A Pilot Study of Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab
Phase: PHASE1
Conditions: Cardiotoxicity, Risk Factor, Cardiovascular, Toxicity Due to Chemotherapy, Breast Cancer, Cardiomyopathies, Heart Failure
Sponsor: Abramson Cancer Center at Penn Medicine

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A PILOT STUDY OF RISK-GUIDED CARDIOPROTECTION 
WITH 
CARVEDILOL 
IN 
BREAST 
CANCER 
PATIENTS 
TREATED WITH DOXORUBICIN AND/OR TRASTUZUMAB 
 
 
 
 
 
Principal Investigator 
Bonnie Ky, MD, MSCE 
Department of Medicine, Cardiovascular Division 
3400 Civic Center Blvd, 11-105 SCTR 
215-573-6606 
bonnie.ky@uphs.upenn.edu 
Investigational Product: 
 
Individually dosed Carvedilol (3.125mg - 25mg, twice daily) 
IRB Number: 
 
 
UPCC Number: 
832105 
 
 
12118 
IND/ IDE Number: 
 
Exempt per OCR (11/30/2018) 
 
 
 
ClinicalTrials.gov Number       
 
 
 
 NCT04023110 
 
Initial version 
v1 11/10/18 
Amended 
v2 12/11/18  
     (response to stipulations from OCR IND group and IRB) 
Amended 
v3 01/23/19 
(increase target enrollment, update Risk Score) 
Amended 
v4 09/10/19  
(research echocardiogram at baseline) 
Amended 
v5 09/11/2020 
(change to block randomization, identify targeted AEs) 
Amended 
v6 10/01/2021 
(eligibility, AE attribution, SDOH) 
 
 
 

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Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS.....................................................................................................................V 
STUDY SUMMARY ................................................................................................................................. 6 
BACKGROUND AND STUDY RATIONALE ............................................................................................ 8 
INTRODUCTION ...................................................................................................................................... 8 
1.1 
BACKGROUND AND RELEVANT LITERATURE ................................................................................. 8 
1.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ........................................................ 9 
1.2.1 
Nonclinical Data ................................................................................................................ 10 
1.3 
DOSE RATIONALE ................................................................................................................... 13 
2 
STUDY OBJECTIVES .................................................................................................................. 13 
2.1 
PRIMARY OBJECTIVE ............................................................................................................... 13 
2.2 
SECONDARY OBJECTIVES ........................................................................................................ 14 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 14 
3.1 
GENERAL DESIGN ................................................................................................................... 14 
3.1.1 
Screening, Risk Calculation, and Randomization .............................................................. 14 
3.1.2 
Study Intervention Phase .................................................................................................. 15 
3.1.3 
Follow Up Phase .............................................................................................................. 15 
3.1.4 
Allocation to Interventional Group ..................................................................................... 15 
3.2 
STUDY ENDPOINTS.................................................................................................................. 16 
3.2.1 
Primary Study Endpoints................................................................................................... 16 
3.2.2 
Secondary Study Endpoints .............................................................................................. 16 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION .................................................... 16 
4.1 
INCLUSION CRITERIA ............................................................................................................... 16 
4.2 
EXCLUSION CRITERIA .............................................................................................................. 16 
4.3 
SUBJECT RECRUITMENT .......................................................................................................... 17 
4.4 
DURATION OF STUDY PARTICIPATION ........................................................................................ 17 
4.5 
TOTAL NUMBER OF SUBJECTS .................................................................................................. 17 
4.6 
VULNERABLE POPULATIONS: .................................................................................................... 18 
5 
STUDY INTERVENTION ............................................................................................................... 18 
5.1 
DESCRIPTION ......................................................................................................................... 18 
5.2 
INTERVENTION REGIMEN .......................................................................................................... 18 
5.3 
RECEIPT ................................................................................................................................ 18 
5.4 
STORAGE ............................................................................................................................... 18 
5.5 
PREPARATION AND PACKAGING ................................................................................................ 18 
5.6 
ADMINISTRATION AND ACCOUNTABILITY ..................................................................................... 18 
5.7 
SUBJECT COMPLIANCE MONITORING ......................................................................................... 18 
5.7.1 
Return or Destruction of Investigational Product ................................................................ 19 
6 
STUDY PROCEDURES ................................................................................................................ 19 
6.1 
SCREENING, CALCULATION OF CTX RISK SCORE, AND RANDOMIZATION ....................................... 21 
6.2 
STUDY INTERVENTION PHASE ................................................................................................... 22 
6.2.1 
Baseline Visit .................................................................................................................... 22 
6.2.2 
First Titration Visit (Week 1 or 2) - Elevated Risk Subjects Randomized to Carvedilol only 22 
6.2.3 
Second Titration Visit (Week 3 or 4) - Elevated Risk Subjects Randomized to Carvedilol only
 
22 
6.2.4 
Third Titration Visit (Week 6) – Elevated Risk Subjects Randomized to Carvedilol only ..... 23 
6.2.5 
Unscheduled Titration Visit ............................................................................................... 23 
6.2.6 
Study Visit (On Intervention) ............................................................................................. 23 
6.3 
FOLLOW UP PHASE OF THE STUDY ........................................................................................... 24 
6.3.1 
Off-Intervention Follow-up - Elevated Risk Subjects Randomized to Carvedilol Only ......... 24 

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6.3.2 
Study Visit (Off Intervention) ............................................................................................. 24 
6.4 
SUBJECT WITHDRAWAL ........................................................................................................... 24 
6.4.1 
Data Collection and Follow-up for Withdrawn Subjects ...................................................... 24 
7 
STUDY EVALUATIONS AND MEASUREMENTS ......................................................................... 25 
7.1 
CLINICAL COVARIATES ............................................................................................................. 25 
7.2 
VITAL SIGNS ........................................................................................................................... 25 
7.3 
LABORATORY EVALUATIONS ..................................................................................................... 25 
7.4 
PREGNANCY TESTING .............................................................................................................. 25 
7.5 
OTHER EVALUATIONS, MEASURES ............................................................................................ 26 
7.5.1 
TRANSTHORACIC ECHOCARDIOGRAM: ....................................................................................... 26 
7.5.2 
LVEF FOR CALCULATION OF RISK SCORE ................................................................................. 26 
7.5.3 
ELECTROCARDIOGRAM ............................................................................................................ 27 
7.5.4 
SYMPTOMS AND ACTIVITY QUESTIONNAIRES .............................................................................. 27 
7.5.5 
SDOH MEASURES .................................................................................................................. 27 
7.5.5.1 
INDIVIDUAL SDOH .............................................................................................................. 27 
7.5.5.2 
STRUCTURAL SDOH ........................................................................................................... 28 
7.5.6 
DRUG DIARY, COMPLIANCE, AND PILL COUNT – ELEVATED RISK SUBJECTS RANDOMIZED TO 
CARVEDILOL ONLY ............................................................................................................................... 29 
8 
STATISTICAL PLAN .................................................................................................................... 29 
8.1 
PRIMARY ENDPOINT ................................................................................................................ 29 
8.2 
SECONDARY ENDPOINTS ......................................................................................................... 29 
8.3 
SAMPLE SIZE AND POWER DETERMINATION ............................................................................... 30 
8.4 
STATISTICAL METHODS............................................................................................................ 30 
8.4.1 
Safety Analysis ................................................................................................................. 31 
8.5 
SUBJECT POPULATION(S) FOR ANALYSIS ................................................................................... 31 
9 
SAFETY AND ADVERSE EVENTS .............................................................................................. 31 
9.1 
DEFINITIONS ........................................................................................................................... 31 
9.1.1 
Adverse Event .................................................................................................................. 31 
9.1.2 
Serious Adverse Event ..................................................................................................... 31 
9.2 
RECORDING OF ADVERSE EVENTS ............................................................................................ 32 
9.3 
RELATIONSHIP OF AE TO STUDY AND EXPECTEDNESS ................................................................ 33 
9.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................. 33 
9.4.1 
FOLLOW-UP REPORT ............................................................................................................... 34 
9.4.2 
INVESTIGATOR REPORTING TO PENN ENTITIES ........................................................................... 34 
9.4.3 
INVESTIGATOR REPORTING TO THE FDA.................................................................................... 34 
9.5 
MEDICAL MONITORING............................................................................................................. 35 
9.5.1 
DATA AND SAFETY MONITORING PLAN ...................................................................................... 35 
10 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................. 35 
10.1 
CONFIDENTIALITY .................................................................................................................... 35 
10.2 
DATA COLLECTION AND MANAGEMENT ...................................................................................... 35 
10.3 
RECORDS RETENTION ............................................................................................................. 35 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 36 
11.1 
STUDY MONITORING PLAN ....................................................................................................... 36 
11.2 
AUDITING AND INSPECTING....................................................................................................... 36 
12 
ETHICAL CONSIDERATIONS ...................................................................................................... 36 
12.1 
RISKS .................................................................................................................................... 36 
12.1.1 
Risks of Carvedilol ........................................................................................................ 36 
12.2 
BENEFITS ............................................................................................................................... 40 
12.3 
RISK BENEFIT ASSESSMENT ..................................................................................................... 41 
12.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ........................................................... 41 
13 
STUDY FINANCES ....................................................................................................................... 41 
13.1 
FUNDING SOURCE ................................................................................................................... 41 

