Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Heart Failure (PREVENT-HF): A Phase 2b Randomized Placebo-Controlled (Carvedilol) Trial
Phase: PHASE2
Conditions: Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm
Sponsor: Children's Oncology Group

 
 
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CHILDREN’S ONCOLOGY GROUP 
 
ALTE1621 
 
 
Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer  
Survivors at Risk for Heart Failure (PREVENT-HF): A Phase 2b Randomized  
Placebo-Controlled (Carvedilol) Trial  
 
 
A Groupwide Study  
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON 
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING 
PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
Activated: 
4/4/2016 
Version Date: 
12/08/2020 
Closed: 
01/22/2021 
Amendment: 
4 

 
 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
4 
LIST OF ABBREVIATIONS 
6 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Aim 
11 
1.2 
Secondary Aims 
11 
1.3 
Exploratory Aim 
11 
2.0 
BACKGROUND AND HYPOTHESES 
11 
2.1 
Risk of HF in Childhood Cancer Survivors 
11 
2.2 
Mechanism of Anthracycline-Related HF 
13 
2.3 
Current Options for HF Risk Reduction 
13 
2.4 
Early markers of HF risk reduction 
17 
2.5 
Pharmacogenetics 
20 
2.6 
Significance 
21 
2.7 
Hypotheses 
22 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
22 
3.1 
Study Enrollment 
22 
3.2 
Patient Eligibility Criteria 
25 
3.3 
Cumulative Anthracycline Dose Calculation 
27 
3.4 
Recruitment 
28 
3.5  
Eligibility Screening 
28 
4.0 
TREATMENT PLAN 
29 
4.1 
Overview of Treatment Plan 
29 
4.2 
Concomitant and Repeat Therapy 
29 
4.3 
Dose Escalation and Up-Titration Period 
29 
4.4 
Maintenance Period 
31 
4.5 
Follow-up Visits 
31 
4.6 
Long-term Follow-up 
31 
5.0 
EMERGENCY UNBLINDING 
32 
6.0 
DRUG INFORMATION 
32 
6.1 
Carvedilol (IND exempt, Coreg, NSC #751177)    (06/28/17) 
32 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
37 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
37 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
38 
8.1 
Criteria for Removal from Protocol Therapy 
38 
8.2 
Off Study Criteria 
39 
9.0 
STATISTICAL CONSIDERATIONS 
39 

 
 
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9.1 
Study Design 
39 
9.2  
Patient Accrual and Expected Duration of the Trial 
39 
9.3 
Data Analytic Plan 
40 
9.4 
Power and Sample Size 
44 
9.5 
Interim Monitoring 
47 
9.6 
Gender and Minority Accrual Estimates 
48 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
49 
10.1 
Parameters to be Measured 
49 
10.2 
Endpoints: Echocardiography 
49 
10.3 
Endpoints: Blood Biomarkers 
50 
10.4 
Pharmacogenetics Measures 
52 
10.5 
Specimen Storage 
52 
10.6 
Other Study Procedures 
52 
10.7 
Questionnaire Data 
53 
11.0 
DATA COLLECTION FORMS AND SUBMISSION SCHEDULE 
54 
11.1 
Eligibility Screening, Registration and Enrollment 
54 
11.2 
Cardiac Imaging and Specimen Submission Forms 
55 
11.3 
Cardiac Event Form 
55 
11.4 
Other Event Form 
55 
11.5 
Treatment Interruptions 
55 
11.6 
Study End Form 
55 
12.0 
EVALUATION CRITERIA 
55 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
55 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
56 
13.1 
Purpose 
56 
13.2 
Determination of Reporting Requirements 
56 
13.3 
Reporting of Adverse Events for Commercial Agents - via CTEP-AERS 
57 
13.4 
Routine Adverse Event Reporting 
57 
13.5 
Syndrome Reporting 
58 
14.0 
RECORDS AND REPORTING 
58 
14.1 
CDUS 
58 
14.2 
Data Safety and Monitoring Committee 
58 
REFERENCES 
59 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
65 
APPENDIX II: INTERIM MONITORING 
67 
APPENDIX III: YOUTH INFORMATION SHEET 
69 
 
 

 
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AGENT 
 
Carvedilol, NSC# 751177, Commercial 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
A-HF 
Anthracycline-induced heart failure 
AE 
Adverse event 
AHA/ACC 
American Heart Association/American College of Cardiology 
ANP 
Atrial natriuretic peptide 
BID 
Twice daily 
BNP 
B-type natriuretic peptide 
BPM 
Beats per minute 
CAD 
Coronary artery disease 
CARMEN trial 
Carvedilol ACE inhibitor Remodeling Mild Heart Failure Evaluation trial 
CHOA 
Children’s Healthcare of Atlanta 
COG 
Children’s Oncology Group 
CPIR 
Consortium for Pediatric Interventional Research 
CTCAE 
Common Terminology Criteria for Adverse Events 
cTnI 
Cardiac troponin I 
cTnT 
Cardiac troponin T 
CV 
Cardiovascular 
DMD 
Duchenne muscular dystrophy 
E/A ratio 
Peak early atrial divided by peak late atrial velocities 
EF 
Ejection fraction 
ESWS 
End-systolic wall stress 
ET 
Ejection time 
HD 
High-dose 
HF 
Heart failure 
HRQL 
Health-related quality of life 
HSC/SickKids 
Hospital for Sick Children 
IVCT 
Isovolumetric contraction time 
IVRT 
Isovolumetric relaxation time 
LTFC 
Long-Term Follow-up Clinic 
LV 
Left ventricular 
LVEDD 
LV end-diastolic dimension 
LVEDV 
LV end-diastolic volume 
LVESD 
LV end-systolic dimension 
LVESV 
LV end-systolic volume 
LVESVI 
LV end-systolic volume index 
LV P 
LV pressure 
LVPWD 
LV posterior wall thickness at end-diastole 
LVPWS 
LV posterior wall thickness at end-systole 
LV T 
LV thickness 
LV T-D 
LV posterior wall thickness-dimension ratio 
LV V 
LV volume 
MCI 
Myocardial contractility index 
MPI 
Myocardial performance index 
MUCHA trial 
Multicenter Carvedilol Heart Failure Dose Assessment trial 

 
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MV 
Mitral valve 
NT-Pro-BNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
PMH 
Princess Margaret Hospital 
QD 
Once daily 
SAVE trial 
Survival and Ventricular Enlargement trial 
SF 
Shortening fraction 
SJCRH 
St. Jude Children’s Research Hospital 
SNPs 
Single nucleotide polymorphisms 
SOLVD-P 
Study of Left Ventricular Dysfunction-Prevention  
UM 
University of Michigan 
UMCCC 
University of Michigan Comprehensive Cancer Center 
WCI 
Winship Cancer Institute 
WMSI 
Wall motion score index 
 
 
 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, 
and/or possible threat of harm to self or others. 
 
 
ABSTRACT 
 
Heart failure [HF], is one of the leading causes of late morbidity and premature death after successful 
treatment of childhood cancer with anthracycline chemotherapy.1-4 In fact, childhood cancer survivors are 
at a 15-fold increased risk of developing HF compared to age-matched healthy controls.5 The risk is higher 
among those exposed to anthracyclines at a young age, and among those with concomitant exposure to 
chest radiation.6-9 This anthracycline-related cardiotoxicity presents as a continuum from asymptomatic 
structural or functional cardiac abnormalities detected on imaging studies, to clinically symptomatic HF.10-
12 There is a strong dose-dependent relationship between anthracycline chemotherapy exposure and HF risk. 
Anthracycline-related cardiotoxicity is dose-dependent: the incidence of A-HF is < 5% with cumulative 
anthracyclines exposure of < 250 mg/m²; the incidence approaches 15% at doses between 250 and 
500 mg/m²; and exceeds 30% for doses > 600 mg/m².1,6,8-10 Outcome following anthracycline-related HF is 
poor; 5-year overall survival rate is < 50%.13,14 Nearly 60% of all childhood cancer survivors carry a history 
of prior anthracycline exposure.9,15 The decades of life saved among the rapidly growing anthracycline-
exposed childhood cancer survivors, makes it imperative that we develop strategies (informed by the 
pathogenic basis of anthracycline-related cardiotoxicity) to reduce the risk of HF in the vulnerable 
populations.16,17  
 
Anthracycline cardiotoxicity results from direct cardiac injury due to formation of free radicals; this injury 
initiates cardiac remodeling and subsequent deterioration of left ventricular (LV) function. β-blockade or 
angiotensin-converting enzyme (ACE)-inhibition have been successfully used to prevent HF in adult non-
oncology populations with asymptomatic LV dysfunction,18-20 as well as in pediatric non-oncology 
populations with genetic predisposition to HF (but with preserved cardiac function at the time of 
intervention).21 There is increasing evidence supporting a comprehensive reversal of parameters used to 
measure cardiac remodeling, with the use of third generation β-blockers such as carvedilol (combined β1, 
β 2, α1 blockade) when compared with ACE inhibitors (afterload reduction alone) following exposure to 
cardiotoxic agents (such as HD-anthracyclines).4,17,20 However, despite clear physiologic rationale, as well 
as evidence of clinical efficacy in non-oncology populations, clinicians are reluctant to use pharmacologic 
intervention in childhood cancer survivors, primarily due to a paucity of randomized clinical trials that 
would provide evidence for benefit from such an intervention.22,23 We address this gap in the proposed trial: 
a randomized, double-blind, placebo-controlled Phase 2b trial in asymptomatic childhood cancer survivors 
with prior exposure to HD-anthracyclines (≥ 250 mg/m2).  
 

 
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This study will provide critical information regarding a physiologically plausible pharmacological risk-
reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF. The 
proposed intervention has the potential to significantly reduce ongoing cardiac injury via interruption of 
neuro-hormonal systems responsible for LV remodeling, resulting in improved cardiac function and 
decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric 
and adult non-oncology populations, yet remains unstudied in the pediatric oncology population. The 
intervention will rely on reproducible and clinically relevant echocardiographic and blood biomarkers of 
early cardiac remodeling. Finally, the proposal leverages the well-established clinical trials network of the 
Children’s Oncology Group (COG), allowing participation by geographically diverse patient populations. 
 
 

 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
Childhood cancer survivors treated with 
high-dose anthracycline (≥ 250 mg/m2) 
RANDOMIZE 
End Protocol 
Therapy 
* Carvedilol or placebo will be administered for a total of 2 years, beginning with the first dose 
of study drug. 
 
The primary endpoint is left ventricular posterior wall thickness to dimension ratio, which will 
be measured at baseline and on a semi-annual basis.  
 
Blood draws will be scheduled semi-annually for measurement of circulating markers of 
efficacy and safety. A complete list of required observations can be found in Section 7.1. 
End Protocol 
Therapy 
2 week trial period of Carvedilol at 
3.125 mg once daily 
2 week trial of placebo of  
equal size and shape once daily 
If 3.125 mg once daily tolerated, then 
Carvedilol 6.25 mg once daily for 
4-6 weeks. If not tolerated, then patient 
will go off protocol therapy. 
If 6.25 mg once daily is tolerated, then 
Carvedilol 6.25 mg twice daily for 
2 years.* If twice daily dosing is not 
tolerated, then stay at 6.25 mg once daily 
for 2 years.*  
If tolerated, then placebo of equal size and 
shape once daily for 4-6 weeks.  
If not tolerated, then patient will go off 
protocol therapy. 
If once daily is tolerated, placebo of equal 
size and shape twice daily for 2 years.*  
If twice daily dosing is not tolerated, then 
stay at once daily for 2 years.*  

 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aim 
To determine the impact of a two-year course of low-dose carvedilol on surrogate 
echocardiographic indices of heart failure (HF) risk, including: 
 Left Ventricular (LV) Posterior Wall Thickness-Dimension Ratio (LV T-D) a well-
established index of early myocardial remodeling and subsequent HF risk (primary 
endpoint). 
 LV Systolic and Diastolic Function, and Afterload – established echocardiographic 
indices associated with HF risk. 
 Natriuretic Peptides, Troponins, and Galectin-3 – circulating biomarkers associated 
with myocardial injury, and HF risk. 
 
1.2 
Secondary Aims 
1.2.1 
To establish safety and tolerability of this two-year course of low-dose carvedilol, 
assessing both objective measures (hepatic function) and patient reported 
outcomes. 
 
1.2.2 
To examine the modifying effect of demographic, clinical, and molecular 
characteristics on the risk: benefit ratio from this two-year carvedilol intervention. 
 
1.3 
Exploratory Aim 
To evaluate the long-term efficacy of carvedilol in preventing cardiomyopathy and/or heart 
failure in high-risk childhood cancer survivors. 
 
 
2.0 
BACKGROUND AND HYPOTHESES 
 
2.1 
Risk of HF in Childhood Cancer Survivors  
Anthracyclines (doxorubicin, daunomycin, idarubicin and mitoxantrone) are widely used 
in the treatment of childhood cancer; the use of these agents has led to significant advances 
in the outcome of many childhood cancers;2 current 5-year survival rates approach 80%.24 
Clinically, one of the most widely recognized side-effects of anthracycline therapy is dose-
dependent cardiotoxicity, manifesting as a continuum from asymptomatic cardiac 
dysfunction identified by abnormalities of cardiac function/structure on imaging studies, to 
the clinically overt heart failure.2 Outcome following diagnosis of anthracycline-induced 
heart failure (A-HF) is generally poor, with overall survival of less than 50% at 5 years.22,25 
Current estimates indicate that nearly 60% of the 400,00026 survivors of childhood cancer in 
the U.S. will have been treated with anthracyclines7,8 – a vulnerable sub-population at risk 
for symptomatic heart disease, and therefore representing a critical need for interventions to 
decrease/reverse this morbidity.9,12 
 
2.1.1 
Magnitude of Risk of A-HF 
Childhood cancer survivors are at a 15-fold increased risk of developing A-HF, and 
at a 7-fold increased risk of dying from a cardiac cause, compared with age- and sex-
matched general population.1,27 Survivors of Hodgkin lymphoma, renal tumor and 
Ewing sarcoma are at a 12 to 13-fold increased risk of cardiac death. Finally, the risk 
of dying from cardiac causes increases with time from diagnosis of primary cancer.27 
Thus, it is abundantly clear that anthracycline-related cardiac morbidity and 
mortality is significantly elevated in long-term survivors of childhood cancer. 

 
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2.1.2 
Risk Modification by Anthracycline Dose, Length of Follow-up, and Age at 
Exposure  
Individuals treated with anthracyclines at a younger age (< 5 years) are at an 
increased risk of A-HF, in part, because of cardiotoxic insult to a growing 
myocardium.28 Younger age at diagnosis is associated with severity of LV 
myocardial thinning, and abnormal cardiac contractility.29,30 Radiation therapy 
involving the heart is known to damage the myocardium by injuring capillary 
endothelial cells, which causes obstruction of the capillary lumen, formation of 
platelet and fibrin thrombi, and subsequent myocyte death.6 Over time, this process 
leads to myocardial fibrosis and restrictive cardiomyopathy that is characterized by 
combined diastolic and systolic dysfunction.6,31 Childhood cancer survivors exposed 
to both anthracyclines and chest radiation have a significantly increased risk of 
developing A-HF when compared to those treated with either therapeutic approach 
alone, and the risk continues to increase with longer follow-up.23,28,32 
 
Anthracycline-related cardiotoxicity is dose-dependent: the incidence of A-HF is 
< 5% with cumulative anthracycline exposure of < 250 mg/m²; the incidence 
approaches 15% at doses between 250 and 500 mg/m²; and exceeds 30% for doses 
> 600 mg/m².1,6,8-10 A recent report27 found the adjusted risk of A-HF after 
exposure to > 250 mg/m2 to be 13-fold (Odds Ratio [OR]=13.3, p < 0.01) higher 
than those not exposed to anthracyclines; the risk was nearly 6-fold (OR=5.7, 
p < 0.01) higher for individuals exposed to high-dose anthracyclines, when 
compared to < 250 mg/m². Similarly, other reports,28-31 indicate the risk of A-HF 
to be greatest for survivors treated with cumulative doses ≥ 250 mg/m²; and have 
also demonstrated that the risk of A-HF for survivors exposed to < 250 mg/m2 was 
equivalent to those with no exposure; the incidence of cardiac abnormalities 
continues to increase with longer follow-up.6,28,29,32,33 These studies suggest that 
childhood cancer survivors treated with cumulative anthracycline doses exceeding 
250 mg/m² are at a significantly higher risk of developing A-HF. 
 
