
x 
x 
x 
x 
x 
x 
Safety Labs (CMP,BNP, 
CBC) 
X 
x 
Exercise Test 
x 
x 
Study Drug Medication 
X-initiate 
X-
uptitration 
1 
X-
uptitration 
2 
X-no 
change 
after visit stop 
study 
medication*** 
*-exercise test from screening phase may be used if visit 1 exercise test if done within 14 days of visit 1,  
**-may be phone visit  
***dose of study medication decreased during weeks 6 and 31 and then stopped 
 
C.7.2. Windows for measurements 
To ensure adequate time for patients obtaining maximum tolerated dose of carvedilol 
prior to visit 6 and visit 12 exercise testing, visits 1,2,3,4,7,8,9,10 and will occur as 
outlined ± 7 days.  Visit 5 and 11 will occur as outlined ± 14 days.  Visit 6 and visit 12 
will occur as outlined ± 14 days. 
 
 


 
 
32
C.7.3. Exercise Testing 
All Exercise Tests for study purposes will be performed at the Children’s Medical Center 
of Dallas.  Studies will be performed by experienced pediatric EKG technicians and 
exercise physiologists.  An attending cardiolgist will be immediately available per 
institutional protocol for any adverse event experienced during the exercise test.  The 
exercise test will provide peak oxygen consumption, peak heart rate, ventilatory 
efficiency of carbon dioxide as well as submaximal exercise test performance.  As 
previously described these data are associated with outcomes in the SV population and 
therefore were chosen as the primary and secondary endpoints.  Exercise tests will be 
performed on Visit 1,  6, 7, and 12.  
 
C.7.4. Vital Signs  
Vital signs will include heart rate, blood pressure and pulse oximetry. Vital signs will be 
obtained by a pediatric research coordinator or appropriate designee. As previously 
described, bradycardia and hypotension are possible adverse events of treatment with 
carvedilol.  
Bradycardia will be defined as: 
1. Heart rate that is less than two standard deviations below age normal that 
is associated with at least one of the following: 
1. New symptoms of syncope, pre-syncope, lightheadedness, dizziness or 
nausea 
2. Hypotension 
3. Heart block (2nd or 3rd degree) 
4. New symptoms of dyspnea, fatigue or palpitations 
5. Development of any new symptom that is deemed to be due to 
bradycardia by a study investigator 
 
Hypotension will be defined as:  
1. For patients < 18 years of age, systolic and/or diastolic blood pressure less     
than 2 standard deviations from the age/sex/height normal values43; for 
patients 18 years of age or older a systolic blood pressure of less than 


 
 
33
85mmHg and/or diastolic blood pressure of less than 55 mmHg; and is 
associated with at least one of the following: 
1. Syncope, pre-syncope, dizziness, lightheadness or nausea 
2. Newly developed bradycardia 
3. Heart block 
4. New symptoms of dyspnea, fatigue, or palpitations 
5. Development of any new symptom that is deemed to be due to 
hypotension by a study investigator 
 
Response to Bradycardia or Hypotension: 
1. Heart rate and/or blood pressure will be confirmed by two repeat 
measures after initial measurement with at least 5 minutes between 
measurements, the average of all three measurements will be 
recorded 
2. The study investigator will reduce the dose of study drug back to 
previously tolerated dosing 
3. If hypotension or bradycardia develop after initiation prior to uptitration, 
study drug will be stopped  
 
C.7.5. NYHA Classification 
New York Heart Association classification of heart failure symptoms is a frequently 
used method of classifying the degree of heart failure symptoms a patient is 
experiencing.  The NYHA classification is shown below in Table 6.  The classification 
will be assessed on visits 1, 2, 3, 4, 6, 7, 8, 9, 10, 12.  It will help objectively measure 
the degree of heart failure symptoms and the response of heart failure symptoms to 
carvedilol versus placebo in the study population.  NYHA classification will be 
assessed by the principal investigator, study investigator, research coordinator or 
appropriate designee. 
   