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13.2 
CONFLICT OF INTEREST ........................................................................................................... 41 
13.3 
SUBJECT STIPENDS OR PAYMENTS ........................................................................................... 41 
14 
PUBLICATION PLAN ................................................................................................................... 41 
15 
ATTACHMENTS ........................................................................................................................... 42 
16 
REFERENCES ............................................................................................................................. 42 
 
 
 
 
 
 
 

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List of Abbreviations 
 
 
 
AE: Adverse event 
CCT: Cardiotoxicity of Cancer Therapy Cohort (IRB #811155 / UPCC 09110, Ky PI) 
CTX: cardiotoxicity 
CV: Cardiovascular 
HF: Heart Failure 
HR: Heart Rate 
IDS: Penn Investigational Drug Service 
LVEF: Left ventricular ejection fraction 
TTE: Transthoracic Echocardiogram (Echo) 
TNBC: Triple negative breast cancer 
SBP: Systolic Blood Pressure 
 
 
 
 
 
 
 
 

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Study Summary 
Title 
A Pilot Study of Risk-Guided Cardioprotection with Carvedilol In Breast Cancer 
Patients Treated with Doxorubicin and/or Trastuzumab 
 
Short Title 
CCT-Guide Pilot 
IRB# / UPCC# 
832105 / 12118 
Phase 
Phase I 
Methodology 
Randomized, Open Label 
Study Duration 
3.5 years 
Study Center 
University of Pennsylvania Health System  
Objectives 
We will determine the feasibility and safety of a risk-guided cardioprotective 
treatment strategy with carvedilol, as compared to usual care, in breast cancer 
patients undergoing treatment with doxorubicin, trastuzumab (or trastuzumab-
anns), or the combination. 
Number of Subjects 
We plan to enroll up to 110 patients for a target of 56 elevated risk patients 
Main Inclusion and 
Exclusion Criteria 
Inclusion Criteria: 
• 
Women ≥18 years old 
• 
Diagnosed with Stage I-III breast cancer and scheduled for treatment 
with doxorubicin and/or trastuzumab (or trastuzumab-anns) in the 
adjuvant or neo-adjuvant setting 
Exclusion Criteria: 
• 
Contraindication to carvedilol 
• 
Current therapy with beta blocker 
• 
Pregnant or breast feeding 
• 
Inability to provide consent 
Investigational 
Product  
 
Carvedilol initiated at 3.125mg twice daily and uptitrated as tolerated in a 
stepwise fashion to a maximum dose of 25mg twice daily or to a SBP of 110-
120mmHg or HR of 50-55 beats per minute (bpm) 
Duration of 
administration 
12 months 

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Reference therapy 
Patients will be stratified according to elevated or low CV risk, based upon a 
validated CV risk prediction score.  Subjects in the elevated risk group will be 
randomized to open label, individually dosed carvedilol for 1 year vs usual care.  
Subjects in the low risk group will be assigned to usual care and followed 
prospectively (no prospective cardiovascular intervention).  
Statistical 
Methodology 
We will summarize the characteristics of all patients included in the study, 
overall, as well as stratified by study arm, cancer treatment, and baseline CV 
risk.  An intent-to-treat approach will be used in all analyses.  The primary 
analysis will examine the feasibility of the trial and the safety and tolerability of 
carvedilol. 
Safety Evaluations  
We will assess for adverse events using the CTCAE version 5.0; we will 
specifically 
evaluate 
for 
symptomatic 
hypotension 
(SBP<90mmHg), 
bradycardia (HR<50 bpm), and fatigue at all visits.  
Data and Safety 
Monitoring Plan  
The PI will be responsible for monitoring the data quality and the ongoing safety 
of subjects.  The study will also be subject to monitoring by the Abramson 
Cancer Center Data Safety and Monitoring Committee. 
 
 
 

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BACKGROUND AND STUDY RATIONALE 
 
This study will be conducted in full accordance all applicable University of Pennsylvania Research Policies 
and Procedures and all applicable Federal and state laws and regulations. All episodes of noncompliance 
will be documented. 
 
Introduction 
1.1 
Background and Relevant Literature  
Highly effective cancer drugs, such as doxorubicin and trastuzumab (Herceptin®) are used widely and have 
led to critical survival gains. However, these agents carry a significant risk of cardiovascular (CV) morbidity 
and mortality in a growing cancer population of over 14 million individuals worldwide.1 Doxorubicin-induced 
CV dysfunction occurs in approximately 10-15% of patients at 240mg/m2.2 Doxorubicin and trastuzumab in 
combination cause CV dysfunction in approximately 18-34% of individuals, and severe, symptomatic heart 
failure (HF) in 2-4%.3 Moreover, cardiotoxicity (CTX) results in treatment interruptions, and potentially worse 
oncologic outcomes. It is critically important to advance our understanding of CTX risk; this need for robust 
risk stratification has been recognized as a high priority by the NIH, oncology and CV societies 
internationally.3-5 This proposed study responds directly to these needs by defining “risk assessment 
strategies that can best identify subgroups that are most likely to receive the greatest benefit from 
pharmacologic approaches to prevent CTX during treatment.”4  
 
The prophylactic use of cardioprotective pharmacotherapies in all patients undergoing cancer therapy 
results in the unnecessary treatment of low-risk patients, and raises concerns over adherence, adverse 
effects, and patient quality of life/tolerability. As a result, cardioprotective agents are not routinely used in 
cancer patients. Better selection of patients for treatment through risk prediction models would maximize 
benefit and minimize risk. However, risk scores, while widely used in cardiology and oncology,6-11 have not 
yet been applied to cardio-oncology. In this proposed study, we leverage the critical insights gained in R01 
HL118018, focused on understanding individual patient risk and the functional and biologic perturbations 
secondary to cardiotoxic cancer therapy in the Penn Cardiotoxicity of Cancer Therapy (Penn CCT) 
longitudinal cohort study. We have developed and validated a simple, but robust risk score to predict CTX 
using readily obtained and highly accessible patient-level data at baseline. We have comprehensively 
defined the perturbations in CV function using detailed echocardiographic measures (diastolic function 
(E/e’); longitudinal and circumferential strain, ventricular arterial coupling) and CV biomarkers (high 
sensitivity TroponinT; NT-proBNP). Now, in this subsequent study, we propose to test a strategy of risk-
guided cardioprotection. We will apply our risk model to breast cancer patients prior to cancer therapy; 
identify patients with elevated baseline CV risk; and randomize the elevated risk subgroup to prophylactic 
treatment with carvedilol (an established HF therapy that improves clinical outcomes, CV remodeling, and 
patient symptoms) versus usual care.12-22 We will use echocardiographic and biomarker measures to 
determine the changes in CV function. 
 