2.1.3 
Natural History of Cardiotoxicity  
The American College of Cardiology/American Heart Association (ACC/AHA) 
2005 guidelines for the diagnosis and management of heart failure (HF) describe 
HF as a progressive disorder (Figure 1).18 
 
LV dysfunction begins with some injury to, or stress on, the myocardium (Stage A) 
and is progressive even in the absence of a new identifiable insult to the heart. The 
eventual manifestation is a change in the geometry or structure of the left ventricle 
(Stage B) which precedes clinically overt signs and symptoms (Stage C). If left 
untreated or if the cardiac injury is too severe, an individual will progress to 
Stage A 
At high risk for HF but 
without structural 
disease or symptoms 
Stage B 
Structural heart 
disease but without 
symptoms of HF 
 
Stage C 
Structural heart 
disease with 
symptoms of HF 
Stage D 
Refractory HF 
requiring 
interventions 
 
At Risk for Heart Failure 
Clinical Heart Failure  
Figure 1: ACC/AHA Guidelines 

 
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refractory disease (Stage D). According to the ACC/AHA guidelines, patients 
either remain in their current stage or advance from one stage to the next, but do 
not revert back to an earlier stage. It is well-recognized that there is a long latency 
between asymptomatic (Stage A/B) and clinically evident (Stage C/D) disease. 
Over time, anthracycline exposure leads to a decrease in LV wall thickness, 
increase in LV dimension, and subsequent increase in LV end-systolic wall stress 
(ESWS) – a critical component of the neuro-hormonal imbalance and a well-
recognized precursor to A-HF.6,16,34 In survivors treated with high-doses of 
anthracyclines, nearly 60% of asymptomatic individuals have markedly abnormal 
indices of myocardial remodeling, with a clear dose-response relationship with 
anthracyclines.16,35-38 
 
Once an individual develops A-HF, the overall survival is less than 50% at 5 years 
from diagnosis.7,22,23 The poor outcome highlights the importance of early 
intervention strategies for the prevention of A-HF in childhood cancer survivors. 
 
2.2 
Mechanism of Anthracycline-Related HF  
Anthracycline cardiotoxicity is thought to be related to direct myocardial injury due to 
formation of free radicals.10 Reactive oxygen species can be generated by a variety of 
pathways including redox cycling, iron complexation, and disruption of the electron 
transport chain.39-41 Anthracyclines can also alter antioxidant defense systems and DNA 
repair pathways.42,43 The subsequent effect on the myocardium may include: damage to 
nuclear DNA, disruption of sarcomeric proteins, changes in calcium handling and cellular 
contractility, and suppression of transcription factors that regulate cell survival and 
sarcomeric protein synthesis.11,13,14 If enough myocardial injury occurs, the heart expands 
in size and the chamber walls become thinner, creating a clinical picture similar to dilated 
cardiomyopathy.6 
 
Once the myocardium has been damaged by anthracyclines, changes in contractility ensue 
over time, resulting in increased renin activity, followed by increase in afterload, and 
sympathetic activation.9,15,16 The compensatory increases in afterload and sympathetic 
activation are mediated by β1, β2, and α1 receptors as well as the renin-angiotensin system. 
Chronic activation of all three sympathetic pathways (β1, β2, α1) further worsens 
myocardial injury which, over time, leads to myocardial decompensation and clinical 
HF.17,19,20 The characteristically delayed manifestation of symptomatic cardiotoxicity after 
anthracycline exposure is likely related to the eventual failure of a reduced number of 
cardiomyocytes in response to the increase in afterload and/or sympathetic activation.2,16 
Blockade of these pathways relatively soon after anthracycline exposure, by using a third 
generation β–blocker such as carvedilol in prevention of A-HF holds considerable appeal, 
and is discussed in Section 2.3.6. 
 
2.3 
Current Options for HF Risk Reduction  
For non-oncology populations (prior myocardial infarction, or idiopathic LV dilatation and 
hypokinesia), there is universal agreement about the importance of instituting appropriate 
pharmacologic intervention in at risk patients as soon as possible, and definitely before the 
onset of heart failure.18,19  
 
2.3.1 
Treatment Strategies in Adults at High Risk for HF  
The largest trials to date in the treatment of Stage B (asymptomatic) disease are 
the Study of Left Ventricular Dysfunction-Prevention (SOLVD-P) and the 
Survival and Ventricular Enlargement (SAVE) trial.44 The SOLVD-P trial enrolled 

 
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4,228 asymptomatic or mildly symptomatic patients with reduced ejection fraction 
(EF), who were assigned to receive either placebo or ACE-inhibitor, enalapril for 
48 months. After follow-up of 37 months, patients receiving enalapril showed a 
trend toward increased survival and a significant reduction in the risk of 
development of clinical heart failure.44 A subsequent extended follow-up study (12 
years) of patients enrolled in the SOLVD-P trial showed that the survival benefit 
in the enalapril arm persisted long past trial termination, suggesting that the 
preventive effects of ACE-inhibition likely continue, in part, because of the early 
intervention.45 The SAVE trial enrolled 2,231 patients after myocardial infarction, 
with asymptomatic LV dysfunction (ACC/AHA classification: Group B), who were 
assigned to placebo or a different ACE-inhibitor, captopril. After a follow-up of 42 
months, a significant reduction of both mortality (19%) and hospitalization for heart 
failure (22%) was observed.44 These results in asymptomatic or nearly asymptomatic 
patients, together with subsequent studies,20,46,47 validated the paradigm of neuro-
hormonal antagonism for heart failure prevention. As a result, there has been a shift 
in 
therapeutic 
intent 
from 
management 
of 
symptoms 
to 
addressing 
pathophysiology.18-20,46 
 
2.3.2 
Beta Blockers in at Risk Adult Populations  
It is increasingly recognized that maladaptive sympathetic activation continues in 
patients with asymptomatic LV dysfunction despite treatment with ACE inhibitors. 
In post-hoc analyses of the SOLVD-P48 and SAVE49 trials, it was evident that those 
who received β-blockade in addition to afterload reduction had significantly 
improved overall outcomes when compared to those not receiving β-blockers. In 
addition, patients with non-ischemic cardiomyopathy did not appear to derive the 
same clinical benefit from ACE-inhibitors as the patients with ischemic 
cardiomyopathy. 
 
More recently, the Carvedilol ACE inhibitor Remodeling Mild Heart Failure 
Evaluation (CARMEN) trial47 randomized participants with mild heart failure to: 
enalapril (ACE-inhibition), carvedilol (combined β1-2, α1 blockade), or both. LV 
remodeling was assessed by serial LV end-systolic volume index (LVESVI) 
measurements for 18 months. Carvedilol significantly reduced LVESVI (p < 0.01) 
compared to baseline, whereas enalapril did not. All study arms showed similar 
safety profiles and withdrawal rates. As a result, it was concluded that while 
enalapril alone may have attenuated further myocardial remodeling, carvedilol 
reversed the process, resulting in greater decrease in LVESVI and improvement in 
EF. This improvement in outcome was attributed to concurrent afterload reduction 
(α1-blockade) and blockade of adrenergic activation (combined β1-2) provided by 
carvedilol. The findings from the CARMEN study reinforce the importance of 
early, comprehensive (combined β1-2, α1 blockade as offered by carvedilol), 
intervention for reversal of myocardial remodeling and neuro-hormonal imbalance 
in populations at risk for HF. 
 
2.3.3 
Beta Blockers in Pediatric Population  
Several studies have evaluated the efficacy and safety of β-blockers in children 
with idiopathic dilated cardiomyopathy, muscular dystrophy, or congenital heart 
disease.50-57 Carvedilol has been the most frequently utilized drug due to its 
favorable safety profile and broad multi-receptor blockade.  
 

 
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The studies by Azeka52 and Shaddy55 compared safety and tolerability of carvedilol 
using a randomized, placebo-controlled study design; the frequency of adverse 
events (hypotension, dizziness, fatigue and weakness) or withdrawal rates were 
equivalent between the two arms. The severity of symptoms correlated with 
severity of heart failure, a finding also reported in several large adult trials.17 
Information regarding safety and tolerability of carvedilol in children with 
asymptomatic disease is scarce, but it would follow from the reports above that 
both the frequency and severity of adverse events would be fewer among patients 
with asymptomatic disease. Two single-arm studies57,58 in children and adolescents 
with mild dilated cardiomyopathy due to muscular dystrophy reported no adverse 
events which necessitated dose reduction or drug discontinuation. These studies 
illustrate the following: 1) carvedilol is an efficacious option for reversal of cardiac 
dysfunction 
in 
at-risk 
children 
and 
adolescents 
with 
non-ischemic 
cardiomyopathy; 2) in the setting of mild HF or asymptomatic disease, low-dose 
carvedilol is a safe and well-tolerated therapeutic option for HF risk reduction.  
 
2.3.4 
Secondary Pharmacologic Intervention in Pediatric Patients at High Risk for HF 
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle 
weakness and eventual cardiac involvement. Much like A-HF, cardiac 
involvement begins as minor electrocardiographic abnormalities at a young age, 
evolves toward cardiomyopathy with dilation of cardiac chambers and subsequent 
decrease in LV EF. Most develop refractory dilated cardiomyopathy, which is 
responsible for nearly 50% of patient deaths.  
 
Treatment with ACE-inhibitors or β-blockers has been shown to improve cardiac 
function among patients with Stage C disease and delay onset of refractory (Stage 
D) disease.59 However, few have lasting improvement in outcomes. Most patients 
develop progressive disease despite pharmacologic intervention due, in part, to the 
prolonged myocardial remodeling and neuro-hormonal imbalance which precedes 
clinically overt disease. The only secondary prevention trial randomized children 
with DMD (range 9.5 – 13 years old) with preserved EF to afterload reduction v 
placebo.60 Median EF at study entry was 65.0% ± 5.5% and none had clinical 
evidence of HF. In this double-blinded, multi-center trial, overall survival in the 
intervention arm was significantly superior to placebo at 10 years (93% v 65.5%). 
All deaths were due to cardiopulmonary failure. This study was one of the first to 
demonstrate the critical importance of intervention prior to onset of clinically 
evident disease in patients with preserved EF, but known to be at high risk for 
developing HF, a strategy advocated in the current protocol. 
 
2.3.5 
Pharmacologic Intervention for Survivors of Childhood Cancer at Risk for A-HF  
Clinicians caring for childhood cancer survivors have been hesitant to use 
secondary pharmacologic intervention strategies (either ACE-inhibitors or β-
blockers) in asymptomatic at risk populations, in large part because of the paucity 
of well-conducted randomized interventional clinical trials that would provide the 
evidence for such an intervention.61,62  
 
A retrospective review of 18 doxorubicin-exposed survivors of childhood cancer 
revealed that treatment with enalapril for a median of 10 years was associated with 
improvement in LV dimension, afterload, and shortening fraction (SF) in all 
patients.61 However, the beneficial effects appeared to be transient. The 6 patients 
with symptomatic disease progressed to cardiac transplantation or death, 

 
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reinforcing the previously reported poor outcomes when intervention is initiated 
after onset of clinically symptomatic disease. Of the 12 patients with asymptomatic 
disease, 3 developed heart failure or died. However, due to the relatively small 
number of asymptomatic individuals included in the study as well as to the non-
randomized nature of the intervention, it was unclear what effect, if any, ACE-
inhibition played in the prevention of progression to clinical HF. 
 
The only randomized clinical trial of afterload reduction (α1-blockade with ACE 
inhibitors) in asymptomatic survivors exposed to any dose of anthracyclines 
conducted thus far,62 failed to demonstrate a clinically detectable difference in the 
primary endpoint (myocardial contractility index [MCI]). However, there was 
significant reduction in ESWS that persisted over the study period. More 
importantly, there were seven individuals who were taken off study due to 
deterioration in cardiac function. Six of seven (86%) had been randomly assigned 
to placebo, and one had been randomized to ACE inhibitors (p = 0.06). All but one 
in the placebo arm who developed progressive dysfunction had received high-dose 
anthracyclines. The one individual randomized to the intervention arm was 
receiving concurrent growth hormone replacement (reported by some to 
exacerbate progression of cardiac dysfunction). Due to small numbers, the 
investigators were unable to make recommendations regarding secondary 
pharmacologic intervention. 
 
2.3.6 
ACE-inhibitors v β-blockers for Prevention of A-HF in Childhood Cancer Survivors 
As detailed in Section 2.2, injury to the myocardium results in activation of α1 and 
β1,2 receptors, and neurohormonal overstimulation. Myocardial loss occurs by 
adrenergically-mediated acceleration of apoptosis, increase in myocardial oxygen 
consumption, and wall stress, with subsequent fibrosis and worsening cardiac 
function.57 As a result, individuals with asymptomatic LV dysfunction treated with 
ACE-inhibitors alone (selective α1-like blockade) would continue to have 
adrenergic stimulation of the myocardium.48,49 Over time, this chronic stimulation 
could worsen myocardial injury and further compromise contractility. Third 
generation beta-blockers such as carvedilol have been shown to reverse 
myocardial remodeling via combined α1 and β1,2 receptor blockade,47 making 
carvedilol a more efficacious option for childhood cancer survivors at high risk for 
A-HF. Carvedilol is well-tolerated in children and adolescents with clinical HF, 
and has a more favorable safety profile when compared to ACE-inhibitors. 
Currently, there is a U.S. boxed warning against the use of enalapril, an ACE-
inhibitor, in women who are pregnant or planning on becoming pregnant, because 
it can cause injury and death to the developing fetus when used in the second and 
third trimesters.63 Carvedilol is a pregnancy category C drug, and the potential 
benefits may warrant use of the drug in pregnant women despite potential risks. 
The current trial will not include individuals who are pregnant or planning on 
becoming pregnant. However, we believe the more favorable risk profile of 
carvedilol adds additional weight to the choice of carvedilol over enalapril in the 
preventive care setting. 
 

 
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Thus, with regards to A-HF, the following issues are clear:  
 
i) Children exposed to ≥ 250 mg/m2 are at high risk of developing 
cardiomyopathy;  
ii) If left unattended, asymptomatic cardiomyopathy (Stage B) often progresses 
to A-HF;  
iii) A-HF is associated with poor survival;  
iv) There is a need for a comprehensive intervention approach to halt and 
reverse the anthracycline-related cardiac damage relatively early in its 
course in order to prevent the progression to A-HF;  
v) Studies in non-oncology populations have demonstrated safe and effective 
options for secondary pharmacologic intervention. However, there remains 
a gap in knowledge regarding the preventive strategies in anthracycline-
exposed survivors.  
 
The current study will address these gaps in knowledge by evaluating the benefit 
of pharmacologic intervention targeted to survivors at highest risk for A-HF. We 
believe, that the proposed intervention with carvedilol will provide a more 
comprehensive reversal of myocardial remodeling through concurrent sympathetic 
inactivation (β1,2-blockade) and afterload reduction (α1-blockade), increasing the 
likelihood of clinically significant risk reduction. 
 
2.4 
Early markers of HF risk reduction 
One of the recognized challenges to conducting clinical trials that evaluate secondary 
prevention strategies is the long latency between asymptomatic and clinically overt 
disease.6,12,16,64 Prevention trials focusing on cardiovascular disease have increasingly 
relied on surrogate endpoints for assessment of response to an intervention.34,61,62,65,66 While 
blood biomarkers exist, most evaluations are based on serial echocardiographic 
measurements of early myocardial remodeling. 
 
2.4.1 
Blood Biomarkers 
Troponin, a thin-filament-associated complex regulating the formation of actin-
myosin cross bridges in striated muscle, consists of three subunits: troponin T, C, 
and I.67 Cardiac troponins T (cTnT) and I (cTnI) are specific and sensitive 
biomarkers for myocardial cell injury, and have established diagnostic and 
prognostic value in acute coronary syndrome and other forms of myocardial 
injury.67,68 cTn’s have successfully been used as biomarkers to monitor acute 
anthracycline-related cardiotoxicity.69-72 However, little is known regarding their 
utility for diagnosis and monitoring of long-term chronic cardiac injury or response 
to pharmacotherapy.67 cTn levels have failed to identify mild heart dysfunction in 
patients followed long-term,73-75 arguing against their use as a biomarker of 
response to pharmacologic intervention. 
 
Natriuretic peptides (NP) are hormones produced in the atrium (ANP) and 
ventricle (NT-Pro-BNP, BNP) in response to myocardial wall stress.76,77 They act 
as potent natriuretics and vasorelaxants to improve myocardial performance, and 
have become established biomarkers for the diagnosis of heart failure.77 NPs serve 
as independent risk factors for adverse cardiovascular events, and are being 
increasingly advocated as objective markers to monitor and adjust anti-congestive 
treatment.78,79 However, there are limitations to their widespread use due to their 
low specificity and wide variability in the measured value, determined both by the 

 
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specific peptide assay as well as by physiologic conditions.67,80 Compared to cTn, 
clinical studies have been more consistent regarding the diagnostic value of NPs 
in A-HF monitoring.67 Several studies have documented that BNP levels, if 
persistently elevated, correlate well with echocardiographic indices of myocardial 
dysfunction.81-83 Due to wide inter-patient variability of NP values in individuals 
with asymptomatic LV dysfunction, the establishment of an appropriate cutoff for 
therapeutic response measurement is difficult. 
 