 
 


 
 
34
Table 6. NYHA Heart Failure Symptom Classification 
 
 
C. 7.6. Adverse Drug Reaction Screening  
At all study visit, the principal investigator, study investigator, research coordinator or 
other appropriate designee will assess the presence of possible side effects from 
carvedilol. The study participant will be screened for the presence of the following 
symptoms: dizziness, syncope, palpitations, fatigue, lethargy, mood changes, behavior 
changes, sleep disturbances, nightmares, headache, gastrointestinal pain, nausea, 
emesis, constipation, peripheral edema, wheezing, shortness of breath, myalgias, back 
pain, cough, chest pain. CMP and BNP will be reviewed at visits 6 and 12 for presence 
of hepatic or renal dysfunction as previously described. If the patient is experiencing any 
of the listed side effects and it is felt by the study investigator and/or PI to be from the 
study drug, then the dose of study drug will be reduced to previously tolerated dose 
 
C.7.7 Laboratories 
CBC, CMP and BNP will be performed as part of the screening phase (Visit 1) as 
previously outlined. CMP, BNP will be performed at visits 6, 7, and 12.  All laboratories 
will be drawn at the Children’s Medical Center by a medical professional experienced in 
phlebotomy.  As previously mentioned, topical anesthestic will be used when deemed 
appropriate.  After proper labeling, blood will be sent to the Children’s Medical Center 
laboratory for immediate analysis. Urine pregnancy tests will be performed only on 
female participants 12 years of age and will be performed at Children’s Medical Center 
during the screening phase. 
 
 
 


 
 
35
C.8. Statistical Analysis Plan 
C.8.1. Statistical Analysis 
Each exercise outcome is a continuous variable.  Linear mixed-effects models will be 
used to estimate the difference in the average post-phase outcomes between Carvedilol 
and placebo, adjusting for pre-phase values, study phase (treatment phase 1 or 2) and 
treatment sequence.  Exploratory subgroup analyses will be performed by grouping 
patients according to ventricular morphology (right/mixed versus left), baseline serum B-
type natriuretic peptide (≥100pg/ml vs. <100pg/ml).  P-values < 0.05 will be considered 
statistically significant. 
 
C.8.2. Power Calculations 
All power calculations were done with consultation from a biostastician, assuming an 
alpha level of 0.05 and 2-sided hypothesis testing.  Average peak VO2 for Fontan 
patients in a large multi-institutional study was 26ml/kg/min.28  A previous study in adult 
heart failure demonstrated that a 6% increase in peak VO2 was associated with 
reduction in cardiovascular mortality and cardiovascular hospitalization.41  Therefore we 
conservatively chose a 10% change in peak VO2 to be clinically meaningful, setting the 
desired detectable difference in the change in peak VO2 to be 2.6ml/kg/min.  The 
standard deviation of peak VO2 in the before mentioned multi-institutional study was 
6.3ml/kg/min.  Prior research in a different study of adults with pulmonary and cardiac 
disease suggests that repeated V02 measurements are highly correlated (r=0.95).42 To 
be conservative, for the purposes of power calculations we used an r-value of 0.8, 
allowing us to estimate the standard deviation of the V02 change scores to be ~3.98.  
Under these assumptions, enrolling n=20 subjects in this cross-over trial provides 80% 
power to detect a clinically significant difference between subjects’ peak V02 under the 2 
treatment conditions’ (Carvedilol vs. placebo). Therefore, a goal of 30 enrolled study 
participants was set to account for potential non-completion of the trial.   
 
 
 


 
 
36
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Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia-hypoplastic left 
heart syndrome. N Engl J Med. Jan 6 1983;308(1):23-26. 
2. 
Bozer Y, Tuncah T. Superior vena cava-right pulmonary artery anastomosis (Glenn 
operation). Turk J Pediatr. Jul 1968;10(2):66-72. 
3. 
Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax. May 1971;26(3):240-
248. 
4. 
Dean PN, Hillman DG, McHugh KE, Gutgesell HP. Inpatient Costs and Charges for 
Surgical Treatment of Hypoplastic Left Heart Syndrome. Pediatrics. Oct 10 2011. 
5. 
Khairy P, Ionescu-Ittu R, Mackie AS, Abrahamowicz M, Pilote L, Marelli AJ. Changing 
mortality in congenital heart disease. Journal of the American College of Cardiology. Sep 
28 2010;56(14):1149-1157. 
6. 
Manlhiot C, Knezevich S, Radojewski E, Cullen-Dean G, Williams WG, McCrindle BW. 
Functional health status of adolescents after the Fontan procedure -- comparison with 
their siblings. Can J Cardiol. Sep 2009;25(9):e294-300. 
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