We are uniquely positioned to successfully execute this research, as one of the few centers in cardio-
oncology in the US and internationally with detailed CV data obtained through the highly unique Penn CCT 
study (R01 HL118018, IRB #811155 / UPCC 09110). We have enrolled, rigorously phenotyped, and defined 
the biologic and functional perturbations in 571 breast cancer patients treated with doxorubicin and/or 
trastuzumab over a maximum follow-up of 7 years.  
 
Our fundamental scientific premise is that there is a critical need to develop personalized strategies to 
identify and treat patients at risk for cancer therapy cardiotoxicity in the modern treatment era. 
Anthracyclines still play an important role in the current treatment of breast cancer, particularly those with 
high risk or triple negative breast cancer (TNBC).23 Here, improvements in disease free survival with 
anthracycline containing regimens has clearly been demonstrated.24 Trastuzumab is a humanized 
monoclonal antibody that disrupts ErbB2 (HER2/neu) signaling and has revolutionized the care of HER2+ 
breast cancer, but can result in clinically significant CTX. In breast cancer alone, over 3 million survivors 
are estimated to be at risk for cardiotoxicity (CTX).27,28 In the long term, breast cancer survivors demonstrate 

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an increase in CV mortality that exceeds oncologic mortality.29 Yet, robust strategies to identify patients 
who will suffer from CTX and who will derive the most benefit from prophylactic cardioprotective strategies 
still are not used in cardio-oncology.30,31 Our ultimate goals are to ensure the safe delivery of necessary 
cancer therapies, by avoiding dose interruptions, delays, or early cessation of potentially life-saving 
treatment. Enhanced risk stratification would enable the early implementation of cardioprotective strategies 
when appropriate; prevent the interruption or cessation of potentially life-saving cancer therapies secondary 
to CTX; improve long-term CV health; and enable the maximum utilization of the most effective cancer 
therapies. 
 
Risk scores have been used extensively in oncology and in cardiology to guide therapy, but not as of yet in 
cardio-oncology. Risk stratification through the identification of a clinical, biologic, or functional phenotype 
forms the basis of much of medical decision making, particularly in oncology and CV medicine. For example, 
the Gail model is a widely used breast cancer risk tool to inform the role of chemoprevention.32 The risk of 
recurrence and choice of chemotherapy treatment are based upon integration of data for each individual 
data.9-11  Decisions to treat with anticoagulation to prevent stroke in atrial fibrillation and to use lipid-lowering 
therapy for the prevention of CV disease are guided by risk prediction algorithms. These strategies are 
used in everyday clinical practice,6,7 but have not yet been applied to cardio-oncology. This paradigm has 
the potential to directly and positively impact both CV and oncologic outcomes, and this proof-of-concept 
trial is a critically important step in determining the utility of risk-guided cardioprotection. 
 
We plan to assess the feasibility and safety of a risk-guided cardioprotective treatment strategy with 
carvedilol, as compared to usual care, in breast cancer patients undergoing treatment with doxorubicin, 
trastuzumab, or the combination (Figure 1).  Patients who will be treated with trastuzumab-anns (Kanjinti), 
which is a biosimilar to trastuzumab, will also be included.  Our overarching hypothesis is that a risk-guided 
treatment strategy that initiates carvedilol in high risk patients prior to cancer therapy will result in a 
decreased incidence of CTX, as compared to usual care. For this pilot study, we propose to evaluate the 
feasibility of such a trial and safety of our intervention.  Carvedilol will be administered in an open label 
fashion and compared to usual care. 
 
 
 
1.2 
Name and Description of the Investigational Product  
 

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Carvedilol (Coreg) is a safe, widely prescribed, guideline recommended, and FDA approved HF therapy 
with demonstrated benefits in CV outcomes (mortality, HF hospitalizations), remodeling (LVEF, longitudinal 
and circumferential strain, diastolic function), and patient symptoms. 
 
Carvedilol phosphate (PCCID 2585) is an alpha/beta-adrenergic blocking agent indicated for the treatment 
of: (1) mild to severe chronic heart failure; (2) left-ventricular dysfunction following myocardial infarction in 
clinically stable patients; and (3) hypertension. 
a. PHARMACOLOGY: carvedilol is a racemic mixture in which nonselective beta-adrenergic blocking 
activity is present in the S(-) enantiomer and alpha-1-adrenergic blocking activity in both the R(+) 
and S(-) enantiomers.  It has no intrinsic sympathomimetic activity.  Blocking beta-adrenergic 
activity causes vasodilation and a reduction in peripheral vascular resistance which results in a 
reduction in cardiac output, tachycardia, renin production, and reflex orthostatic tachycardia.  
Blocking alpha-adrenergic activity results in a reduction in standing blood pressure, more so than 
supine blood pressure.  Vasodilation, increase in stroke volume reduction in pulmonary capillary 
wedge pressure, pulmonary artery pressure, heart rate, systemic vascular resistance and right 
arterial pressure may all contribute to the beneficial effects seen in congestive heart failure. 
 
b. PHARMACOKINETICS: 
i. 
Absorption: Carvedilol is rapidly absorbed systemically and plasma concentrations 
achieved are correlated to the dose.  It is extensively absorbed with a bioavailability of 25-
30% due to first-pass metabolism.  Food delays the rate but not the extent of absorption.  
Taking with food can minimize the effects of orthostatic hypotension.  The onset and peak 
of antihypertensive effect are approximately 30 minutes and 1-2 hours respectively. 
ii. 
Distribution: Carvedilol is highly protein bound (>95%).  There is substantial distribution 
into extravascular tissue with a steady state volume of distribution of 115L. 
iii. 
Metabolism: Carvedilol undergoes extensive hepatic metabolism primarily by cytochrome 
P450 (CYP) 2D6 and 2C9, with a minor contribution from CTP3A4, 2C19, 1A2, and 2E1 
resulting in the formation of 3 active metabolites with beta receptor blocking activity.  The 
metabolite 4-hydroxyphenyl is approximately 13 times more potent than the parent 
compound for beta-andrenergic blockade, however, concentrations of the metabolites are 
approximately one tenth that of the parent compound.  The 3 active metabolites all exhibit 
weak vasodilatory activity.  Plasma concentrations in the elderly and in those with cirrhotic 
liver disease are 4-7 times higher. 
iv. 
Elimination: Glucuronidated and sulfated secondary metabolites of carvedilol are excreted 
primarily through bile into the feces.  Following oral administration, the mean systemic 
elimination half-life ranges from 7-10 hours. 
 