Most biomarkers such as troponin and BNP are released into the circulation as a 
result of harmful cellular processes, and therefore represent ‘bystander’ 
biomarkers. Galectin-3, a protein produced by activated macrophages, is a member 
of a family of β-galactoside-binding lectins and promotes cardiac fibroblast 
proliferation and collagen synthesis following myocardial injury; 84,85 inhibition of 
galectin-3 appears to block or reverse the process.86 As a result, galectin-3 is 
considered a ‘culprit’ biomarker, analogous to viral load, low-density lipoprotein, 
and glucose.85 Increased myocardial expression of galectin-3 is seen during early 
stages in myocardial remodeling and may help identify individuals with preclinical 
risk factors who are more likely to develop overt heart failure.87 Serial 
measurement of Galectin-3 may be helpful for monitoring of response to 
pharmacologic intervention. Whether serial blood biomarker measurements 
could be useful for evaluation of response to pharmacologic intervention 
remains to be defined; currently, the use of biomarkers in the management of 
heart failure remains a Class III recommendation.88 The current trial will afford us 
the ability to evaluate: i) whether changes in biomarkers correlate with 
corresponding changes in echocardiographic indices; and ii) the independent role 
of specific biomarkers as surrogates in predicting the risk of progressive disease.  
 
2.4.2 
Echocardiographic Detection of Myocardial Dysfunction 
Traditionally, the detection of late-occurring anthracycline-related cardiotoxicity 
has relied upon serial screening of at risk survivors using resting EF and SF.89 
These parameters have increasingly been recognized as inadequate for detecting 
subtle changes in myocardial function.90,91 Myocardial biopsy studies have 
demonstrated that myocyte dysregulation and apoptosis occur years prior to 
changes in EF, and a significant proportion of the myocardium would have to be 
damaged to exceed the threshold for detection.90,92,93 Often, at the point when 
changes in EF or SF are detected, functional deterioration proceeds rapidly and is 
mostly irreversible. The limitations of relying on changes in LV EF to intervene 
are further compounded by the knowledge that among the non-oncology 
populations, nearly half of all heart failure occurs in patients who maintain a 
normal EF,90,94,95 emphasizing the need for echocardiographic indices that detect 
changes at an earlier stage in myocardial compromise, as described below. 
 
Anthracycline exposure over time leads to a decrease in LV wall thickness and 
increase in LV end-diastolic dimension (LVEDD), resulting in decreased LV 
thickness dimension ratio (LV T-D). The decreased LV T-D and concurrent increase 
in LV end-systolic wall stress (ESWS) is a well-recognized precursor A-HF.6,16,34 
 
Left ventricular thickness-dimension ratio (LV T-D) is a well-established load-
independent composite echocardiographic parameter of myocardial remodeling, 
and takes into consideration changes in LVEDD and LV wall thickness, over time. 
Among survivors exposed to high-dose anthracyclines, LV T-D is expected to 

 
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decrease with follow-up, despite relative preservation of global LV systolic 
function, as measured by EF and SF. 6,16,21 Thus, decrease in LV T-D is a critical 
component of the neuro-hormonal imbalance and is a well-recognized early 
precursor to A-HF.6,16,34 Furthermore, LV T-D has been reliably used as an 
endpoint in other chemoprevention trials in both oncology and non-oncology 
populations.15,57,61,62 As a result, LV thickness-dimension ratio will serve as the 
primary endpoint in the current study. 
 
Left ventricular end-systolic wall stress (ESWS) is an echocardiographic measure 
of LV afterload and is derived from La Place’s law describing the relationship 
between LV pressure (P), volume (V), and wall thickness (T): Wall stress α (P x 
V)/T.15 For survivors treated with high-dose anthracyclines, decrease in LV 
thickness (T), and increase in LV volume (V), results in increased ESWS. Similar 
to LV T-D, ESWS continues to increase over time, despite normal- to reduced 
blood pressure, due to decreased LV thickness and mass. Studies have shown that 
pharmacologic intervention with afterload reduction can improve ESWS in 
asymptomatic survivors.61,62 It remains to be seen if this decrease in ESWS can 
provide effective and lasting reversal of myocardial remodeling, as measured by 
LV T-D. In the current trial, ESWS will serve as a secondary endpoint. 
 
Myocardial performance index (MPI)49 is a Doppler-derived parameter that 
provides global assessment of systolic and diastolic function. MPI is defined as the 
ratio of the sum of isovolumic relation time and isovolumic contraction time, to 
the ejection time – all parameters that can be obtained from routine Doppler 
imaging studies. MPI is attractive as an echocardiographic index because it is 
independent of heart rate and blood pressure; provides information regarding 
diastolic and systolic function; is load independent; does not rely on geometric 
assumptions about ventricular shape; and is highly reproducible in adult non-
oncology populations at risk for HF.96,97 MPI has been shown to be predictive of 
HF in a cohort of elderly men who had not yet developed LV dysfunction98 and in 
predicting clinical response to medical treatment for individuals with both systolic 
heart failure and heart failure with preserved EF.99 Preliminary studies in childhood 
cancer survivors treated with anthracyclines have shown MPI to be a useful pre-
clinical marker of myocardial dysfunction;100-102 larger studies are needed to 
evaluate the utility of MPI for routine screening and management of myocardial 
dysfunction in childhood cancer survivors. In the current trial, MPI will serve as a 
secondary endpoint. 
 
Several studies evaluating early changes in cardiac function during and after 
anthracycline treatment have noted primarily diastolic impairment which precedes 
systolic dysfunction.101,103 Commonly used LV diastolic measurements include: 
mitral inflow E/A ratio (peak early atrial divided by peak late atrial velocities), and 
isovolumic relaxation time (IVRT) – interval between aortic valve closure and 
mitral valve opening, and a component of MPI.103 Reduction in E/A ratio in the 
absence of systolic dysfunction is often observed in long-term survivors treated 
with anthracyclines. 101,103 However, the predictive value of this and other diastolic 
parameters is not yet known. Other echocardiographic measurements of early 
myocardial dysfunction include: changes in end-diastolic and systolic diameters 
(LVEDD, LVESD), decrease in systolic LV posterior wall thickness (LVPWS), 
increase in wall motion score index (WMSI), and decrease in LV mass.2,16,104 These 
indices will be included as secondary endpoints in the current trial. 

 
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Electrocardiograms (ECG) are readily available and noninvasive, but lack 
sensitivity in detecting anthracycline-related cardiotoxicity and do not measure LV 
function. Previous studies have suggested that prolongation of the QTc interval 
may be useful in early detection of anthracycline-induced subclinical 
cardiotoxicity and a marker of overall cardiac health.38,83,105 However, changes in 
QTc interval are non-specific and there is low correlation between 
electrocardiographic changes and the morphologic or clinical findings of 
anthracycline cardiomyopathy.28 Because of the lack of sensitivity or specificity, 
ECG will not be considered as a biomarker for detection of anthracycline-related 
cardiotoxicity; however, ECG will be routinely monitored during the trial to assess 
the safety of the pharmacologic intervention. 
 
2.5 
Pharmacogenetics  
There is widespread recognition that despite the beneficial effect of β-blockers in the 
prevention of HF, there remains significant inter-patient variability in drug response,106,107 
suggesting the role of genetic susceptibility in the response to β-blockers. Genetic 
polymorphisms affecting proteins in the adrenergic receptor pathways as well as drug 
metabolism have been identified as modifiers of β-blocker response and heart failure 
risk.106-110 As a result, clinical trials have increasingly relied on pharmacogenetics to 
evaluate sub-populations which may derive most benefit from an intervention.111-113 
 
Twenty-six β1-receptor and 20 β2-receptor single nucleotide polymorphisms (SNPs) have 
been described, but only two variants of each receptor are common and extensively studied 
with respect to carvedilol response and cardiovascular function.109,114,115 Polymorphisms in 
other adrenergic receptors (α2c-AR) and the norepinephrine transporter108 may further 
modulate pharmacologic response via alteration of pre-synaptic norepinephrine re-uptake 
and transport.108,111,116 On the other hand, polymorphisms in genes involved in beta blocker 
metabolism (CYP2D6) may modulate the dose required for a desired therapeutic 
response.110 Table 1 details specific SNPs that have been identified as candidate genetic 
modifiers and will be included in the current clinical trial. These polymorphisms were 
selected based on the following concepts: i) a candidate gene approach will be used; ii) 
functional polymorphisms will be evaluated; iii) genes will be identified by virtue of the 
fact that they have been previously documented as modifiers of carvedilol response or 
clinical course of HF. 
 
 

 
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2.6 
Significance 
There is convincing evidence that childhood cancer survivors treated with HD-
anthracyclines are at risk of developing A-HF, and that the risk increases with duration of 
follow-up.3,25,33,104,121,122 It is also well-recognized that for adult non-oncology populations, 
early intervention is critical for reversal of neuro-hormonal imbalance and myocardial 
remodeling which occurs following ischemic or non-ischemic injury.19,20,123 In addition, 
among children with genetic predisposition to dilated cardiomyopathy, secondary 
pharmacologic intervention has been shown to significantly improve long-term 
cardiovascular outcomes.60 There is a paucity of well-conducted randomized interventional 
trials in childhood cancer survivors at high-risk for A-HF. Previous studies have shown 
that while ACE-inhibition may attenuate myocardial remodeling, this improvement is 
short-lived.61,62 By providing combined β1, β2, and α1 blockade, carvedilol has the 
potential to reverse early myocardial remodeling in this high risk population.17 Given that 
cardiovascular complications are a leading cause of morbidity and mortality in long-term 
Table 1. Candidate genes with a potential role in modifying carvedilol response 
Gene, polymorphism, and 
allelic frequency (AF) 
Function 
Functional change 
(in vitro) 
Genotype/phenotype 
associations 
β 1-Adr. receptor (β1-AR) 
- Ser49Gly, AF: 0.12-0.28 
- Arg389Gly, AF: 0.20-0.46 
↑CO: ↑HR, ↑impulse 
conduction, contraction 
increased LV volume 
β1-AR down-regulated 
in chronic HF. 
Ser49>Gly: resistance 
against 
desensitization106 
Arg→Gly: 
↓responsiveness to 
agonist stimulation106 
DCM: Gly49 allele lower 
risk of death or cardiac 
transplant.117 
Carvedilol: Arg389-
homozygous improved 
LVEF v Gly-389 
homozygous114 
β 2-Adr. receptor (β2-AR) 
- Gln27Glu, AF: 0.39-0.51 
- Arg16Gly, AF: 0.09-0.25 
Cardiac: similar activity 
as β1-AR; relative up-
regulation in HF. 
Alter extent to which 
receptors undergo 
downregulation.106 
Carvedilol: Glu27 carriers 
w/HF improved LVEF (62% 
of cases) compared to Gln 
homozygous (26% of 
cases)115 
α2c-Adr. receptor (α2c-
AR) 
- Ins/Del, AF: 0.04-0.41 
Pre-synaptic inhibitory 
autoreceptors involved 
in control, release of  
NE from sympathetic 
and adrenergic neurons 
↓ Agonist binding and  
↓ G-protein coupling → 
enhanced pre-synaptic 
release of NE116 
Associated w/survival in 
severe DCM118. Synergistic 
activity of β-blockade, 
improved outcome in 
individuals with β1-AR 
Arg389Arg111 
NE transporter (NET-
182C) 
- T-182C, AF: 0.27-0.47 
Regulate reuptake of 
pre-synaptic NE 
Located in promoter 5’ 
region of NET gene, 
alters transcription 
regulation108 
T-182C associated with 
improved LVEF while on β-
blockers 
182CC resistant to β-
blockade108 
Cytochrome p450 
(CYP2D6)119 
- 12 Variations, AF: 0.05-
0.40 
 
Encodes for the 
cytochrome p-450 
(CYP) 2D6 enzyme 
which is involved in 
metabolism of beta 
blockers120 
Extensive metabolizers: 
2 wild-type alleles; 
Intermediate: one wild-
type and partially 
deleted; 
Poor metabolizers 
(PM): 2 null alleles. 
Poor metabolizers (2 null 
alleles) require higher dose 
of carvedilol to achieve 
therapeutic levels when 
compared to those who are 
not.110 
Abbreviations: Adr, Adrenergic; CO, cardiac output; HR, heart rate; cAMP, cyclic AMP; NE, norepinephrine; 
DCM, dilated cardiomyopathy 

 
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survivors of childhood cancer, we are compelled to develop targeted intervention studies 
for those at highest risk. Thus, we propose a comprehensive pharmacologic intervention 
trial for reversal of LV myocardial remodeling in childhood cancer survivors who have 
received HD-anthracyclines as part of the management of their cancer. 
 
2.7 
Hypotheses 
We hypothesize that carvedilol delivered at a dose of 12.5 mg per day for two years will 
be an efficacious and safe option for HF risk reduction in childhood cancer survivors at 
very high risk of developing HF due to previous exposure to high-dose anthracyclines. We 
also hypothesize that there exists a subgroup within the patient population who will derive 
the most benefit from taking carvedilol for HF prevention with least risk. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry Module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. For 
CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must 
be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new 
studies at the site after March 1, 2019. Local IRB review will continue to be 

 
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accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue 
to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
 
Local IRB documentation; 
 
IRB-signed CTSU IRB Certification Form; and/or 
 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of 
the IRB/REB approval record to be completed: 
 
Holds an active CTEP status; 
 
Rostered at the site on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating roster; 
 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 
Includes the IRB number of the IRB providing approval in the Form 
FDA 1572 in the RCR profile; and 
 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
 
An active Federal Wide Assurance (FWA) number; 
 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); and 
 
Compliance with all protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I.  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 

 
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Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review.  
 
3.1.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis.  
 
Requirements for OPEN access:   
 
A valid CTEP-IAM account; 
 
To perform enrollments or request slot reservations: Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 
with the role of Registrar. Registrars must hold a minimum of an Associate 
Plus (AP) registration type; 
 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars 
must hold the OPEN Registrar task on the DTL for the site; and 
 
Have an approved site registration for the protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving investigator 
for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used 
on the site’s IRB approval on their Form FDA 1572 in RCR. If a DTL is required 
for the study, the IVR or NPIVR must be assigned the appropriate OPEN-related 
tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your 
records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website 
at https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact 
the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
After the initial COG registration and enrollment, all data entry will go 
directly to the coordinating center at City of Hope. 
 
3.1.4 
Timing 
Patients must be enrolled before taking the first dose of study drug. The date that 
study drug is projected to start must be within 45 days of the eligibility screening. 

 
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If eligibility screening procedures were completed on multiple days, patients must 
start the study drug within 45 days of the first day. 
 
Patients who are found ineligible for enrollment, and were never enrolled on 
ALTE1621, may be brought back at a future date for rescreening, if in the 
investigator’s judgment, the relevant exclusion criteria no longer apply. A repeat 
screening visit will be scheduled at such time that the investigator believes the 
patient is likely to meet all study inclusion and exclusion criteria. A patient may 
be screened for eligibility no more than 2 times. 
 
The required observations for the eligibility screening are listed in Section 7.1. 
 
3.1.5 
Inclusion of Women and Minorities 
Both male and female subjects of all races and ethnic groups are eligible for this study. 
 
3.1.6 
Randomization 
Randomization will occur after enrollment and must be completed within 45 days 
of the eligibility screening. If randomization and enrollment are taking place on 
the same day, then randomization can take place before enrollment. This will allow 
ample time for the pharmacist to receive the kit assignment. 
 
If eligibility screening procedures were completed on multiple days, patients must 
be randomized within 45 days of the first day. 
 
Randomization will take place through a third party drug distributor called “Sharp 
Clinical Services” (Phoenixville, PA). See the “Study Drug Packet” on the 
ALTE1621 web page on the COG website for details on timing and randomization 
through the IVRS system.  
 
Sharp Clinical Services will randomize the subject to carvedilol or placebo using 
a blocked, stratified randomization design with age at diagnosis (2 strata: 
< 5 years, ≥ 5 years), time since diagnosis (2 strata: < 10 years, ≥ 10 years), and 
cardiac irradiation (2 strata: any, none), as stratification factors (8 strata total) and 
a block size of 4 to balance the number of participants in each arm. Blinded study 
drug will then be assigned to the patient. City of Hope, the coordinating center, 
will be notified that randomization is complete. 
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record which will serve as the source document for verification at the 
time of audit.  
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 

 
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INCLUSION CRITERIA 
3.2.1 
Current Weight for Males and Females 
3.2.1.1 Males and Females must weigh ≥ 40 Kg.  
 
3.2.2 
Age at Cancer Diagnosis 
Patient must have had a cancer diagnosis < 22 years of age, irrespective of current 
age. 
 