1.2.1 
Nonclinical Data 
Animal models of doxorubicin CTX support a beneficial CV effect of carvedilol on oxidative stress, 
endothelial, and mitochondrial dysfunction,33-35 which are central to the pathophysiology of anthracycline 
CTX. 
 
1.2.2 
Clinical Data to Date 
Here, we detail the preliminary data that support the use of our risk model (CCT Risk Model) as well as the 
use of carvedilol to mitigate CV risk. 
 

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Preliminary Data Supporting the 
CCT Risk Model 
Randomized clinical trials in 
cardio-oncology have evaluated 
the 
potential 
role 
for 
cardioprotection prophylaxis in 
“all 
comers,” 
which 
we 
hypothesize has resulted in the 
observed lack of substantial CV 
benefit. We propose that the use 
of a risk guided strategy will 
identify those patients who may 
identify the greatest benefit and result in practice-changing guidelines. Our scientific premise is that a 
patient’s clinical characteristics can be used to determine individual CTX risk with cancer therapy and to 
guide preventive strategies, and that carvedilol will mitigate CTX in elevated risk patients.  
 
Our track record and results support the scientific premise and feasibility of this proposal. We have enrolled 
625 patients since the initiation of the Penn CCT cohort study (IRB#811155 / UPCC 09110 / 
NCT01173341). We have developed an internally validated risk model for determination of risk at baseline 
(Table 1). The risk model was developed using LASSO applied to the Penn CCT cohort data, in order to 
identify the most important predictors for the binary outcome of CTX (consistently defined in all our work as 
an LVEF decline ≥10% to <50%) in the year after baseline. Model performance estimates in the Penn CCT 
cohort are based on leave-one-out cross-validation.  
 
The CTX risk score [coefficients on log hazards scale] is as follows: -0.06 * Caucasian race (yes/no) + 
0.47 * Non-AA/Non-Caucasian race (yes/no) +0.13 * tobacco use (yes/no) + 0.01* systolic BP (mmHg) 
+ 0.53*diabetes (yes/no) + 0.10* hypertension (yes/no) -0.10 * LVEF -0.76 * trastuzumab (yes/no) + 1.2 
* doxorubicin + trastuzumab (yes/no).  This score is comprised of a parsimonious set of measures that 
are readily accessible to clinical providers (oncologists, cardiologists), enhancing the applicability of our risk 
score to everyday use. Our risk model (Table 1) demonstrates an area under the curve (AUC) of 0.72 in 
Penn CCT. More important than the AUC, our model has favorable properties for a risk-guided treatment 
strategy. Our goal is to increase the likelihood of treatment of high risk patients while not withholding 
treatment due to false negative prediction. In particular, the model’s risk threshold for “elevated risk” was 
selected to maximize the NPV, thus minimizing the risk of false negatives and ensuring that the majority of 
high risk patients are treated, given the burden of CTX (Table 1). Defining a predicted probability of CTX 
>4.6% as elevated risk results in an estimation that 54% of patients will be designated as elevated risk at 
baseline. This pre-specified elevated risk threshold correctly identifies 82% of patients experiencing CTX 
(i.e. sensitivity) and yields a NPV of 85%. As a result, the PPV is 12% in the Penn CCT cohort; this PPV is 
~2.1 times greater than the observed CTX rate in the cohort at 1 year. Given the biosimilarity of trastuzumab 
and trastuzumab-anns, the risk score for patients treated with trastuzumab-anns or trastuzumab-
anns+doxorubicin will be calculated as if they were being treated with trastuzumab.   
Table 1: Baseline Risk Assessment – Model Variables:  diabetes, 
hypertension, treatment, left ventricular ejection fraction (LVEF) 
Study 
Sensitivity 
Specificity 
NPV 
Proportion 
Elevated 
Risk 
Penn CCT 
(derivation 
cohort and 
study 
population) 
0.82 
0.45  
 
0.85  
 
0.54 

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Inclusion of baseline characteristics resulted in a model with the highest discriminative value. Addition of 
baseline imaging and biomarker measures did not provide value to our risk score and lessen the 
generalizability of our score. We propose that a simple risk score comprised of readily obtained clinical 
variables will facilitate its use.  
 
Preliminary Data to Support the Use of Carvedilol 
Carvedilol is an FDA approved HF therapy with improved CV outcomes (mortality, HF hospitalizations), 
remodeling (LVEF, longitudinal and circumferential strain, diastolic function), and symptoms. The studies 
by Guglin, Avila, Kalay (Table 2) each demonstrate a modest, potential benefit to carvedilol. We postulate 
that the modest effect sizes observed in these RCTs are related to the treatment of a low risk population 
with a low prevalence of CV risk factors. As an example, the Guglin study suggests that the subgroup 
receiving both doxorubicin+trastuzumab derived a benefit from carvedilol, compared to trastuzumab-only 
patients. Based on our risk model, patients receiving both doxorubicin and trastuzumab sequential therapy 
is associated with a 7-fold increased risk of CTX. A sub-analysis of our own Penn CCT cohort data support 
our hypothesis that carvedilol use attenuates the declines in LVEF, longitudinal strain, and NT-proBNP 
observed with exposure to cancer therapy (Fig. 2). Longitudinal trends suggest that in patients treated with 
carvedilol at baseline, there was a consistent attenuation of the adverse changes seen in the non-carvedilol 
treated group.  
 
In cardio-oncology, clinical trials have suggested a benefit from carvedilol (Table 2). In contrast, the data 
indicating a benefit with Angiotensin II receptor blockers (ARBs) and Angiotensin-converting enzyme 
inhibitors (ACE-Is) have been less consistent, with some RCTs showing a very modest CV benefit on LVEF 
alone 44 and others demonstrating no effect on LVEF43 and no effect on other indices of cardiac injury and 
stress.48 In addition, a recent trial subanalysis suggested superiority of carvedilol over ACE-Is in patients 
receiving doxorubicin and trastuzumab (a variable in our risk model).8 We propose that carvedilol is more 
mechanistically relevant to both the biologic and functional perturbations that occur secondary to 
doxorubicin and trastuzumab. Animal models of doxorubicin CTX support a beneficial CV effect of carvedilol 
on oxidative stress, endothelial, and mitochondrial dysfunction,49-51 which are central to the pathophysiology 
of anthracycline CTX. Our preliminary data also support this (Figure 2). Variables in our risk model further 
support the use of carvedilol. The model includes cancer treatment, diabetes, and hypertension. Carvedilol 
targets each of these factors; it attenuates the LVEF declines observed with doxorubicin and trastuzumab, 
improves insulin sensitivity, and decreases blood pressure (BP). 
 
Clinical trial data to date suggest that carvedilol can be used safely in cancer patients undergoing 
chemotherapy, but the beneficial effects may be limited to high risk patients. No serious adverse events 
were reported in any of these studies (Table 2). However, carvedilol currently is not standard of care 
because of the lack of definitive benefit to date. We postulate that the modest reported effects of carvedilol 
are secondary to the “one size fits all” approach and dilution of a detectable benefit of carvedilol given 
Figure 2: Effects of Carvedilol on Cardiac Function and Mechanics in Penn CCT Positive changes 
observed with LVEF and negative changes in longitudinal strain and NT-proBNP in carvedilol treated 
patients (blue) indicate beneficial changes. 
 

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inclusion of a low risk population. The Guglin study (Table 2) described no effect by carvedilol in all comers, 
but had a significant effect in the high risk treatment group comprised of patients receiving anthracyclines 
followed by trastuzumab (a variable in our risk prediction model). Other CTX risk factors have been 
underrepresented in carvedilol trials to date, making it unfeasible to definitively determine if there is role for 
carvedilol in high CTX risk patients in posthoc analyses. For example, only ~3% of carvedilol treated 
participants had a history of hypertension in the CECCY trial9 (Table 2), a significant factor in our CTX risk 
prediction model, which also contrasts with a prevalence of 30-60% encountered in everyday care. The 
existing trial data support the need to identify and target a high risk population to test a targeted CV risk 
reduction strategy in cardio-oncology. 
 
Table 2: Studies Investigating the Impact of Carvedilol in Cardio-Oncology 
Reference 
Design and Study Population 
Results 
Kalay, et al. 
JACC. 2006 
40 
Single blind, placebo controlled RCT 
of 50 breast, lymphoma or other 
cancer 
receiving 
anthracyclines; 
12.5mg once daily of carvedilol 
versus 
placebo 
for 
6 
months 
(Population 
characteristics 
not 
noted) 
No significant change in LVEF in carvedilol group; significant 
decline in control group from 68.9 to 52.3% at a mean of 5.2 
1.2 months (p<0.001) 
Avila, et al. 
JACC. 
2018.39 
Double-blind, RCT of 192  breast 
cancer 
patients 
receiving 
anthracyclines, 
comparing 
carvedilol (goal 25mg twice daily) vs 
placebo; Her2+ excluded; 6.3% 
HTN 
No significant effect on clinical LVEF at 6 months; 
attenuation of TroponinI increases (p=0.003) and diastolic 
dysfunction (p=0.039) within 6 months of carvedilol initiation 
Guglin, et al. 
ACC 
2018 
(Late 
Breaking 
Clinical Trial) 
Double-blind, RCT of 468 breast 
cancer, 
patients 
receiving 
trastuzumab 
+/- 
anthracyclines 
comparing placebo, lisinopril, or 
carvedilol; only 4% of patients with 
HTN; 38% treated with doxorubicin 
+ trastuzumab 
No effect on rate of cardiotoxicity (LVEF decline>10%) 
across entire population (HR 0.71, 95% CI 0.47-1.07, 
p=0.052); however, in patients receiving anthracyclines and 
trastuzumab (n=189), carvedilol reduced the incidence of 
cardiotoxicity (HR 0.49, 95% CI 0.27, 0.89, p=0.009); Effect 
of carvedilol more pronounced than lisinopril (HR 0.53, 95% 
CI 0.39, 0.94, p=0.015) 
 
 
 
1.3 
Dose Rationale  
Subjects in the elevated risk group who are randomized to risk-guided intervention will be initiated at 
3.125mg carvedilol twice daily and uptitrated as tolerated, at visits occurring at 1 or 2, 3 or 4, and 6 weeks. 
Carvedilol will be uptitrated in a stepwise fashion to 6.25mg twice daily to 12.5mg twice daily to a maximum 
dose of 25 mg twice daily, or to a SBP of 110-120mmHg or HR of 50-55 bpm.  If excessive and symptomatic 
hypotension (SBP <90mmHg) occurs, the dose will be decreased.  This dosing is consistent with clinical 
practice for patients with heart failure or hypertension. 
 
2 
Study Objectives 
This is a pilot study intended to assess the feasibility of the study design, and the safety of a risk-guided 
approach to carvedilol prescription in breast cancer patients undergoing treatment with doxorubicin, 
trastuzumab, or the combination.   
 
2.1 
Primary Objective 
The primary aim of this pilot study is to determine feasibility and safety/tolerability.  We will determine 
whether breast cancer patients can be enrolled, have their CTX risk calculated, randomized, retained and 
will comply with the study intervention (where applicable). Moreover, we will determine the safety and 
tolerability of carvedilol in this setting. 

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2.2 
Secondary Objectives 
The secondary objectives of the study are to (1) to prospectively validate our CTX risk score, (2) to explore 
the impact of a risk-guided cardioprotective treatment strategy with carvedilol, as compared to usual care, 
on measures of CV function and stress, derived from echocardiography and blood biomarkers, and on 
clinical heart failure, and (3) to determine the associations between individual and structural social 
determinants of health and CTX risk. 
 
3 
Investigational Plan  
 
3.1 
General Design 
This is a single-center, randomized clinical trial, testing a method for calculating CTX risk score in breast 
cancer patients treated with doxorubicin and/or trastuzumab cancer therapy.  Subjects who are identified 
as having elevated CTX risk will be randomized to individually-dosed, open-label carvedilol vs usual care. 
We will use a stratified block randomization according to trastuzumab therapy (yes/no) to ensure balance 
across treatment regimens, given the different durations of therapy across treatment groups.  Subjects 
being treated with trastuzumab-anns will also be included; for the purposes of stratification and risk-score 
calculation, trastuzumab-anns will be considered equivalent to trastuzumab.  Clinical, echocardiographic, 
and biomarker data will be collected on all patients at baseline and standardized time intervals during and 
after therapy at approximately 3, 6, 9, 12, and 24 months.  
 
3.1.1 
Screening, Risk Calculation, and Randomization 
Subjects will be recruited from the Rena Rowan Breast Cancer Clinic.  Subjects who will be newly beginning 
treatment with anthracyclines and/or trastuzumab therapy and who appear to meet eligibility criteria for this 
study will be identified by the study team via review of PennChart.  The study team will contact the treating 
oncologist for permission to approach the subject.  The study team will then contact the patient (either in 
person during a regularly scheduled visit at PCAM or over the phone) to assess whether subjects are 
interested and gather additional information about eligibility criteria if necessary.  If interested, subjects will 
be scheduled for a screening visit.  The visit will include consent; a medical history; an echocardiogram (if 
value of LVEF from pre-chemotherapy clinical echocardiogram is not documented in the EMR), pregnancy 
test (if applicable and none available in the medical record within 10 days).  At the end of the screening 
visit, the study staff will schedule time for the PI to speak with the patient about their risk score and (if 
applicable) their treatment arm assignment. 
 
A study investigator will review the data gathered during screening to determine eligibility.  The study team 
will calculate CTX risk using a risk score calculation module in the study REDCap database.  The CTX risk 
score [coefficients on log hazards scale] is as follows: -0.06 * Caucasian race (yes/no) + 0.47 * Non-
AA/Non-Caucasian race (yes/no) +0.13 * tobacco use (yes/no) + 0.01* systolic BP (mmHg) + 0.53*diabetes 
(yes/no) + 0.10* hypertension (yes/no) -0.10 * LVEF -0.76 * trastuzumab (yes/no) + 1.2 * doxorubicin + 
trastuzumab (yes/no).  High (or elevated) risk is defined as a predicted CTX risk > 4.6%.  This threshold 
optimizes the sensitivity and NPV and helps ensure to that all high risk individuals are identified. For the 
purposes of risk-score calculation, trastuzumab-anns will be considered equivalent to trastuzumab, given 
the biosimilarity of the two agents. 
 
The PI will inform the subject of their risk group (Low or Elevated), and provide counseling about this 
information.  For subjects in the elevated risk group, the PI will randomize them using a stratified block 
randomization module (according to trastuzumab therapy, yes/no) built into the study REDCap database, 
and inform the subject of their treatment arm assignment (individually dosed carvedilol vs usual care).  
Blocks of 4 will be used for the randomization. In general, this conversation will take place during a 
scheduled phone call 1-2 days prior to the start of treatment; if necessary, it may be done over the phone 
or in person on the day of treatment. 
 