3.2.3 
Lifetime Anthracycline Dose 
Patient must have a lifetime cumulative anthracycline dose of ≥ 250 mg/m2 
DOXOrubicin equivalent without the protection of dexrazoxane (Zinecard) 
therapy (see Section 3.3). The anthracycline dose threshold must be met as part of 
the treatment of a cancer that was diagnosed at < 22 years of age. 
 
Note: Institutional records (e.g., clinic note, treatment summary, chemotherapy 
roadmap) can be used to document lifetime receipt of anthracycline dose. 
 
3.2.4 
Timing from Cancer Treatment to Study Entry 
Patient must have completed cancer treatment ≥ 2 years prior to study enrollment. 
 
EXCLUSION CRITERIA 
3.2.5 
Cardiac Treatment or Conditions 
3.2.5.1 Receiving treatment for cardiomyopathy or heart failure. 
3.2.5.2 Ejection fraction of < 50% (by radionuclide angiogram or echocardiogram) 
or shortening fraction of < 25% (by echocardiogram). 
Note: for instances where both are reported, and one is below the threshold, 
the site will have the option to re-measure it centrally at the core lab. 
3.2.5.3 Uncorrected primary obstructive or severe regurgitative valvular disease:  
 
Nondilated (restrictive); or 
 
Hypertrophic cardiomyopathy; or 
 
Significant systemic ventricular outflow obstruction. 
3.2.5.4 Sustained or symptomatic ventricular dysrhythmias uncontrolled with 
drug therapy or implantable device.  
3.2.5.5 Significant conduction defects (i.e. second or third degree atrio-ventricular 
block or sick sinus syndrome). 
3.2.5.6 Bradycardia: heart rate < 50 Beats per minute (BPM). 
3.2.5.7 Use of an investigational drug or beta adrenergic blockers, including 
metoprolol, sotalol, within 30 days of enrollment. 
3.2.5.8 History of drug sensitivity or allergic reaction to alpha or beta-blockers. 
 
3.2.6 
Low Blood Pressure or Blood Pressure Medication 
3.2.6.1 Low resting systolic blood pressure: < 90 mmHg. 
3.2.6.2 Use of any other blood pressure lowering medication for treatment of 
hypertension within 30 days of enrollment except calcium channel blockers 
and diuretics.  

 
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3.2.7 
Other Exclusion Criteria 
3.2.7.1 History or current clinical evidence of moderate-to-severe obstructive 
pulmonary disease or reactive airway diseases (i.e. asthma) requiring 
therapy. 
3.2.7.2 Serum AST and/or ALT > 3 times upper limit of institutional normal.  
3.2.7.3 Gastrointestinal, or biliary disorders that could impair absorption, 
metabolism, or excretion of orally administered medications. 
3.2.7.4 Endocrine disorders (such as primary aldosteronism, pheochromocytoma, 
hyper- or hypothyroidism) not controlled with medication. 
3.2.7.5 Uncontrolled diabetes (Controlled diabetes per the American Diabetes 
Association and International Diabetes Center’s Glycemic Target Goals is 
Hemoglobin A1C < 7%). 
3.2.7.6 Anemia (hematocrit < 28%). 
3.2.7.7 Currently using select CYP2D6 inhibitor or inducer medications (full list, see 
Section 6.1.7). 
3.2.7.8 Inability to swallow pills. 
 
3.2.8 
Pregnancy and Breast Feeding 
3.2.8.1 Female patients who are pregnant are not eligible. Women of childbearing 
potential require a negative pregnancy test prior to starting study drug. 
3.2.8.2 Lactating females are not eligible unless they have agreed to not breastfeed 
their infants. 
3.2.8.3 Sexually active female patients of reproductive potential are not eligible 
unless they agree to use an effective contraceptive method during study and 
for 2 months after stopping the study drug. Abstinence is an acceptable 
method of birth control. 
 
3.2.9 
Regulatory Requirements 
3.2.9.1 All patients and/or their parents or legal guardians must sign a written 
informed consent. 
3.2.9.2 All institutional, FDA, and NCI requirements for human studies must be met. 
 
3.3 
Cumulative Anthracycline Dose Calculation 
Lifetime cumulative anthracycline dose will be calculated by multiplying the total dose of 
each anthracycline (doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone) 
by a factor that reflects the cardiotoxic potential of each drug and then summing the 
individual doses.124 Conversion factors are 
shown in Table 2. Any anthracycline dose given 
with Dexrazoxane will not be counted towards 
the cumulative dose. Patients who received 
more than one anthracycline prior to study entry 
should have each individual agent cumulative 
dose converted to doxorubicin equivalent and 
added together (e.g., a patient who received 
Table 2. Anthracycline Conversion 
Agent 
Conversion Factor to 
Doxorubicin Dose 
Doxorubicin 
Multiply total dose x 1 
Daunorubicin Multiply total dose x 1 
Idarubicin 
Multiply total dose x 5 
Mitoxantrone Multiply total dose x 4 
Epirubicin 
Multiply total dose x 0.67 

 
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cumulative dose of Daunorubicin at 200 mg/m2 and Mitoxantrone 48 mg/m2 has a total 
doxorubicin dose equivalent of 392 mg/m2 (200 mg/m2 x 1 + 48 mg/m2 x 4)). 
 
3.4 
Recruitment 
Each institution should follow the best recruitment strategy for their site and patients. The 
below recruitment procedures are recommendations only. 
 
3.4.1 
Retrospective Recruitment 
Prior participants in any of the active COG long-term cancer survivorship clinics or 
associated clinical registries who are alive and eligible based on medical record 
review will be mailed a letter and study brochure describing the study. The letter lets 
them know that a representative from the study will be calling to tell them more 
about the study, unless they opt out (i.e., passive refusal). Upon contact, the patient 
will be given another opportunity to opt out. Patients who agree to be prescreened 
will be interviewed per the Phone Scripts (see study web page).  
 
3.4.2  Prospective Recruitment 
The study will be introduced to eligible patients at the end of their survivorship 
clinic visit; a brochure describing the study will be given to eligible subjects to 
take home to read. The study clinical research associate (CRA) or clinical research 
nurse (CRN) will then follow up with a phone call within approximately 7-10 days 
to assess interest and confirm interest in eligibility screening. Patients may also 
self-identify and call in to a local site via recruitment advertising.  
 
3.5  
Eligibility Screening  
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
will be done only after obtaining written informed consent. Studies or procedures that were 
performed for clinical indications (not exclusively to determine eligibility), and no more 
than 45 days before enrollment, may be used for baseline values even if the studies were 
done before informed consent was obtained. 
 
3.5.1 
Eligibility Screening 
Patients will undergo an eligibility screening to assess all the inclusion and 
exclusion criteria. Patients may be screened and enrolled at the same visit; 
however, all screening procedures must be completed and reviewed prior to 
enrollment. All required observations for the eligibility screening are listed in 
Section 7.1. 
 
 
 

 
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4.0 
TREATMENT PLAN 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
Subjects will be randomized 1:1 to receive low-dose carvedilol or placebo daily for 
24 months. Randomization will be stratified according to rules outlined in Section 3.1.6. 
Subjects will be instructed to swallow the capsule whole, with water or another non-
alcoholic liquid, preferably at the same time each day. They may take the capsules with 
food. If they forget a dose, participants will be asked to take it when they remember, and 
then take the next dose as usual, but if they do not remember until their next dose, do not 
take extra capsules to make up the missed dose. 
 
4.2 
Concomitant and Repeat Therapy 
No concomitant therapy is allowed with the exception of continued medications for chronic 
illnesses and necessary medications for unrelated acute illnesses that may occur during the 
study (cold, flu, infection, etc.). Any such medications must be recorded. 
 
4.3 
Dose Escalation and Up-Titration Period 
The goal of the up-titration period is to reach the highest dose level that will be continued 
throughout the maintenance phase. After enrollment and randomization, all subjects will 
be entered into the up-titration period, during which they will receive carvedilol or placebo. 
The first dose of the double-blind medication will be administered with food at the clinic. 
At one- and two- hours after administration of the dose, heart rate and blood pressure will 
be assessed. The first titration of carvedilol (or matched placebo) will occur two weeks 
following randomization (± 2 calendar days), with the subsequent titration occurring four 
weeks later (± 7 calendar days). The initial daily dose will be 3.125 mg once daily. The 
target final titration dose will be 6.25 mg twice daily (BID) (standard schedule, carvedilol 
dosing). 
 
The titration dose levels of carvedilol or matched placebo are: 
Level  
 
Dose 
 
 
Frequency 
1 
 
 
3.125 mg 
 
once daily (QD) 
2 
 
 
6.25 mg 
 
once daily (QD) 
3 
 
 
6.25 mg 
 
twice daily (BID) 
 
During the up-titration from level 1 to 2, subjects will be instructed to not take their usual 
dose of the study medication the morning of their study visit. This dose will be given in 
clinic, after visit assessments have been completed. 
 
For titration from level 2 to 3, subjects will be instructed to take their daily carvedilol dose 
the evening prior to their clinic visit, and to refrain from taking the study medication the 
morning of their study visit. This dose will be given in clinic, after visit assessments have 
been completed. 

 
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At each up-titration visit, the following parameters will be assessed: 
 
Interim history and physical examination (except Day 0). 
 
Sitting pre-dose blood pressure and heart rate. 
 
Sitting 1- and 2-hour post-dose blood pressure and heart rate. 
 
Concomitant medication assessment. 
 
Study medication compliance using the Adherence Tracking Form (except Day 0). 
 
Investigator’s assessment of subject’s ability to tolerate the study medication, including 
acute tolerability for at least 2 hours after the first dose of each up-titration level. 
 
If the dose level is judged by the investigator to be tolerated based on the criteria in 
Section 4.3.1, the dose of carvedilol or matching placebo will be increased to the next level.  
 
4.3.1 
Criteria for Assessment of Drug Tolerability Prior to Dose Escalation 
The goal of the up-titration period is to reach the highest dose level that will be 
continued throughout the maintenance phase. Subjects who are unable to tolerate 
escalation from dose level 1 to 2 (Day 14) will go off protocol therapy. Subjects at 
dose level 2 will be escalated to dose level 3 or maintained at level 2, depending 
on tolerability. Dose tolerability will be determined following administration of 
study drug in clinic. Symptoms will be monitored for a minimum of 2 hours post 
medication administration. Individuals who meet the following criteria at the end 
of the evaluation period will be deemed ineligible for dose escalation: 
 
 
Low resting systolic blood pressure: < 90 mmHg. 
 
Bradycardia: heart rate < 50 BPM. 
 
Sustained or symptomatic ventricular dysrhythmia. Significant conduction 
defects (i.e. second or third degree atrio-ventricular block) on ECG. 
 
Dizziness: moderate unsteadiness or sensation of movement (Grade 2 toxicity). 
 
Flushing: moderate symptoms, limiting instrumental ADL (Grade 2 toxicity). 
 
Other reasons not listed above, but deemed related to study drug per the 
investigator. 
 
Prior to escalation to the next dose level, investigators will complete a Dose 
Escalation Form, confirming that the individual did not demonstrate any of the 
above signs or symptoms. 
 
4.3.2 
Subjects on Dose Level 1 (3.125 mg/Placebo Daily) 
At two weeks post-randomization, subjects will return to clinic for a clinical 
evaluation. During that visit, there will be two options: 
 
 
Increase to level 2, or 
 
If dose escalation is considered inadvisable by the investigator, to discontinue 
the study drug. 
 
Subjects unable to tolerate dose level 1 should be taken off therapy per Section 8.0. 
Adverse events that occur within 30 days of study drug discontinuation must be 
reported and followed to resolution. Adverse events considered to be of suspected 
or probable or definite relationship to study medication will be reported and 
followed to resolution whenever they occur (see Section 8.1). The reason for 
removal from protocol therapy will be recorded. 

 
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4.3.3 
Subjects on Dose Level 2 (6.25 mg/Placebo Daily) 
Four weeks following escalation from dose level 1 to 2, subjects will return to 
clinic for a clinical evaluation. During that visit, there will be two options: 
 
 Increase to dose level 3, or 
 Maintain at the current dose level if dose escalation is considered inadvisable 
by the investigator. 
 
Individuals on dose level 2 who are unable to tolerate dose escalation to level 3 
have the option to return in 2 weeks, where there will be another attempt at dose 
escalation. If at that time, dose escalation is not considered advisable by the 
investigator, then subjects will remain on dose level 2 for the duration of the study. 
For these individuals, dose level 2 will be considered the fixed maintenance dose. 
 
4.4 
Maintenance Period 
At the completion of the up-titration period, subjects will enter the maintenance phase of 
the study which will last 24 months from the first dose of study drug. For the purposes of 
this study, the initial maintenance visit will be synonymous with the “end of up-titration” 
visit. Subjects will enter the maintenance phase receiving the highest dose of study 
medication that was tolerated in the up-titration phase. This may be dose level 2 or 3.  
 
During the maintenance period, study visits will be scheduled on 90, 180, 365, 540, and 
730 days. These study visits may occur within +/- 10 business days of the calculated visit 
day. Additional visits may be scheduled by the investigator, as appropriate, based on 
clinical indication. The study CRA/CRN will follow-up with a telephone call in between 
clinic visits, as outlined below. 
 
4.5 
Follow-up Visits 
Study participants will be asked to return their pill kits on Day 90 for a pill count, refill of 
the medication, and clinical evaluation; patient reported symptoms will be accessed via a 
standardized Symptom Log (see study web page on the COG website). For the Day 90 visit 
only, the patient has the option to do an in-person visit or a phone follow up, depending on 
their ability to easily return to the clinic. 
 
Subsequent return clinic visits will occur on Days 180, 365, 540 and 730 following 
randomization. The following parameters will be assessed according to the study 
observations (see Section 7.1). 
 
On Days 270, 455, and 630 a phone visit will be conducted (these calls may occur within 
± 10 business days of the calculated due date). During the telephone call, there will be 
collection of patient reported symptoms via standardized Symptom Log, medication refill, 
and pill count reported on the Adherence Tracking Form.  
 
A City of Hope Adverse Event (AE) collection form will be submitted by study personnel 
on Days 180, 365, 540, and 730. 
 
4.6 
Long-term Follow-up 
After trial completion, study participants will continue clinic follow-up per standard of 
care, with their first return visit scheduled one year after their Day 730 study visit. All 
organ 
function 
assessments 
included 
in 
the 
COG 
survivorship 
guidelines 

 
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(www.survivorshipguidelines.org) should be performed, including an echocardiogram. 
Special attention should be paid to symptoms and signs of cardiac dysfunction on all 
subsequent annual follow-up survivorship clinic visits. Follow up should be reported using 
the long-term cardiac outcomes report form for 3 years after the Day 730 study visit. 
 
Monitoring for cardiac dysfunction that may occur after the two-year intervention, will 
occur during the annual survivorship clinic visits which will include a complete physical 
examination and an echocardiogram per the COG survivorship guidelines. Information 
regarding new cardiac events will be obtained from the survivorship clinic using the 
Cardiac and Other Event Form. 
 
 
5.0 
EMERGENCY UNBLINDING 
Only in the event of a serious adverse event wherein the investigator feels that the patient cannot 
be adequately treated without knowing the identity of the study medication may the medication 
code be broken for a particular subject. If emergency un-blinding is required, 
 
 
 must be 
contacted as soon as possible. The Study Chair or Vice-Chair will log onto the Sharp Clinical 
Services website, unblind the patient, and contact the site investigator with the drug or placebo 
information. In the event of un-blinding, the patient will be removed from protocol therapy. 
 
 
6.0 
DRUG INFORMATION  
 
6.1 
Carvedilol (IND exempt, Coreg, NSC #751177)  
 
 
(06/28/17) 
 
6.1.1 
Source and Pharmacology: 
Carvedilol is a racemic mixture in which nonselective β-adrenergic blocking activity 
is present in the S(-) enantiomer and with α1-blocking activity is present in both R(+) 
and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic 
activity. It is (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-
propanol. Carvedilol is a racemic mixture with the following structure:  
 
 
 
 
 
 
 
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a 
molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble 
in methylene chloride and methanol; sparingly soluble in 95% ethanol and 
isopropanol; slightly soluble in ethyl ether; and practically insoluble in water, gastric 
fluid (simulated, pH 1.1), and intestinal fluid (simulated, without pancreatin, pH 7.5). 
 
Pharmacokinetics: Carvedilol is rapidly and extensively absorbed following oral 
administration, with absolute bioavailability of approximately 25% to 35% due to 
a significant degree of first-pass metabolism. Following oral administration, the 

 
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apparent mean terminal elimination half-life of carvedilol generally ranges from 7 
to 10 hours. Plasma concentrations achieved are proportional to the oral dose 
administered. When administered with food, the rate of absorption is slowed, as 
evidenced by a delay in the time to reach peak plasma levels, with no significant 
difference in extent of bioavailability.  
 
Carvedilol is extensively metabolized. Following oral administration of 
radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 
7% of the total radioactivity in plasma as measured by area under the curve (AUC). 
Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is 
metabolized primarily by aromatic ring oxidation and glucuronidation. The 
oxidative metabolites are further metabolized by conjugation via glucuronidation 
and sulfation. The metabolites of carvedilol are excreted primarily via the bile into 
the feces. Demethylation and hydroxylation at the phenol ring produce 3 active 
metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-
hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol 
for β-blockade. 
 
Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating 
activity. Plasma concentrations of the active metabolites are about one-tenth of 
those observed for carvedilol and have pharmacokinetics similar to the parent. 
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of 
R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following 
oral administration in healthy subjects. The mean apparent terminal elimination 
half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours 
for the S(-)-enantiomer. 
 
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-
carvedilol in human liver microsomes are CYP2D6 and CYP2C9 and to a lesser 
extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme 
in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 
3A4. CYP2C9 is thought to be of primary importance in the O-methylation 
pathway of S(-)-carvedilol. 
 
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers 
of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher 
plasma concentrations of R(+)-carvedilol compared to extensive metabolizers. In 
contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in 
poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by 
cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol 
do not appear to be different in poor metabolizers of S-mephenytoin (patients 
deficient in cytochrome P450 2C19). 
 
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. 
The plasma-protein binding is independent of concentration over the therapeutic 
range. Carvedilol is a basic, lipophilic compound with a steady-state volume of 
distribution of approximately 115 L, indicating substantial distribution into 
extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min. 
 
Pregnancy: There are no adequate and well-controlled studies in pregnant women. 
 

 
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6.1.2 
Toxicity 
Incidence 
Toxicities 
Common 
(>20% of patients) 
 Fatigue 
 Dizziness 
Occasional 
(4-20% of patients) 
 Hypotension 
 Pain in chest 
 Bradycardia 
 Shortness of breath 
 Generalized edema 
 Peripheral edema 
 Syncope 
 Headache 
 Nausea 
 Diarrhea 
 Weight gain 
 Hyperglycemia 
 Dry mouth 
 Insomnia 
 Blurred vision  
 Anxiety  
 Concentration impairment 
Rare 
(<3% of patients) 
 Paresthesia 
 Muscle cramps 
 Blurred vision 
 Impotence 
 Insomnia 
 Anemia 
 Thrombocytopenia  
 Hypersensitivity reaction 
 Stevens-Johnson syndrome or toxic epidermal necrolysis 
Pregnancy & 
Lactation 
Females of childbearing age should avoid pregnancy while taking 
study medication and for two months after discontinuation. The use 
of barrier or other contraceptive measures is strongly recommended 
during the study period and for two months thereafter. 
It is not known if carvedilol is excreted in breast milk. Due to the 
potential for serious adverse reactions in the nursing infant, the 
manufacturer recommends a decision be made whether to 
discontinue nursing or to discontinue the drug, taking into account 
the importance of treatment to the mother.  
 
6.1.3 
Formulation and Stability: 
Carvedilol 3.125 mg, 6.25 mg capsules, and matching placebo will be shipped at 
room temperature. The capsules should be stored at a controlled room temperature 
of 20-25°C (68-77°F) in the 3-month supply kits. Temperature excursions up to 

 
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30°C are allowed without concern for stability of the drug. Carvedilol or matching 
placebo will be stored and dispensed in the original containers. 
 
6.1.4 
Guidelines for Administration: 
See Treatment and Dose Modification sections of the protocol, Section 4.0. 
 
6.1.5 
Supplier: 
Carvedilol is available in 3.125 mg, 6.25 mg, 12.5 mg, and 25 mg tablets. For this 
trial, generic 3.125 mg and 6.25 mg capsules and matching placebo capsules will 
be manufactured by Sharp Clinical Services (Phoenixville, PA). Do not use 
commercial supply. 
 
6.1.6 
Obtaining the Agent: 
Agent Ordering: 
Distribution of study drug will be performed by a third party at Sharp Clinical 
Services. Details regarding drug randomization and distribution are on the study 
web page (see “Study Drug Packet”). 
 
Agent Returns: 
All unused or expired study drug should be destroyed per institutional guidelines. 
 
6.1.7 
Drug Interactions: 
The following drugs have been reported as inhibitors or inducers of CYP2D6 
which is the major P450 enzyme that metabolizes carvedilol. Concomitant use of 
strong and clinically significant moderate inhibitors will not be allowed while on 
study. 
 

 
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Strong CYP2D6 inhibitors 
(not allowed on study): 
bupropion  
fluoxetine  
paroxetine  
quinidine  
Clinically significant 
moderate CYP2D6 inhibitor 
(not allowed on study): 
duloxetine  
Other moderate CYP2D6 inhibitors 
(should be avoided while on study): 
cinacalcet 
mirabegron  
terbinafine  
Weak CYP2D6 inhibitors 
(should be avoided while on study): 
amiodarone  
cimetidine  
thioridazine  
Other possible CYP2D6 inhibitors 
(will be tracked on study): 
celecoxib  
chlorpheniramine* 
chlorpromazine  
citalopram  
clemastine * 
clomipramine  
 
desvenlafaxine 
diphenhydramine * 
doxepin  
doxorubicin  
escitalopram  
halofantrine  
haloperidol  
hydroxyzine * 
labetolol 
levomepromazine  
lopinavir  
methadone 
metoclopramide 
midodrine  
moclobemide  
perphenazine  
ranitidine * 
ritonavir  
ticlopidine  
tipranavir  
tripelennamine 
sertraline 
vemurafenib 
other histamine H1 receptor 
antagonists** 
Possible CYP2D6 inducers 
(will be tracked while on study): 
dexamethasone  
rifampin  
 
Virtually no effect on CYP2D6: 
venlafaxine (Effexor) – preferred 
antidepressant while on study 
*Available over the counter 
**Examples: cetirizine, dimenhydrinate, doxylamine, fexofenadine, loratidine, 
meclizine, pheniramine  
 
 
 

 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care. 
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 
(except where explicitly prohibited within the protocol). 
 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
Studies 
PRIOR to 
Enrollment 
Days on Study Drug 
 
Eligibility 
Screening 
1st  
day of 
drug 
14 
42 
90@ 180 270 365 455 540 630 730 
±2 
calendar 
days 
±7 
calendar 
days 
±10 Business Days 
History and physical 
X 
 
X 
X 
X@ X 
 
X 
 
X 
 
X 
Cardiac Evaluations 
Echocardiogram& 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Electrocardiogram 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Lab Tests 
Pregnancy Test* 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematocrit Blood Draw 
X 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers Blood Draws  
(see Section 10.3) 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
CBC and Comprehensive Metabolic 
Panel (Creatinine, liver panel 
(bilirubin, AST/ALT))  
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Questionnaires (available in English and Spanish) 
Demographics, Medical and Family 
History Forms  
X 
  
  
  
  
  
  
  
  
  
  
  
HRQoL Form 
X 
 
 
 
 
X 
  
X 
  
X 
  
X 
Treatment Management and Adherence Monitoring 
Follow-up phone call# 
 
 
 
 
X@ 
 
X 
  
X 
  
X 
  
Symptom Log, Study Tablet dispersal 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X%  
& COG institutions will receive additional per-case reimbursement for this study to allow institutions to pay for the two 
echocardiograms (month 6 and month 18) that are not considered standard of care. 
@ For the Day 90 visit only, the patient has the option to do an in-person visit or a phone follow up, depending on their ability 
to easily return to the clinic. If Day 90 is a phone follow up, the History and Physical is not required.   
* Women of childbearing potential require a negative pregnancy test prior to starting study drug; females of reproductive 
potential may not participate unless they have agreed to use an effective contraceptive method during the study and for at least 
2 months after the last dose of study drug. Abstinence is an acceptable method of birth control. For female participants of 
childbearing age, investigators will follow-up regarding their pregnancy status at each clinic visit. A pregnancy test is required 
at the eligibility screening and then throughout the study period as deemed necessary by the investigator. 
# Follow-up phone calls are to confirm medication tolerance after the screening day and in-between clinic visits to determine 
(and reinforce) adherence, complete the Symptom Log, and arrange medication refill. The medication refills are either 
picked up by the patient or sent via FedEx to their home. 
% No study medication is dispensed at Day 730. 

 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
a) Physician determines it is in the patient’s best interest. 
b) Inability to tolerate dose escalation from level 1 to level 2. 
c) Treatment interruption longer than 90 consecutive days. 
d) A cardiac event (see Section 8.1.1 for definition). 
e) Pregnancy. 
f) Adverse Event requiring removal from protocol therapy (see Section 13.4). 
g) Diagnosis of a new malignancy requiring systemic chemotherapy or radiation. 
h) Adherence < 50% in any 90 day period. 
i) Emergency un-blinding (see Section 5.0) 
j) Study is terminated by Sponsor. 
 
Patients who are taken off protocol therapy do not require any additional study 
observations/evaluations unless they experienced a cardiac event or have become pregnant. 
 
8.1.1 
Study End Form 
All patients withdrawn from study medication must have the reason for withdrawal 
recorded on the Study End Form located on the ALTE1621 webpage on the COG 
website (including subjects who complete the study). All adverse events leading 
up to withdrawal of study medication must be fully documented and followed up 
as appropriate. To ensure that all withdrawals due to adverse events are correctly 
identified, “Adverse Event” should only be marked as the reason for withdrawal 
on the Study End Form for those patients whom an adverse event was considered 
to have been the direct cause of withdrawal from the study medication. This is 
particularly important when adverse events are ongoing at the time of withdrawal, 
but the reason for withdrawal is not related to the adverse event. 
 
A cardiac event is defined as: 1) acute heart failure with pulmonary edema and 
S3 gallop without obvious correctable cause (i.e., intravenous fluid overload 
during surgery), or 2) EF < 50%, shortening fractional (SF) < 25% or a 20% drop 
from an earlier test. Subjects who develop a cardiac event while on study will be 
referred to a cardiologist for proper diagnostic work-up and management. These 
individuals will be taken off study drug. 
 
Participants must not be planning to become pregnant for two years to be eligible 
for the study, and they will be warned about the importance of not becoming 
pregnant while on study at the time of enrollment. They will be advised to use 
contraception for all sexual activity during the course of the study and for 2 months 
afterwards. Nevertheless, occurrence of an unplanned intrauterine pregnancy while 
on study will be an indication for immediately stopping treatment and the patient 
must withdraw from the study. If the patient should become pregnant while on 
study, or within 2 months after discontinuing therapy, her treatment assignment 
will be unblinded immediately (see Section 5.0). Whenever possible, a pregnancy 
should be followed to term, any premature terminations reported, and the status of 
the mother and child should be reported to the study team after delivery. 

 
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8.2 
Off Study Criteria 
a) Withdrawal of consent for any further data submission. 
b) Death. 
c) Completion of planned study assessments. 
d) Lost to follow up (defined as no contact with patient for ≥ 90 consecutive days after a 
required observation). 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
The following section includes the protocol that was active at the time of study initiation and 
amendments that were made resulting from a reduction in study sample size from 125 per arm to 
91 per arm. With Amendment #4, revisions were made to the detectable treatment effect size and 
interim analyses. The analysis plan remains the same. 
 
9.1 
Study Design 
This is a Phase 2b randomized double-blind placebo controlled clinical trial to examine the 
effect of carvedilol on preventing cardiovascular morbidity/mortality associated with 
anthracycline exposure during childhood cancer treatment. Childhood cancer survivors 
who were previously treated with ≥ 250 mg/m2 cumulative dose of anthracyclines will be 
randomized 1:1 between the 2 arms: carvedilol arm and the placebo arm. Randomization 
will be stratified by age at diagnosis (2 strata: < 5 years, ≥ 5 years), time since diagnosis (2 
strata: < 10 years, ≥10 years), and cardiac irradiation (2 strata: any, none), as stratification 
factors (8 strata total) and a block size of 4. Daily treatment with carvedilol and placebo 
will continue for 2 years. Cardiovascular functions will be assessed at baseline and semi-
annually. The primary endpoint is LV thickness-dimension ratio (LV T-D) derived from 
echocardiogram. 
 
9.2  
Patient Accrual and Expected Duration of the Trial 
It is estimated that approximately 50-60% of the 450,000 survivors of childhood cancer 
who are alive in the U.S. today have received anthracyclines. Many pediatric cancer 
patients (approximately 20-25%) are being treated with anthracyclines with cumulative 
dose ≥ 250 mg/m2, such as those with bone cancer and AML. Although exact estimates are 
not available, using the conservative estimates of 50% and 20% to calculate, >30,000 
survivors would meet the current eligibility criteria. We expect thousands of childhood 
cancer survivors meeting such criteria are currently being followed at member COG 
institutions.  
 
ACTIVATION PROTOCOL: 
To answer the scientific questions, 250 randomized subjects (125 per arm) is required. 
Through a different mechanism, 82 patients have already been accrued and randomized. 
Therefore, this COG protocol aims to enroll and randomize an additional of 168 patients 
through this protocol, with a maximum accrual of 177 patients to account for up to 5% of 
ineligible enrollments. Given the large pool of potential eligible patients, we expect to 
complete the accrual, including the time it takes to open the study at COG institutions, over 
4 years.  
 
WITH AMENDMENT #4: 
To answer the scientific questions, 182 subjects (91 per arm) who are randomized and start 
study drug are required. Through a different mechanism, 87 patients have already been 
accrued and randomized. Therefore, this COG protocol aims to enroll, randomize and start 

 
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treatment for an additional 95 patients through this protocol. To account for attrition, 
enrollment through this COG trial may proceed up to 109 patients. Given the large pool of 
potential eligible patients, we expect to complete the accrual, including the time it takes to 
open the study at COG institutions, over 5 years.  
 
9.3 
Data Analytic Plan 
Aim 1.1: To determine the impact of a two-year course of low-dose carvedilol on 
surrogate echocardiographic indices of heart failure (HF) risk. 
 
9.3.1 
LV Thickness-Dimension Ratio (LV T-D) 
The primary endpoint of this trial is LV thickness-dimension ratio (LV T-D) 
z-score. LV thickness is reported in terms of LV posterior wall dimension in 
systole, while LV dimension will be based on the internal diameter in diastole. Z-
scores will be calculated using the formula: (LVPWD/ LVEDD – 0.18) / 0.025.21  
 
LV T-D Z-score will be determined at baseline, 6 months, 12 months, 18 months 
and 24 months. The z-scores will be appropriately transformed to normality as 
necessary. The analysis will be conducted accounting for correlation among 
repeated measurements within individuals. This may be done using the 
Generalized Estimating Equation (GEE) approach or by the restricted maximum 
likelihood estimation (REML) approach with the mixed effect model with random 
effects. Various covariance structures will be assumed, including the unstructured, 
compound symmetry, and autoregressive lag-1 correlation. GEE and REML will 
be implemented using GENMOD and MIXED procedures in SAS. 
 
LV T-D z-scores will be modeled as a linear function of time. Under the intention-
to-treat principle, the efficacy of carvedilol will be examined by comparing the 
slopes of the longitudinal linear models of LV T-D z-score between carvedilol and 
placebo control group. The difference in slopes by treatment group will be 
introduced by including an interaction term of time with group indicator (0 for 
placebo, 1 for carvedilol). Treatment effect will be tested by a 1-df test for the 
interaction. Non-linear effects will be tested by including an interaction of a 
quadratic term in time with the group indicator. 
 
To examine other than the linear model, we will also fit an unstructured mean 
model, which is a non-parameterized model with four indicator variables of time. 
Interactions of the time and group indicators will be included to allow for treatment 
differences at follow-up time points. This will enable us to examine other than 
linear or quadratic trends in time.  
 
Because of randomization, we expect no difference between the expected values 
of LV T-D z-scores at t0 between the treatment groups. However, we will evaluate 
the success of the randomization by examining between-group differences in 
demographic and clinical characteristics (i.e. age at anthracycline exposure, chest 
radiation, time from treatment), study site, as well as the mean LV T and D z-
scores at baseline. If imbalance is evident, our analysis will take into account the 
covariates with significant imbalance. 
 
Low dose carvedilol will be considered effective if the 1-df test in the linear model 
is significant and the expected LV T-D z-score is lower for placebo at follow-up 

 
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time points, indicating the effectiveness of low-dose carvedilol in preserving LV 
T-D. 
 
In addition to unadjusted analyses which are appropriate under the randomization 
principle, adjusted analysis will also be performed. Significantly imbalanced 
covariates and covariates known to be prognostic for HF, such as age at 
anthracycline exposure, chest irradiation, and time from completion of treatment, 
will be incorporated in the longitudinal models before including and testing the 
time by treatment group interaction. 
 