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All necessary variables for calculating baseline CTX risk will be available at the time of the screening visit.  
LVEF will be derived from the clinical echocardiogram report. Subjects will not be consented if this 
information is not available.  In the unlikely event that CTX cannot be calculated for a consented patient 
(for example, if LVEF is not able to be derived due to poor echocardiographic windows), the subject will be 
considered a screen failure post-consent and will not be randomized. 
 
3.1.2 
Study Intervention Phase  
 
Subjects in the elevated risk group randomized to carvedilol will be initiated at 3.125mg twice daily, starting 
the evening of first chemotherapy.  This will be performed in an open label fashion. Dose will be uptitrated 
as tolerated at visits occurring at 1 or 2; 3 or 4; and 6 weeks.  These visits will be timed to coincide with 
clinical visits to the greatest extent possible.  Titration will occur in a stepwise fashion, to 6.25mg twice daily 
to 12.5mg twice daily to 25mg twice daily, or to a SBP of 110-120mmHg or to a HR of 50-55bpm.  If adverse 
events such as excessive and symptomatic hypotension (SBP<90mmHg) occurs or significant bradycardia 
(HR <40bpm) occurs, the dose will be adjusted by the PI.  The duration of the intervention will be 12 months.  
Adherence will be assessed by pill count and study diary, and by patient questionnaire (Hill-Bone 
Compliance scale). All other subjects will be treated according to usual care.  There will be no placebo 
control given this is a Phase 1 safety/feasibility study.  The low risk group will not receive a prospective 
intervention, but will be treated according to usual care. 
 
All subjects will have study visits (including echo, blood draw, medical chart review, and questionnaire) at 
regular intervals during and after the intervention phase.  The exact number and timing of visits is 
determined by cancer treatment regimen.  We will perform a stratified block randomization to ensure 
balance across treatment regimens. Blocks of 4 will be used for the randomization. 
 
3.1.3 
Follow Up Phase 
Subjects in the elevated risk group assigned to carvedilol will take the study medication for 12 months, after 
which they will be instructed to stop.  Carvedilol can be safely discontinued without a need for stepwise 
down-titration.  Subjects assigned to carvedilol will have a final AE assessment (based on chart review and 
phone conversation as needed) 30 days following the final dose of study medication.  In the event that 
patients are hypertensive (SBP>140mmHg on multiple readings), they will be referred to their primary care 
doctor or cardiologist. 
 
All subjects will have a final study visit approximately 2 years after the start of chemotherapy.   
 
In addition, subjects in the doxorubicin and trastuzumab cancer treatment group will also have a visit at 
completion of 1 year of trastuzumab therapy (approximately 14 months after start of chemotherapy).   
 
3.1.4 
Allocation to Interventional Group  
After enrollment, we will calculate CTX risk and classify subjects as low or elevated Risk.  The risk model 
is as follows: -0.06 * Caucasian race (yes/no) + 0.47 * Non-AA/Non-Caucasian race (yes/no) +0.13 * 
tobacco use (yes/no) + 0.01* systolic BP (mmHg) + 0.53*diabetes (yes/no) + 0.10* hypertension (yes/no) -
0.10 * LVEF -0.76 * trastuzumab (yes/no) + 1.2 * doxorubicin + trastuzumab (yes/no).  High risk is defined 
as a predicted CTX risk > 4.6%.  We expect 54% of subjects to be classified as elevated risk.  Elevated risk 
subjects will be randomized to treatment with carvedilol (individually dosed) vs usual care (no prospective 
cardiovascular intervention).  Subjects classified as Low Risk will receive usual care.  All subjects will be 
followed serially by blood, survey, and echocardiogram 
 
A randomization module in REDCap, will be used to determine Elevated Risk subjects’ assignment to one 
of two equal sized groups: Randomization will use a block, stratified design (blocks of 4) to determine 
assignment in the high risk group to individually dosed carvedilol vs usual care.  Stratification will be based 
on cancer treatment group (trastuzumab yes/no) to ensure a balanced distribution across arms.  For the 

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purposes of risk score calculation and stratification, trastuzumab-anns will be considered equivalent to 
trastuzumab. 
 
 
3.2 
Study Endpoints  
 
3.2.1 
Primary Study Endpoints 
 
The primary endpoint for this pilot study is feasibility of the study, and safety and tolerability of carvedilol.  
We will track and examine the following: 
1. Feasibility of recruitment (ratio of subjects screened to subjects identified as eligible) 
2. Acceptability of the study (ratio of subjects consented to subjects approached) 
3. Ability to screen and consent subjects, calculate CTX risk score, and randomize elevated risk 
subjects prior to start of chemotherapy 
4. Safety and tolerability of carvedilol  
a. Rate and grade of adverse events overall, and specifically relating to hypotension, 
bradycardia, and fatigue in the Elevated Risk Group 
b. Rate of dose interruptions or delays of cancer therapy in the Elevated Risk Group  
5. Compliance with the study intervention among elevated risk subjects randomized to carvedilol who 
(based on pill count and Hill-Bones Compliance Scale). 
 
3.2.2 
Secondary Study Endpoints 
The secondary endpoints are: 
1. Maximum decline in LVEF during the first year of treatment 
2. Maximum decline in LVEF at 2 years 
3. Echocardiography-derived functional changes (E/e’, longitudinal and circumferential strain, or 
ventricular arterial coupling) 
4. Biologic changes (high-sensitivity TroponinT, NT-proBNP) 
5. Clinical heart failure 
 
4 
Study Population and Duration of Participation  
 
4.1 
Inclusion Criteria 
• 
Females 
• 
≥ 18 years old 
• 
Diagnosed with breast cancer, with treatment plan to include therapy with anthracyclines and/or 
trastuzumab/trastuzmab-anns in the adjuvant or neoadjuvant setting 
• 
Able to swallow tablets 
• 
Study team is able to obtain all necessary information for calculating baseline CTX risk 
(including echocardiographic images for quantitation of LVEF) prior to enrollment 
• 
Standard of care pre-chemotherapy measurement of LVEF by echocardiogram (patients with 
pre-chemo MUGA will be asked to come in for a research echocardiogram as part of screening) 
 
4.2 
Exclusion Criteria 
• 
Known Stage IV breast cancer at enrollment 
• 
Pregnant or breast feeding.  Due to unknown risks and potential harm to the unborn fetus a 
negative pregnancy test (serum or urine) within 10 days prior to enrollment is required in 
women with child-bearing potential.  Due to the potential nursing infant harm, women who are 
currently breast feeding are not eligible for this study.  
• 
Contraindication to carvedilol 
o 
Baseline systolic blood pressure < 90mmHg (if multiple blood pressures are available 
in the medical record within 1 month prior to screening, the average SBP will be 
considered) 

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o 
Baseline heart rate < 55 bpm consistent with severe bradycardia (if multiple resting 
heart rates are available in the medical record within 1 month prior to screening, the 
average heart rate will be considered) 
o 
Allergy to carvedilol 
o 
History of bronchial asthma or related bronchospastic conditions.  If asthma is listed in 
the medical history or problem list in the EMR but the patient reports no current asthma 
diagnosis and there are no medical visits with a diagnosis of asthma in the preceding 
12 months, the patient will be considered not to have asthma and will not be excluded. 
o 
Known history of sick sinus syndrome 
o 
Severe hepatic impairment, defined as serum bilirubin > 3.0x ULN, AST or ALT > 5.0 
ULN within 28 days of enrollment 
o 
Second- or third-degree AV block, as determined by electrocardiogram 
o 
Severe bradycardia (unless permanent pacemaker is in place) 
o 
Patients in cardiogenic shock or decompensated heart failure requiring the use of IV 
inotropic therapy 
o 
Current use of 
 
Bupropion (Wellbutrin) 
 
Fluoxetine (Prozac) 
 
Paroxetine (Paxil) 
 
Quinidine (Quinidex) 
 
Duloxetine (Cymbalta) 
 
Digoxin  
• 
Current treatment with beta blocker 
• 
Unable to provide consent 
 
Subjects currently on another antihypertensive agent (with the exception of beta blocker) may be enrolled, 
provided SBP > 100mmHg.  If classified as elevated risk and randomized to intervention, carvedilol will be 
initiated in addition to current therapy.   
 