To address potential noncompliance, we will also conduct an as-treated analysis, 
considering patients’ actual treatment uptake. Instead of the treatment indicator 
(placebo or carvedilol), we will include adherence rate, i.e. 0 for placebo and a 
number between 0 and 1 for carvedilol determined by pill count, in the linear mixed 
effects model. Time-specific adherence rate and the overall adherence rate will be 
considered. If carvedilol is effective, we may expect to see an increase in LV T-D 
z-score and a greater difference in slope with increasing adherence rate. 
 
The estimates from linear mixed effects model are valid in the presence of 
incomplete response data if missing data occurs at random. However, 
nonparticipation and dropouts may occur differentially between treatment groups 
for various reasons, possibly resulting in non-ignorable missing data. In addition 
to collecting information on reasons for nonparticipation, we will apply two 
analytic approaches to examine the effects of missing data on study results:125 1) 
pattern mixture models and 2) selection models. In pattern mixture models, the 16 
possible missing data patterns (arising from 4 follow-up time points, with no 
missing data at t0, and considering a response as missing if data from 
echocardiographic assessment are missing) will be used as covariates in the above-
described bivariate linear mixed effects model. The effects of missing data on the 
estimate of treatment effect can be assessed. An overall estimate of the treatment 
effect may be obtained by averaging the estimates over the missing pattern groups. 
In the selection model, we will model the probability of dropout using baseline 
covariates to estimate the propensity for dropout. The propensity scores will be 
used as a covariate in the bivariate linear mixed effects model to adjust for the 
effects of dropout on treatment effects. 
 
Secondary echocardiographic efficacy measures (afterload, systolic and diastolic 
measurements) will be evaluated by applying the same methods for longitudinal 
analysis. Significance of the carvedilol effects will be evaluated in the manner 
described above based on testing the significance of the interaction of time by 
group indicator variables. The distribution of continuous variables will be 
examined graphically and appropriate transformations made before applying 
analytical methods based on normal assumption. 
 
9.3.2 
Blood Biomarkers of Myocardial Remodeling 
Natriuretic peptides (BNP), cardiac troponins (cTnT and cTnI), and Galectin-3 will 
be treated as continuous measures. We will apply the linear mixed effects model 
for between group comparisons of measures from the 5 time points. The 
unstructured mean model and linear in time model will be employed. 
Aim 1.2.1: To establish the safety and tolerability of low-dose carvedilol. 

 
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9.3.3 
 Objective Safety Measures 
Adverse events. The number of Grade 2-4 toxicities observed will be tabulated by 
treatment arm. Differences by treatment arm will be evaluated using Fisher exact 
tests. 
 
Biomarkers. Liver function measurements (Bilirubin, AST, ALT) will be treated 
as continuous variables. Study participants will be considered to have elevated 
liver function if the measurements at 6, 12, 18, and 24 months are above the upper 
limit of the institutional reference range and higher than baseline pre-treatment 
level. These data will be coded such that those who are greater than 2-times the 
upper limit of the reference range will be considered to be clinically significant 
(Grade 1 if asymptomatic and requiring no intervention; Grade 2 if 
minimal/local/non-invasive intervention required). The frequency of individuals 
with elevated liver function measures will be compared between treatment groups 
using an exact test on 2x2 tables, stratified on CYP2D6. Logistic regression 
analysis will also be used to compare the frequency of elevated liver function 
between treatments, adjusted for covariates. Linear mixed-effects model for 
normally distributed data will also be used to compare the trends in liver function 
levels between the treatment groups. Procs MIXED and GLIMMIX will be used 
for longitudinal analysis of normally and non-normally distributed data, 
respectively. Proc GENMOD will also be used for normally and non-normally 
distributed data. 
 
9.3.4 
Subjective Safety and Tolerability Measures 
Treatment adherence. Patients will self-report adherence in the study 
questionnaires. Compliance will also be measured by pill counts performed every 
3 months. The number of pills taken out of the total prescribed in a 3- month period 
will be modeled as a random effects binomial regression model.126 The binomial 
rates from 8 time points (month 3 to 24) will be modeled as unstructured mean 
model with 7 indicator variables as well as polynomial models over time. The 
random-intercept and the random intercept and slope models will be considered. 
The significance of the time indicators or parameters by treatment interaction will 
be evaluated for treatment difference in compliance. 
 
Voluntary withdrawals will be examined at the end of the study by comparing the 
percent of withdrawals between the treatment groups using a chi-square test or 
Fisher’s exact test. 
 
Patient reported symptoms. The outcomes will be scored as a 5-point Likert-type 
scale (0 to 4) in response to questions on how much the patients are bothered by 
certain symptoms. The questionnaire will be administered at Days 0, 14, 42 and 
90, and every three months after Day 90, for a total of eleven time points. The 
responses will be treated as normally distributed, as ordinal or dichotomized 
variable, and we will apply the linear mixed effects model or generalized linear 
mixed effects model methods to compare changes between treatment groups. 
Because of additional time points available, in addition to the unstructured mean 
model, we will also fit piecewise models with join point at 6 months, considering 
linear and curvilinear trajectories between 6 m and 24 m time points. 
 

 
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Aim 1.2.2: To examine the modifying effects of demographic, clinical, and molecular 
characteristics on both efficacy and safety markers. 
 
As the primary aim of this trial is to examine the main effects of low-dose 
carvedilol on LV-TD z-score, we will examine the modifying effects of 
demographic, clinical, and molecular characteristics as exploratory analysis. Even 
if time by treatment interaction (main treatment effect) is not significant, 
examining the modifying effects of covariates may reveal subgroups that respond 
differently to carvedilol. A three-way interaction of time by treatment by 
modifying variable will be included in the longitudinal model containing a two-
way time by treatment group interaction. Modifying effects will be considered 
statistically significant if the three-way interaction is significant. The covariates of 
interest are described below. 
 
A. Patient demographics 
The following variables are known to affect HF risk and LV T-D. 
 
Attained age – continuous, time-varying variable. 
 
Body mass index (BMI) – continuous, time-varying variable. It will also be grouped 
into ordinal categories: underweight (<19), normal weight (19-24), overweight 
(25-29), obese (30-39), morbidly obese (40+). 
 
Cardiovascular disease – coronary artery disease (angina, acute myocardial 
infarction, coronary artery bypass graft surgery [CABG], percutaneous coronary 
intervention), ventricular or atrial arrhythmias, cerebrovascular disease, congenital 
heart lesions. 
 
CV risk factors – Hypertension, dyslipidemia, diabetes, renal insufficiency, 
chronic lung disease, thyroid disorder, smoking history (includes smoking status, 
and if quit, date of cessation). All CV risk factors will be recorded as dichotomous 
variables (present/absent), with recording of date of onset. 
 
Family history of cardiovascular disease – dichotomous (yes/no), constant over 
the study period. Outcomes of interest will include: sudden cardiac death, 
conduction system disease, cardiomyopathy, and coronary artery disease (CAD). 
For the CAD, we will also examine the frequency of the following classifications: 
0 = no direct blood relatives (parents, siblings) with CAD; 1 = one or more with 
CAD at age ≥ 55 years for male relatives or ≥ 65 years for female relatives; 2= one 
or more with CAD at age less than 55 years for male relatives or less than 65 years 
for female relatives. 
 
B. Clinical treatment characteristics. 
The following variables are known to influence HF risk among childhood cancer 
survivors. 
 
Chest radiation – continuous, time-invariant. We will also dichotomize per the 
stratification factor for randomization. 
 
Age at exposure to anthracyclines – continuous, time-invariant. We will also 
categorize per the stratification factor for randomization. 

 
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Latency from radiation therapy – continuous, time-varying. We will examine if 
intervention effects vary by time since exposure to therapeutic radiation. 
 
C. Molecular characteristics 
The following variables are known to influence efficacy of carvedilol in the 
treatment of HF patients and will be analyzed at a later date. 
 
CYP variants – dichotomous (yes/no), constant over the study period 
 
β 1, 2 and α1-Adrenergic receptor and Norepinephrine transporter variants 
(Section 2.5) – dichotomous (yes/no), constant over the study period. 
 
In addition to testing their significance as effect modifiers, we will also examine 
their relationship with the outcome variables (LV T-D, ESWS, Natriuretic 
peptides, MPI etc.) to validate known relationships. Proc Mixed for normal data 
and Proc GLMMIX for non-normal data in SAS 9.1 (Cary, North Carolina) will 
be used for analysis. 
 
9.3.5 
Exploratory Aim 1.3: 
To evaluate the long-term efficacy of carvedilol in preventing cardiomyopathy 
and/or heart failure in high-risk childhood cancer survivors. 
 
For this exploratory aim, long term overall and cardiac health status will be 
described for study participants and as exploratory analyses compared between the 
2 study arms.. The majority of these childhood cancer survivors are expected to be 
in active follow-up and routine clinical information (including annual 
echocardiograms) is already being collected as part of the patients’ standard care. 
In support of this aim, ascertainment of basic information regarding overall and 
cardiac health status: vital status, development of cardiomyopathy/heart failure, 
most recent ejection fraction and shortening fraction data in order to determine if 
there has been a cardiac event (as defined in Section 8.1.1) for up to 5 years after 
study enrollment. 
 
9.4 
Power and Sample Size 
Primary Aim - Determine the impact of a two-year course of carvedilol on LV T-D: 
For sample size calculation, we let Y, the response, be the z-score expected for LV T-D in 
both groups. Because of randomization, we expect no difference between the expected 
values of Y at t0 between treatments. However, if the intervention is efficacious, we expect 
the linear slopes of the two groups to diverge over time, with no significant change in the 
slope of LV T-D for the carvedilol arm. Power/sample size calculation was conducted by 
assuming a linear change in LV T-D z-score over time. With this assumption, longitudinal 
power calculation requires specification of the following: 1) expected values of Y at t0 the 
carvedilol and control arms, 2) the expected difference in Y at 24 months between the two 
arms, and 3) the correlations between the repeated measurements over time. These were 
obtained from the following sources: 1) Expected baseline value of LV T-D was derived 
from a cross-sectional study evaluating cardiac function in 150 long-term survivors of 
childhood cancer treated with anthracyclines at City of Hope (median age at evaluation, 
24.2 years, time since diagnosis 12.5 years).127 Mean LV T-D z-score for survivors exposed 
to HD-anthracycline (≥ 250 mg/m2) was -0.72 (SD 1.0), compared to -0.03 (SD 1.1) in 
those treated with lower doses (< 250 mg/m2); p< 0.05.127 2) Projected decline in LV T-

 
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D between baseline and 24 months was derived from two clinical trials21,128 These studies 
were selected because they provided reliable longitudinal data of cardiac function, obtained 
from multi-institutional clinical trials that used a centralized core echo lab. Patients treated 
with higher dose anthracyclines had a decline in LV T-D Z-score of approximately 
0.2/year, providing us with an estimated rate of LV-TD decline for the placebo arm of the 
current study. Given these findings, we project that mean LV T-D z-score will be -0.7 at 
baseline for both arms of the trial, mean LV T-D z-score for the placebo arm will decline 
to -1.1 at the end of the 2-year intervention, and there will be preservation of LV T-D z-
score for the carvedilol arm, resulting in a projected difference at 24 months between the 
two arms of 0.4. We acknowledge the possibility that instead of preservation of LV T-D, 
there could be further decline in LV T-D for the carvedilol arm, decreasing the observed 
effect size at 24 months to < 0.4.  
 
ACTIVATION PROTOCOL: 
However, as discussed 
below, the current trial 
will 
have 
adequate 
power 
to 
detect 
prevention effects that 
are 12.5% to 37.5% 
lower than the projected 
differences 
between 
carvedilol and placebo 
arms. 3) Correlation 
between measurements 
over time was based on 
preliminary data examining LV T-D values for the 40 patients enrolled onto the clinical 
trial not through this COG study but through a different mechanism with at least a baseline 
and six month time point; the correlation between these two time points was 0.7. Since we 
do not know what the correlation will be after 2 years, Table 3 depicts detectable 
differences for correlations ranging from 0.6 to 0.8. In addition, we show detectable 
differences for important secondary endpoints such as: EF, LVEDV, LVESV. Of note, as 
in LV T-D, estimated baseline mean values for these echocardiographic endpoints and their 
standard deviations were derived from our recently completed study evaluating cardiac 
function in comparable survivors of childhood cancer,127 as well as from patients currently 
enrolled on the clinical trial. Correlation between measurements over time (baseline to 6 
months) for these indices ranged from 0.6 (EF) to 0.8 (LVEDV, LVESV).  
 
The longitudinal power calculations were conducted using the program RMASS2.129 We 
assumed a Type I error of 0.05, power of 0.80, 2-sided test, linear trend, and compound 
symmetry correlation matrix ([ρ] ranging from 0.6 to 0.8). An attrition rate of 15% per 
arm/year (voluntary withdrawal, discontinuation due to drug intolerance, unexpected 
events [pregnancy/ relapse]) was assumed, taking into consideration the observed attrition 
rate (13%/year) in the study to date. Table 3 shows the minimum effect size at 24 months 
that can be detected for a given correlation between measures. For example, with 125 
individuals in each group, we have 80% power to detect a difference of at least 0.32 in LV 
T-D z-score between the two arms if the correlation between baseline and the 2 year LV 
T-D z-score is 0.6. Thus, if the absolute difference between the carvedilol and placebo arms 
is smaller than 0.4, the current sample size will still be sufficiently powered to detect a 
lower degree of remodeling prevention. With regards to the secondary endpoints of 
efficacy, 3-6 mL increases in LVESV, 6-10 mL increases in LVEDV, or 3-5% drops in LV 
Table 3. Detectable differences in endpoints by correlation estimates 
Sample size: 125/arm; Attrition: 15%/yr; Power: 0.8; Type I error: 0.05 
Endpoint 
Baseline 
Value 
Estimated 
SD 
Correl. Between measurements 
      0.6              0.7            0.8 
Primary 
LV T-D (Z) 
-0.7 
1.0 
0.32 
0.28 
0.23 
Secondary 
LVEDV (mL) 
105.7 
26.9 
8.6 
7.5 
6.2 
LVESV (mL) 
45.0 
11.7 
3.7 
3.3 
2.7 
LVEF (%) 
60.0 
5.0 
1.6 
1.4 
1.2 

 
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EF (from normal resting LV EF) have been associated with adverse cardiovascular 
outcomes in clinical trials with patients with preserved or mildly depressed EF.130-132 Thus, 
effect sizes presented in Table 3 are plausible and clinically meaningful. 
 
WITH AMENDMENT #4: 
As discussed below, the current trial will have adequate power to detect prevention effects 
that are 8.5% to 52.5% lower than the projected differences between carvedilol and placebo 
arms. 3) Correlation between measurements over time was based on preliminary data 
examining LV T-D values for the 40 patients enrolled onto the clinical trial not through 
this COG study but through a different mechanism with at least a baseline and six month 
time point; the correlation between these two time points was 0.7. Since we do not know 
what the correlation will be after 2 years, Table 4 depicts detectable differences for 
correlations ranging from 0.6 to 0.9. In addition, we show detectable differences for 
important secondary endpoints such as: EF, LVEDV, LVESV. Of note, as in LV T-D, 
estimated baseline mean values for these echocardiographic endpoints and their standard 
deviations were derived from our recently completed study evaluating cardiac function in 
comparable survivors of childhood cancer,127 as well as from patients currently enrolled on 
the clinical trial. Correlation between measurements over time (baseline to 6 months) for 
these indices ranged from 0.6 (EF) to 0.9 (LVEDV, LVESV).  
 
The longitudinal power calculations were conducted using the program RMASS2.129 We 
assumed a Type I error of 0.05, power of 0.80, 2-sided test, linear trend, and compound 
symmetry correlation matrix ([ρ] ranging from 0.6 to 0.9). An attrition rate of 19% per 
arm/year (voluntary withdrawal, discontinuation due to drug intolerance, unexpected 
events [pregnancy/ relapse]) was assumed. Table 4 shows the minimum effect size at 24 
months that can be detected for a given correlation between measures. For example, with 
91 individuals in each group, we have 80% power to detect a difference of at least 0.38 in 
LV T-D z-score between the two arms if the correlation between baseline and the 2 year 
LV T-D z-score is 0.6. With regards to the secondary endpoints of efficacy, 3-6 mL 
increases in LVESV, 6-10 mL increases in LVEDV, or 3-5% drops in LV EF (from normal 
resting LV EF) have been associated with adverse cardiovascular outcomes in clinical trials 
with patients with preserved or mildly depressed EF.130-132 Thus, effect sizes presented in 
Table 4 are plausible and clinically meaningful. 
 
Secondary Aim – Establish safety and tolerability of the two-year course of carvedilol. 
 
ACTIVATION PROTOCOL: 
Adverse events: We assume the rate of Grade 2-4 toxicities in the placebo group to be 
low, at 5%. At the end of the study, assuming 88 individuals remaining in each arm (15% 
attrition/year from the original 125/ arm), the study will have at least 80% power to detect 
Table 4. Detectable differences in endpoints by correlation estimates  
Sample size: 91/arm; Attrition: 19%/yr; Power: 0.8; Type I error: 0.05  
Endpoint 
Baseline 
Value 
Estimated SD 
Correl. Between measurements 
0.6 
0.7 
0.8 
0.9 
Primary 
LV T-D (Z) 
-0.7 
1 
0.38 
0.34 
0.28 
0.21 
Secondary 
LVEDV (ml) 
105.7 
26.9 
10.2 
9.1 
7.5 
5.6 
LVESV (ml) 
45 
11.7 
4.4 
4 
3.3 
2.5 
LVEF (%) 
60 
5 
1.9 
1.7 
1.4 
1.1 

 
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an adverse event rate of 19.2% in the carvedilol group based on Fisher’s exact test and 
Type I error=0.05.  
 
Adherence to therapy: We will examine the difference in adherence rates by comparing 
the percent adherence by treatment group. With 125 study participants at baseline per arm, 
assuming a constant adherence rate of 90% in the placebo group, a between-measurement 
correlation of 0.6, 15% yearly attrition, and 2-sided alternative, there will be 80% power 
to detect an adherence rate of 75% in the carvedilol group.  
 
Voluntary withdrawals: We assume that the proportion of patients in the placebo arm 
who will withdraw voluntarily by 24 months is 20% (10%/year); of note, this is less than 
the assumed overall attrition rate of 15%/year because attrition could occur due to other 
reasons such as toxicities, cancer recurrence, etc. With 125 patients in each arm at baseline, 
using Type I error=0.05, the study will have 80% power to detect a >15% absolute 
difference in the voluntary withdrawal rates between the two study arms. 
 
WITH AMENDMENT #4: 
Adverse events: We assume the rate of Grade 2-4 toxicities in the placebo group to be 
low, at 5%. At the end of the study, assuming 56 individuals remaining in each arm (19% 
attrition/year from the 91/arm at baseline), the study will have at least 80% power to detect 
an adverse event rate of 24.7% in the carvedilol group based on Fisher’s exact test and 
Type I error=0.05.  
 
Adherence to therapy: We will examine the difference in adherence rates by comparing 
the percent adherence by treatment group. With 91 study participants at baseline per arm, 
assuming a constant adherence rate of 90% in the placebo group, a between-measurement 
correlation of 0.6, 19% yearly attrition, and 2-sided alternative, there will be 80% power 
to detect an adherence rate of ≤70% in the carvedilol group.  
 
Voluntary withdrawals: We assume that the proportion of patients in the placebo arm 
who will withdraw voluntarily by 24 months is 26% (13%/year); of note, this is less than 
the assumed overall attrition rate of 19%/year because attrition could occur due to other 
reasons such as toxicities, cancer recurrence, etc. With 91 patients in each arm at baseline, 
using Type I error=0.05, the study will have 80% power to detect a >21% absolute 
difference in the voluntary withdrawal rates between the two study arms. 
 
9.5 
Interim Monitoring  
 
9.5.1 
Toxicity Criteria for Study Stopping 
If, on either arm, two or more cases of the same Grade 3-4 toxicity with probably 
or definitely attributions that do not resolve in 72 hours are reported in separate 
patients, accrual will be held until further review by the DSMC to determine 
whether or not the study should be stopped based on the unblinded data available 
at that time. 
 
9.5.2 
Plans for Interim Monitoring for Superiority and Futility 
 
ACTIVATION PROTOCOL: 
The statistician will perform up to two blinded interim analyses for efficacy and 
futility after 33% and 66% of patients have completed all the study endpoints. 
Patients that were taken off study due to an adverse event or cardiac event after 

 
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Day 180 would also be included in the interim analyses. The DSMC will stop the 
trial for clear evidence of superiority or futility if the test statistic on blinded data 
falls within the specified early stopping boundary (Appendix II, Tables s1 and s2). 
In both the interim and final analysis, the intent-to-treat data set will be the primary 
analysis group, with consideration of missing data. 
 
WITH AMENDMENT #4: 
With the amended total n=182, 114 patients are anticipated to complete all study time 
points, after accounting for attrition. As of 6/30/2020, 87 patients had data at all time 
points, corresponding to 76% of the anticipated revised sample size of n=114. Since 
this is close to the final expected updated sample size, no interim analysis for efficacy 
will be performed, but one futility analysis will be performed using the data available 
at 6/30/2020 (Appendix II, Table s3). 
 
9.6 
Gender and Minority Accrual Estimates 
WITH AMENDMENT #4: 
As detailed above in Section 9.2, the study targets to accrue and randomize 182 subjects; 
however, considering the 87 patients already enrolled through a separate mechanism, only 95 
patients are needed to accrue through this COG protocol. To account for attrition, enrollment 
through this COG trial may proceed up to 109 patients. 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska Native 
 
 
 
 
 
Asian 
2 
3 
 
 
5 
Native Hawaiian or Other Pacific Islander 
1 
2 
 
 
3 
Black or African American 
2 
2 
 
 
4 
White 
30 
37 
8 
11 
86 
More Than One Race 
 
 
 
 
 
Total 
35 
44 
8 
11 
98 
 
INTERNATIONAL (INCLUDING CANADA) PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska Native 
 
 
 
 
 
Asian 
 
1 
 
 
1 
Native Hawaiian or Other Pacific Islander 
 
 
 
 
 
Black or African American 
 
1 
 
 
1 
White 
3 
4 
1 
1 
9 
More Than One Race 
 
 
 
 
 
Total 
3 
6 
1 
1 
11 
 
This distribution was derived from the R01 application, adjusted for Children’s Oncology 
Group projections. 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Parameters to be Measured 
 
10.1.1. Parameters to be Measured PRIOR to Enrollment 
There is an eligibility screening to see if the patient meets the inclusion/exclusion 
criteria and then the patient will be enrolled and randomized. It is possible to have 
all three happen at the same visit, but they would need to occur in that order 
(eligibility screening, enrollment then randomization). At the eligibility screening 
visit, a history and physical, CBC, and comprehensive chemistry panel will be 
performed. An echocardiogram will also be performed at that time. Additional 
blood will be collected and placed on hold during the screening visit to measure 
circulating biomarkers and for genotyping at a later date after study enrollment. 
 
10.1.2 Specifications by Methods of Measurements 
The same method and laboratory will be used to characterize each identified and 
reported biological endpoint at baseline and during follow-up. 
 
10.1.3 Parameters to be Measured during Treatment  
All evaluations will be measured per the study calendar schedule using the 
echocardiography and assay methodology outlined in Section 10.2. Analysis of 
results is fully described in Section 9.3. 
 
The following are biologic response endpoints: 
1. Echocardiographic indices of myocardial remodeling and HF risk: LV T-D, 
ESWS, MPI, LVEDD, IVRT, E/A ratio, LVESD, WMSI. 
2. Blood biomarkers of myocardial remodeling and HF risk: Cardiac Troponin 
I (cTNI), NT proBrain Natriuretic Peptide (NT-proBNP), Blood Natriuretic 
peptide (BNP), and Galectin-3. 
 
The following endpoints are measures of safety and tolerability: 
1. Complete Blood Count 
 
2. Comprehensive Metabolic Panel 
3. Electrocardiogram 
4. Symptom logs 
 
10.2 
Endpoints: Echocardiography 
Echocardiograms will be performed at each institution on the day of the eligibility 
screening, and every 6 months thereafter until study completion on Day 730. Studies will 
include 2-dimensional loops recorded as 2 beat digital video clips, M-mode measurements 
as well as spectral Doppler imaging per the AHA/ACC task force practice guidelines for 
the clinical application of echocardiography.133 Refer to the ECHO Protocol posted on the 
study web page on the COG website for detailed instructions. All echocardiograms should 
have a clinical reading by the institutional study cardiologist, to ensure that there are no 
clinically significant decreases in cardiac function (resting EF < 50%, FS < 25%) or a 20% 
drop from an earlier test. Digital copies will be sent for central review at Boston Children’s 
Hospital. 
 
10.2.1 Digital Echocardiographic Imaging Handling and Transfer 
Digital films will be transported from each participating site to the central 
coordinating center at City of Hope using standard DICOM format. Serial 

 
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echocardiograms for each patient will be performed at the same facility using the 
same machine whenever possible. Digital echocardiographic files will be 
submitted as a DICOM format electronic file on CD-ROM to the address below. 
The CD-ROM will be labeled with the subject’s name, COG patient ID number, 
site, and the date of preparation of the CD-ROM. A Cardiac Imaging Submission 
Form will be submitted along with the CD-ROM. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Institutions should de-identify the echo films prior to shipping. If that’s not 
possible, then after the CD-ROM arrives, study staff will remove any electronically 
embedded patient identifiers and procedure dates from the header of each image 
file using a program called ShowCase.  
 
Film IDs will be assigned to each echocardiographic image, consisting of the 
participant ID plus the letter “A”, “B”, “C”, “D” or “E” in random order with 
respect to timing. The procedure date for each echocardiogram will be tracked in 
a database that documents which letter was assigned. Anonymized films will be 
sent via CDROM for central review at Boston Children’s Hospital.  
 
10.3 
Endpoints: Blood Biomarkers 
 
10.3.1 Blood Collection and Processing 
Peripheral blood will be sampled at the eligibility screening and every six months 
while on treatment. 
 
Whole blood will be drawn into: 
 one 6-mL lithium heparin-containing green top, and 
 two EDTA-containing lavender-top (one 4-mL and one 6-mL) vacutainer 
tubes. 
 
All tubes should be gently inverted 8-10 times after being drawn. All tubes will 
require processing at the site and should be transported immediately after blood 
draw to the specimen processing center. An overview of specimen processing and 
handling is provided below. 
 

 
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10.3.2 Handling the Green-Top Tube 
The 6 mL green-top tube should be inverted 8-10 times to gently mix the blood 
in lithium heparin and immediately transported to the CLIA-approved chemistry 
laboratory at the local site for determination of creatinine, and liver function 
(bilirubin, AST/ALT) per institutional protocols. Results will be recorded on the 
Site Lab Values Form and digitally submitted through a secure study website based 
at City of Hope. 
 
10.3.3 Processing and Handling the Lavender-Top Tubes 
The 4 mL lavender-top tube should be inverted 8-10 times to gently mix the 
blood in EDTA and immediately transported to the CLIA-approved hematology 
laboratory at the local site for determination of a complete blood count (CBC) per 
standard protocol. Results will be recorded on the Site Lab Values Form and 
digitally submitted through a secure website based at City of Hope. 
 
The 6 mL lavender-top tube should be inverted 8-10 times to gently mix the 
blood in EDTA. Plasma samples will be prepared by spinning the tube in a 
balanced centrifuge at 1200 x g for 10 min. Plasma is aliquoted into up to 5 study-
labeled cryovials with 0.5 mL in the first aliquot, 0.7 mL in the second, 0.2 mL in 
the third, 0.2 mL in the fourth, and any remaining plasma (up to 1 mL) in the fifth 
aliquot. All aliquots will be placed in a -20°C freezer within 2 hours of collection 
time. All aliquots will be labeled with COG Patient ID number, date of blood draw, 
blood draw tube (“EDTA”), and plasma aliquot number (1-5) using permanent 
marker or a laser printer on cryo-labels.  
 
At the eligibility screening only: the 6 mL EDTA tube with remaining contents 
(after removal of plasma) will also be labeled with COG Patient ID and date of 
blood draw and stored in a -20°C freezer until shipment. All plasma aliquots and 
the EDTA tube will be shipped on dry ice to the address below, accompanied by a 
study-specific Specimen Submission Form. If not shipped on the day of collection, 
blood can be stored in a -20°C freezer until shipment. Specimens may also be 
batched for convenience. Blood should be shipped overnight to City of Hope 
Monday through Thursday only (no holiday shipments). 
 
to receive a 
FedEx label for the shipment. Do NOT use the COG FedEx account. 
 
Ship to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
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10.3.4 Specimen Disposition after Receipt at City of Hope. 
 
Tube # 
Volume 
Tests 
Tube type 
Storage 
City of Hope ships to: 
1 
0.5 
B-type natriuretic peptide 
(BNP) 
4 mL white-
top transport 
tube 
-20oC 
(until shipping) 
External Lab 
2 
0.7 
Cardiac Troponin I (cTNI) 
and proBrain Natriuretic 
Peptide (NT-ProBNP) 
4 mL white-
top transport 
tube 
-20oC 
 
Assayed at City of Hope 
(RAMP tests) 
3 
0.2 
Galectin-3 
1.7 mL 
O-ring tube 
-80oC 
External Lab 
4 
0.2 
Storage (in case of 
shipping or testing failure) 
1.7 mL 
O-ring tube 
-80oC 
Stored at City of Hope 
5 
Remaining 
volume 
Storage (in case of 
shipping or testing failure) 
4 mL white-
top transport 
tube 
-80oC 
Stored at City of Hope 
Blood remaining in the EDTA tube will be stored at -80oC upon arrival and will be used to extract DNA for 
pharmacogenetics studies 
 
10.3.5 Storage of Blood Samples 
All plasma aliquots and the extracted DNA (if applicable) will be transferred to 
City of Hope Outcomes Research Laboratory, where they will be entered into a 
specimen tracking database and stored at -80°C until assays are performed. 
 
10.3.6 Cardiac Blood Biomarkers 
A description of blood biomarkers can be found in Section 2.4.1. The following 
blood biomarkers will be measured: 
1. Cardiac troponin (cTnI) 
2. B-type natriuretic peptide (BNP)  
3. NT proBrain Natriuretic Peptide (NT-proBNP)  
4. Galectin-3  
 
10.4 
Pharmacogenetics Measures 
The remaining blood from the 6 mL lavender-top tube will be processed for DNA to allow 
for analyses of SNPs including the β 1-Adr. receptor, β 2-Adr. receptor, α2c-Adr. receptor 
and NE transporter gene polymorphisms outlined in Section 2.5.  
 
10.5 
Specimen Storage 
Unused biological materials will only be stored for the purposes specifically outlined in 
this protocol. Once the study is complete, all unused specimens will be destroyed.  
 
10.6 
Other Study Procedures 
 
10.6.1 Measurement of Blood Pressure, Heart Rate, Body Weight and Height 
Blood pressure, heart rate, body height and weight will be measured prior to 
enrollment, as well as at each subsequent clinic visit whenever possible. The same 
method should be used to measure blood pressure throughout the study. All 
measurements should be made on the same extremity using appropriate cuff size 
and equipment. Diastolic blood pressure will be measured at the disappearance of 

 
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Kortkoff sounds – Phase V. If possible, measurements will be taken by the same 
staff member at each visit. 
 
Sitting/supine blood pressure and heart rate should be measured after the subject 
has been sitting quietly for at least 5 minutes. Body height and weight should be 
measured without shoes, using the same equipment at each visit whenever 
possible. 
 
10.6.2 Electrocardiogram (ECG) 
A 12-lead ECG will be performed during the eligibility screening, prior to each 
dose escalation (Day 14 and Day 42). A sample of each ECG will be clearly labeled 
with COG patient ID number, protocol number and date recorded. Any clinically 
significant ECG findings present at the eligibility screening that would result in 
exclusion from study (i.e. sustained or symptomatic ventricular dysrhythmias 
uncontrolled with drug therapy or implantable device, significant conduction 
defects: second or third degree atrio-ventricular block or sick sinus syndrome) will 
be recorded in the Eligibility Screening Worksheet. Any subsequent clinically 
significant ECG changes occurring after the start of study medication should be 
documented as an adverse event. 
 
10.7 
Questionnaire Data 
Self-reported and CRA/CRN administered questionnaires will be used to obtain baseline 
data on demographics, family history, and other CV risk factors, as well as to assess patient 
reported symptoms during the course of the study. All these questionnaires will be designed 
as scannable forms, using the Teleform software, such that the data entry is efficient and 
accurate and exported into an electronic database effortlessly. 
 
Patient demographics, family history and baseline CV risk factors: 
Standardized questionnaires will be used to obtain the following prior to study entry (see 
study web page): 
 
Demographics and Medical History Form 
 
Family History Form 
 
The salient domains captured by these questionnaires include date of birth, gender, 
race/ethnicity, socioeconomic status, and both familial and environmental CV risk factors. 
These questionnaires will be administered at the time of initial enrollment. 
 
Clinical Data Regarding Prior Cancer Diagnosis and Treatment: 
The following information will be obtained from medical records using a standardized data 
abstraction form (the Cancer Treatment History Form): date of diagnosis, stage of disease 
(if applicable), data elements regarding chemotherapy including dates, protocols/regimens, 
cumulative doses of therapeutic agents per square meter; and data regarding radiation 
therapy including dates, total lifetime dose, field, fractions, dose per fraction. Institutional 
radiation oncology summary report will be obtained whenever possible. 
 