This protocol does not exclude patients who are participating on other investigational studies.  However, 
enrollment of such patients will only be done with the agreement of the principal investigator of the other 
study.  Therapeutic trials will always take priority. 
 
4.3 
  Subject Recruitment  
Subjects will be recruited from the Rena Rowan Breast Cancer Center.  Patients with Stage I-III breast 
cancer scheduled to receive doxorubicin and/or trastuzumab (or trastuzumab-anns) will be prescreened by 
a clinical research coordinator and their attending oncologist or nurse practitioner through PennChart 
review.  Patients that may be eligible may be contacted by telephone or approached in clinic by their treating 
physician or research staff (with permission from their treating physician).  Research staff or the treating 
physician will approach the patient to assess interest.  If interested, the patient will be given a copy of the 
consent form to review.  Informed consent will be obtained by a research coordinator or attending physician 
trained on the protocol. 
 
Settings that involve subject interaction will be limited to the clinics and research facilities at Penn that will 
be used for this research study.  When possible, the consent process will be done in a private room.  If 
patients are unable to give consent, they will not be enrolled in this study.   
 
4.4 
Duration of Study Participation 
 Subjects will participate in the study for a total of 2 years, with the final study visit approximately 24 months 
after start of chemotherapy.   
 
4.5 
Total Number of Subjects 
We plan to enroll 110 subjects, for a target of 56 subjects in the elevated risk group. 

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4.6 
Vulnerable Populations:  
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study.   
 
5 
Study Intervention  
5.1 
Description 
We will dispense carvedilol in 6.25mg tablets. 
 
5.2 
Intervention Regimen 
Subjects in the Elevated Risk Group randomized to intervention will be treated with open-label carvedilol.  
All other subjects in the Elevated and Low Risk groups will receive usual care. 
 
Study drug will be initiated at 3.125mg twice daily starting the day of the first chemotherapy cycle, and 
uptitrated at visits occurring at 2, 3 or 4, and 6 weeks, in a stepwise fashion to 6.25mg twice daily, to 12.5mg 
twice daily, to a maximum dose of 25mg twice daily, or to a SBP of 110-120mmHg or HR of 50-55bpm.  
  
Subjects will remain on study drug for 12 months. 
 
5.3 
Receipt 
The IDS will purchase the active drug commercially. Upon receipt the drug will be logged into inventory and 
stored securely.   
 
5.4 
Storage 
Medication will be stored at room temperature (20-25 Celsius, with excursions permitted in the range of 15-
30 Celsius).  In the IDS, tablets will be kept in the original manufacturer’s container until transferred to a 
standard prescription bottle for dispensing to individual study subjects.  Once dispensed, subjects should 
keep the tablets in the prescription bottle.  
 
In the event that the study team has to store medication temporarily before it can be given to the subject, it 
will be stored at room temperature in a locked cabinet on a secured floor (11 South Tower, PCAM).  Access 
to this cabinet is limited to authorized members of the study team. 
 
5.5 
Preparation and Packaging 
 Investigational product will be dispensed in tablet form, in standard prescription bottles labeled for the 
individual study subject.  Preparation will follow traditional pharmacy practice, pursuant to a prescription.   
 
The active tablets, as noted above, will be purchased commercially and not altered in any way. 
 
5.6 
Administration and Accountability    
The study team will order study drug from Penn IDS to be picked up the day of study visit, or to be shipped 
directly to the patient.  The study team will maintain investigational product logs at the subject level. 
 
5.7 
Subject Compliance Monitoring 
Compliance will be assessed using pill count, drug diary, and patient questionnaire (see appendix).  
Compliance will be assessed at visits at 1 or 2, 3 or 4, and 6 weeks, while dose is being titrated. After this 
time, study diaries and pill counts will be reviewed at each visit while subject is on study medication.  As 
part of each compliance assessment, patients will also be assessed using the Hill-Bone High Blood 
Pressure Compliance Scale.   
 
Patients will be considered noncompliant if they received < 80% or >120% of the cumulative prescribed 
dose for any period during the titration phase (first 6 weeks), or for any two periods on stable dose. If a 
patient is noncompliant, the study team will re-instruct patients in correct administration of medicine, and 

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will counsel patient regarding importance of taking study drug as instructed.   If a patient is noncompliant 
during the titration phase, the dose will not be titrated until patient has been compliant for at least 2 weeks.   
 
In the event of significant and repeated non-compliance (defined as 3 or more missed study visits, or 
repeated instances (3 or more) with study medication noncompliance as described above), a patient may 
be withdrawn from treatment at the PI’s discretion.    
 
5.7.1 
Return or Destruction of Investigational Product 
At the end of the year-long intervention, if the study team instructs the patient to stop taking study 
medication early, or if patient withdraws from treatment, the study team will collect all remaining study drug 
from the patient and perform a final compliance assessment.  The investigational product will then be 
returned to Penn IDS for destruction. 
 
6 
Study Procedures 
The exact number and timing of visits and duration of intervention will vary depending on which cancer 
therapy regimen patients are prescribed by the treating oncologist, their risk group, and their arm 
assignment. 
 
There are some timepoints that will apply to all subjects: 
• 
Screening, consent, and risk score calculation will take place prior to start of chemotherapy.  This 
may be done the day of first chemotherapy.   
• 
The baseline visit will take place during infusion on the first day of chemotherapy  
• 
Subjects will have a final study visit approximately 2 years after the start of chemotherapy 
 
Subjects in the Elevated Risk Group who are randomized to treatment with carvedilol will have study 
activities at additional timepoints: 
• 
Subjects will take first dose of carvedilol in the evening of the first day of chemotherapy 
• 
Subjects will have Titration Visits at 1 or 2, 3 or 4, and 6 weeks; to the greatest extent possible, 
these will be done in combination with regularly scheduled clinic visits. 
• 
Subjects will remain on study medication for 1 year (365 days). 
• 
Subjects will have a final AE assessment (by phone or in person) approximately 30 days after final 
dose of study medication 
 
All other study visits will occur according to the below guidelines: 
 
• 
For subjects treated with doxorubicin and trastuzumab/trastuzumab-anns: 
o 
Study visits prior to and after doxorubicin 
o 
Study visits prior to and approximately every 3 months while on trastuzumab/trastuzumab-
anns  
o 
Study visit after final trastuzumab/trastuzumab-anns treatment (or after completion of 1 
year of trastuzumab/trastuzumab-anns therapy, if on indefinitely) 
• 
For subjects treated with trastuzumab/trastuzumab-anns (no doxorubicin): 
o 
Study visits prior to and approximately every 3 months while on trastuzumab/trastuzumab-
anns 
o 
Study visit after final trastuzumab/trastuzumab-anns treatment (or after completion of 1 
year of trastuzumab/trastuzumab-anns therapy, if on indefinitely) 
• 
For subjects treated with doxorubicin (no trastuzumab/trastuzumab-anns): 
o 
Visits prior to and after doxorubicin  
o 
Visits at approximately 5, 8, and 11 months following start of chemotherapy (to align with 
timing for doxorubicin + trastuzumab/trastuzumab-anns patients) 
 
Table 3 describes what study activities will be completed at each type of visit. 
 