Patient Reported Symptoms and Adherence to the Intervention Agent: 
Health related quality of life will be assessed at baseline and every 6 months during the 
two-year treatment period (Quality of Life Form and Cardiac Health Questionnaire). The 
health subscales of the Medical Outcomes Study 36-item Short Form Health Survey (SF-
36) is a component of the Quality of Life questionnaire and will be administered to all 
study participants to assess general and physical health as well as vitality. The 

 
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questionnaire has been used in various English-speaking populations ranging from 13 to 
74 years of age, representing a wide spectrum of health states (well to seriously ill). The 
questionnaire has consistently shown strong evidence of internal consistency, stability, 
convergent and discriminant validity and has been successfully administered in a similar 
population of childhood cancer survivors evaluated for asymptomatic cardiac dysfunction 
following anthracycline therapy.38,134 Anticipated time to complete HRQL questionnaires 
is 10 minutes. 
 
Pill counts will be performed to determine adherence to the prescribed intervention using 
the Adherence Tracking Form. Patient compliance will be assessed by recording the 
amount of the study drug remaining in returned bottles. Patients will be considered non-
compliant if they received < 80% or > 120% of the cumulative prescribed dose for two 
consecutive periods. Similar cutoffs have been used to determine compliance to study 
medication in pediatric oncology62,63 and non-oncology55 randomized cardiac intervention 
studies. If a patient is found to be < 50% compliant during any 90 day period, they will be 
removed from the protocol therapy due to non-compliance. Patients should make every 
attempt to complete the protocol as specified. Investigators should encourage patients to 
comply with the protocol and return for all scheduled visits.  
 
Pill counts will occur on Days 14, 42, 90, 180, 270, 365, 455, 540, 630, and 730 (see 
Section 7.1). On days that coincide with scheduled clinic visits (0, 14, 42, 90, 180, 365, 
540, and 730), pill counts will occur in clinic. For non-clinic time-points (270, 455, 630), 
participants will report pill counts via phone interview. Pill counts for these time points 
will also be verified at the next in-person study visit. 
 
Compliance will be calculated separately for each bottle of blinded study medication as 
follows: 
 
 
 
A Symptom Log will be completed by patient interview on Days 0, 14, 42, 90, 180, 270, 
365, 455, 540, 630, and 730 (see Section 7.1). On days that coincide with scheduled clinic 
visits (0, 14, 42, 90, 180, 365, 540, 730), the symptom log will be administered in clinic. 
During non-clinic time-points (270, 455, 630), assessment will be completed via phone 
interview. 
 
 
11.0 
DATA COLLECTION FORMS AND SUBMISSION SCHEDULE 
Specific patient-administered forms to be used and the timing that they will be submitted are 
outlined in Section 10.7. In addition, the CRA/CRN will be responsible for filling out the following 
forms. (All forms are on the ALTE1621 web page on the COG website.) 
 
11.1 
Eligibility Screening, Registration and Enrollment 
The screening interview and visit will take place prior to study enrollment. Once the patient 
is considered eligible for the study, the CRA/CRN will register and enroll through CTSU 
OPEN (as explained in Section 3.1) and all subsequent data will go directly to the 
coordinating center at City of Hope.  
 
 
# of tablets dispensed – number of tablets returned 
 
# of tablets prescribed per day X # of days since last visit  
X 100 

 
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11.2 
Cardiac Imaging and Specimen Submission Forms 
The CRA/CRN will fill out the Cardiac Imaging Submission Form to accompany 
submission of the baseline and semi-annual screening echocardiograms. Scheduling of 
these imaging tests is outlined in Section 10.2.  
 
11.3 
Cardiac Event Form 
The CRA/CRN will fill out the Cardiac Event Form should a subject have a deterioration 
in cardiac function while on study. Should a cardiac event be confirmed, the subject will 
be withdrawn from protocol therapy as outlined in Section 8.1.  
 
11.4 
Other Event Form 
The CRA/CRN will fill out the Other Event Form should a subject require inpatient or 
outpatient procedure that could be potentially related to protocol while on trial. Only for 
specific events outlined in Section 8.1 will the subject necessitate withdrawal from protocol 
therapy.  
 
11.5 
Treatment Interruptions 
The CRA/CRN will fill out a Treatment Withholding Form should a subject report an 
interruption for any reason while on trial. The patient-reported reason and both hold and 
restart dates will be recorded. If the subject voluntarily chooses to stop protocol therapy, 
then a Study End Form will be used instead. However, if the subject chooses to continue 
on protocol therapy, then the Treatment Withholding Form will be submitted. If a patient 
is off study medication for more than 90 consecutive days, then they will go off protocol 
therapy. In that case, the CRA/CRN will submit both Treatment Withholding and Study 
End Forms. 
 
11.6 
Study End Form 
The CRA/CRN will fill out the Study End Form at the time the subject goes off protocol 
therapy, even if they complete the full treatment course. This form records whether or not 
the subject completed the trial per protocol, voluntarily withdrew, or was withdrawn for 
another reason. For voluntary withdrawals, subjects will be asked to clarify if it was due to 
intolerable side effects of treatment or if it was due to another reason. 
 
 
12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE 
v5.0 as referenced on the CTEP website (i.e., v5.02 and all subsequent iterations prior to 
version 6.0). 
 
 

 
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13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
13.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  
 
13.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of 
the adverse event including the grade (severity); 2) the relationship to the study therapy 
(attribution); and 3) the prior experience (expectedness) of the adverse event. 
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. In some cases an agent obtained commercially may be used for 
indications not included in the package label. In addition, NCI may on some occasions 
distribute commercial supplies for a trial. Even in these cases, the agent is still considered 
to be a commercial agent and the procedures described below should be followed. 
 
Determine the prior experience Expected events are those that have been previously 
identified as resulting from administration of the agent. An adverse event is considered 
unexpected, for reporting purposes only, when either the type of event or the severity of 
the event is not listed in:  
 
 
the current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group 
posted on the COG website; or 
 
the drug package insert. 
 
13.2.1 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via 
CTEP-AERS. Three options are available to describe the event:  
 
Leukemia secondary to oncology chemotherapy 
 
Myelodysplastic syndrome  
 
Treatment related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol.  
 
13.2.2 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 

 
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13.3 
Reporting of Adverse Events for Commercial Agents - via CTEP-AERS 
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited Reporting 
System), accessed via https://eapps-ctep.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B. The commercial agent(s) used 
in this study are listed in the front of this protocol immediately following the Study 
Committee roster. 
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event. 
 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy with a Commercial Agent or Within 30 Days1 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, Definite CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial agent, 
regardless of attribution. Any death that occurs more than 30 days after the last dose of 
treatment with a commercial agent that can be attributed (possibly, probably, or definitely) to 
the agent and is not due to cancer recurrence must be reported via CTEP-AERS. 
 
13.4 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on the 
City of Hope case report forms and do not affect the requirements for CTEP-AERS reporting.  
 
Routine reporting is accomplished via the Adverse Event (AE) Form. For this study, 
routine reporting will include all toxicities reported via CTEP-AERS and all Grade ≥ 2 
AEs that can be attributed probably or definitely to the study drug in either study arm. 
 
For all Grade ≥ 3 toxicities that can be attributed probably or definitely to the study 
drug in either study arm, the patient will be unblinded and taken off protocol therapy. 
(See Section 5.0 for emergency unblinding.) 
 
A City of Hope Adverse Event (AE) collection form will be submitted by study personnel 
on Days 180, 365, 540, and 730. 
 

 
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13.5 
Syndrome Reporting 
Unless otherwise specified in this protocol, syndromes should be reported as a single event 
using the CTCAE term for the composite syndrome, and not as the individual events that 
make up the syndrome. For example, Tumor Lysis Syndrome should be reported under the 
composite definition rather than reporting the component events (hyperkalemia, 
hyperphosphatemia, hypocalcemia, hyperuricemia) separately. 
 
 
14.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data Collection 
Documents”. A submission schedule is included. 
 
14.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
14.2 
Data Safety and Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released 
 
 
 

 
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125. Little RJA: Modeling the drop-out mechanism in repeated-measures studies. Jour Am Stat Assoc 
90:1112-1121, 1995 
126. Breslow NE, Clayton DG: Approximate inference in generalized linear mixed models. Journal of the 
American Statistical Association 88:9-25, 1993 
127. Armenian SH, Gelehrter SK, Vase T, et al: Screening for cardiac dysfunction in anthracycline-exposed 
childhood cancer survivors. Clin Cancer Res, 2014 
128. Asselin BL, Devidas M, Zhou T, et al: Cardioprotection and safety of dexrazoxane (DRZ) in children 
treated for newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or advanced stage 
lymphoblastic leukemia (T-LL). J Clin Oncol:abstr 9504, 2012 
129. Hedeker D, Gibbons RD, Waternaux C: Sample size estimation for longitudinal designs with attrition: 
comparing time-related contrasts between two groups. . Journal of Educational and Behavioral 
Statistics 24:70-93, 1999 
130. Dunlay SM, Roger VL, Weston SA, et al: Longitudinal changes in ejection fraction in heart failure 
patients with preserved and reduced ejection fraction. Circ Heart Fail 5:720-6, 2012 
131. Kramer DG, Trikalinos TA, Kent DM, et al: Quantitative evaluation of drug or device effects on 
ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure 
and reduced ejection fraction: a meta-analytic approach. J Am Coll Cardiol 56:392-406, 2010 
132. Konstam MA, Kramer DG, Patel AR, et al: Left ventricular remodeling in heart failure: current 
concepts in clinical significance and assessment. JACC Cardiovasc Imaging 4:98-108, 2011 
133. Cheitlin MD, Armstrong WF, Aurigemma GP, et al: ACC/AHA/ASE 2003 guideline update for the 
clinical application of echocardiography--summary article: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE 
Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am 
Coll Cardiol 42:954-70, 2003 
134. Cox CL, Rai SN, Rosenthal D, et al: Subclinical late cardiac toxicity in childhood cancer survivors: 
impact on self-reported health. Cancer 112:1835-44, 2008 
 
 

 
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APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
 IVR — MD, DO, or international equivalent; 
 NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD); 
 AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such as 
the Roster Update Management System (RUMS), OPEN, Rave, acting as a primary site contact, 
or with consenting privileges; 
 Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
 Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs 
must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
 
Addition to a site roster; 
 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at https://ctep.cancer.gov/
investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov.. 

 
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Protocol Specific Requirements for Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
  
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status 
 
Site registration status may be verified on the CTSU members’ website.  
 
 
Log on to the CTSU members’ website; 
 
Click on Regulatory  at the top of the screen; 
 
Click on Site Registration;  
 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
 
 

 
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APPENDIX II: INTERIM MONITORING 
ACTIVATION PROTOCOL: 
Plans for Interim Monitoring for Toxicity 
Table s1: One-sided interim stopping boundaries for interaction test for treatment effect, concluding 
carvedilol superiority if the conditions are met. 
Superiority Bounds (O’Brien-Fleming boundaries) 
Analysis 
After N  
completes study 
Reject H0 if test statistic  
greater than O-F bound 
Reject H0 if test statistic p 
is less than nominal alpha 
Interim #1 
83 
3.7103 
0.0001 
Interim #2 
166 
2.5114 
0.0060 
Final 
250 
1.9930 
0.0231 
 
In addition to efficacy assessment, two blinded interim analyses will be performed to evaluate futility 
- after approximately 33% and 66% of patients have been accrued and evaluated. Our futility boundaries 
are calculated by using the Lan-DeMets spending approach applied to the O’Brien-Fleming boundaries 
as applied to beta. If the test statistic does not fall within the O’Brien-Fleming boundaries as specified in 
Table below, the DSMC will continue to randomize subjects. However, if the test statistic falls outside 
of the O’Brien-Fleming boundaries at an interim analysis, the DSMC will discuss whether the patients 
are receiving no benefit from carvedilol and consider discontinuing randomization. The O’Brien-
Fleming boundaries in the table below are considered “non-binding”, meaning that the DSMC has the 
option, but not the obligation, of halting the study if the futility boundaries are crossed. 
 
Table s2: One-sided interim stopping boundaries for interaction test for treatment effect, concluding 
that the carvedilol arm shows no improvement over the placebo arm. 
Futility Bounds (O’Brien-Fleming boundaries) 
Analysis 
After N completes 
study 
Reject H1 if test statistic  
less than O-F bound 
Reject H1 if test statistic p  
is greater than nominal alpha 
Interim #1 
83 
-0.2361 
0.5933 
Interim #2 
166 
1.1704 
0.1209 
Final 
250 
1.9930 
0.0231 
 
In both of the interim analyses and the final analysis, the intent-to-treat data set will be the primary 
analysis group. In the interim analyses, the data will be analyzed with consideration of missing data. In 
each interim analysis, we will examine the effects of both pattern mixture models and selection models to 
assess the validity of the main GEE model estimates and particularly the treatment effect. To stop the 
trial, it will not be sufficient merely to show a treatment effect in the main GEE model. We will also look 
for supporting evidence such as a corresponding robustness of effect in the unstructured mean model, 
the pattern mixture models and the selection models. 
 
WITH AMENDMENT #4 
Table s3: One-sided interim stopping boundaries for interaction test for treatment effect, concluding 
that the carvedilol arm shows no improvement over the placebo arm. 
Futility Bounds (O’Brien-Fleming boundaries) 
Analysis 
After N 
completes study 
Reject H1 if test statistic less 
than O-F bound 
Reject H1 if test statistic p 
is greater than nominal 
l h
Interim #1 
87 
1.502 
0.067 
Final 
114 
1.960 
0.025 

 
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In the interim analyses and the final analysis, the intent-to-treat data set will be the primary analysis 
group. In the interim analysis, the data will be analyzed with consideration of missing data. To stop the 
trial, it will not be sufficient merely to show a treatment effect in the main GEE model. We will also look 
for supporting evidence such as a corresponding robustness of effect in the unstructured mean model. 
 
 
 

 
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APPENDIX III: YOUTH INFORMATION SHEET 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ALTE1621 
(for teens from 14 to 17 years of age) 
A Study of Medication and Heart Health in People Who Had Cancer Treatment in Childhood 
 
1. We have been talking with you about the side effects of cancer treatment with drugs that contain 
anthracycline such as Doxorubicin, Daunorubicin, Idarubicin, Mitoxantrone, or Epirubicin. One of 
these side effects is weakening of the heart. 
 
2. We are asking you to take part in a research study because you received anthracycline treatment as a 
child. This study will look to see if taking the medication carvedilol has any effect on weakening of the 
heart. The study will also try to learn more about the safety and side effects of carvedilol. 
 
3. Teens that are part of this study will be given pills to take each day for about two years. The pills may 
be carvedilol (real medication) or placebo (fake medication). This study is called a randomized study, 
because you will be randomly assigned to get carvedilol or placebo. This is like flipping a coin and 
saying, “Heads means I get carvedilol, and tails means I get placebo,” except that a computer decides 
which you will take. Neither you nor your doctor makes this decision or knows which type of pills you 
are given. 
 
4. Teens that are part of this study will have some study tests that would be part of regular care and other 
tests that require additional visits to the doctor. There will be two different tests to check how well your 
heart is functioning throughout the study: an echocardiogram (that uses sound waves to create a visual 
picture of the heart) and an electrocardiogram (that shows the patterns of the heart as it beats). Every 
six months throughout the study, we will ask questions about your background, past medical history 
and how you are feeling, emotionally and physically. This should take about 10 minutes to complete 
each time. 
 
5. As part of this study, you will have some blood taken (about 3 teaspoonfuls) before taking the study 
drug and every six months for a total of 5 times. The purpose of the blood draw is to look at blood cell 
counts, chemistry tests and cardiac biomarkers (chemicals in the body associated with how the heart is 
working). During the first blood draw, we will save some leftover blood to look at how your DNA 
(genetic material in your body) responds to the study drug. 
 
6. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that if you are assigned to 
get carvedilol treatment it may prevent further damage to your heart from your past anthracycline 
chemotherapy. If you are assigned to placebo treatment, you are not expected to benefit. We expect the 
information learned from this study will help other patients in the future, but we don’t know for sure if 
there is any benefit to you of being part of this study. 
 
7. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” There is a risk that you will have bad effects from carvedilol or even the placebo. The 
more common side effects from carvedilol include dizziness and tiredness. For the blood draws, you 
may have pain, bruising, or infection at the site of the needle stick for blood draws. Another risk is 
worry or concern answering study questions. Other things may happen to you that we don’t yet know 
about. 
 

 
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8. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments that your doctor can tell you about. 
Make sure to ask your doctors any questions that you have.