 

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Table 3: Study Activities By Visit Type 
 
Pre-
screening 
contact 
Screening1 
Baseline6 
Titration 
VisitsC 
Study Visits 
(Intervention Phase) 
Final AE 
AssessmentC 
Study Visits 
(Follow-up 
Phase) 
Assess Interest 
X 
 
 
 
 
 
 
Give copy of consent 
form 
X 
 
 
 
 
 
 
Schedule Screening 
X 
 
 
 
 
 
 
Medical Record 
Review 
X 
 
 
 
 
 
 
Consent 
 
X 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
Serum / Urine 
Pregnancy test 
 
X2 
 
 
 
 
 
Eligibility 
 
X 
 
 
 
 
 
Electrocardiogram 
 
X3 
 
 
 
 
 
Clinical Data  
 
X 
X 
XC 
X 
XC 
X 
CTX Risk Score 
 
X 
 
 
 
 
 
RandomizationE 
 
X 
 
 
 
 
 
Symptoms 
Questionnaires 
 
 
X 
 
X 
 
X 
Family/Social History 
 
 
X 
 
 
 
 
SDOH 
 
 
X 
 
 
 
 
Research Blood 
Draw 
 
 
X 
 
X 
 
X 
Echocardiogram 
 
X4 
 
X5 
 
 
X7 
 
X7 
Adverse Event 
Assessment 
 
 
X 
XC 
X 
XC 
 
Compliance 
Assessment 
 
 
 
XC 
XC 
XC 
 
 
1 May be done same day as baseline visit 
2 For women of reproductive potential when a negative pregnancy test is not available in the medical record within the prior 10 days 
3  If none available in the medical record within 28 days prior to enrollment 
4 As standard of care, all breast cancer patients have their LVEF checked prior to starting treatment with Anthracyclines or 
trastuzumab/trastuzumab-anns .  This is typically a TTE, but in some cases, the oncologist will order a MUGA instead.  If patient has 
a MUGA, or if value of LVEF by pre-chemo echo is not documented in the EMR the study will arrange for a research echocardiogram 
as part of screening.   
5 First day of chemotherapy 
6 If no research echo is needed as part of screening, and either the pre-chemo echo is not done at the HUP/PCAM echo lab or the 
pre-chemo echo does not include the necessary images for strain or 3D analyses, the research team may arrange for a research 
echocardiogram at baseline 
7 As standard of care, all breast cancer patients will have an echocardiogram approximately every 12 weeks during treatment with 
trastuzumab or trastuzumab-anns, and between being treated with Anthracyclines and with trastuzumab/trastuzumab-anns.  The 
study team will obtain a copy of these standard of care echocardiograms and use them in place of a research echocardiogram at 
these time points.   
E Subjects in the Elevated Risk Group only  
C Subjects in the Elevated Risk Group who are randomized to carvedilol only 
 
 
6.1 
Screening, Calculation of CTX Risk Score, and Randomization 
The screening visit may be done the same day as the baseline visit.  Consent may be obtained prior to the 
screening visit, but will not be obtained until study staff has verified that all data necessary to calculate risk 
score (including clinical LVEF by echocardiogram) will be available at the screening visit. 
• 
Consent – will be obtained by research coordinator or attending physician 
• 
Medical history  
• 
Electrocardiogram - if none available in EMR within 28 days prior to consent  
• 
Echocardiogram - if patient had pre-chemo MUGA or if documentation of clinical LVEF by 
echocardiogram is not documented in the EMR 
• 
Pregnancy test - if woman of reproductive potential and negative pregnancy test is not available in 
the medical record within the preceding 10 days, a serum or urine pregnancy test will be obtained 

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After the screening activities are complete, the PI (or appropriately trained and delegated attending co-I) 
will confirm eligibility and calculate CTX risk score.  Subjects in the elevated risk group will be randomized 
using a stratified (trastuzumab/trastuzumab-anns yes/no) block randomization module in REDCap.  For the 
purposes of risk score calculation and stratification, trastuzumab-anns will be considered equivalent to 
trastuzumab.  The PI will speak with the patient (on the phone or in person) to notify her of her risk group 
and provide counseling as to what this means.  The PI will also inform subjects in the Elevated Risk Group 
of their treatment assignment during this conversation.      
 
6.2 
Study Intervention Phase 
6.2.1 
Baseline Visit  
The baseline visit will take place on the first day of chemotherapy, during infusion.  At this visit, the following 
activities will be completed: 
• 
Collect clinical data 
• 
Symptoms Questionnaires and SDOH 
• 
Research blood draw (16 mL) 
• 
Family and Social History 
• 
Research Echocardiogram - if the pre-chemo echocardiogram is not done at the Hospital of the 
University of Pennsylvania/Perelman Center for Advanced Medicine Echo Lab or the pre-chemo 
echo does not include the necessary images of for longitudinal and circumferential strain and 3D 
analysis of the left ventricle, the study will arrange for a research echocardiogram to capture these 
images and ensure that complete echo data is available for all patients at baseline.  The research 
echocardiogram may be done at any time between consent and first infusion.   
• 
Subjects in the Elevated Risk Group randomized to carvedilol will be given study medication and 
will be instructed to take first dose of study medication in the evening of the first day of 
chemotherapy 
 
6.2.2 
First Titration Visit (Week 1 or 2) - Elevated Risk Subjects Randomized to Carvedilol only 
Subjects will be asked to come in after 2 weeks on study medication to check vitals (if vitals not available 
in the medical record for this time point).  Study team will also assess for compliance and AEs/SAEs. 
Whenever possible, this will be combined with a clinic or infusion visit in the Perelman Center. 
 
 Dose will be increased to 6.25mg twice daily if all below conditions are met: 
• 
SBP > 110mmHg (if multiple blood pressures available since last visit, average SBP will 
be considered); 
• 
HR > 50bpm (if multiple heart rates available since last visit, average HR will be 
considered); 
• 
No AEs/SAEs which are possibly, probably, or definitely related to the intervention are 
reported; and 
• 
Compliance between 80% and 120% (inclusive) 
 
If one or more of the above conditions is not met, PI will determine whether to continue at current dose, 
uptitrate to next dose level, or hold study drug. 
 
6.2.3 
Second Titration Visit (Week 3 or 4) - Elevated Risk Subjects Randomized to Carvedilol only 
Subjects will be asked to come in after 3-4 weeks on study medication to check vitals (if vitals not available 
in the medical record for this time point).  Study team will also assess for compliance and AEs/SAEs.  
Whenever possible, this will be combined with a clinic or infusion visit in the Perelman Center. 
 
Dose will be increased to 12.5mg twice daily if all below conditions are met: 
• 
SBP > 110mmHg (if multiple blood pressures available since last visit, average SBP will 
be considered); 

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• 
HR > 50bpm (if multiple heart rates available since last visit, average HR will be 
considered); 
• 
No AEs/SAEs which are possibly, probably, or definitely related to the intervention are 
reported; and 
• 
Compliance between 80% and 120% 
 
If one or more of the above conditions is not met, the PI will determine whether to continue at current dose, 
titrate to next higher dose level, or titrate to next lower dose level. 
 
6.2.4 
Third Titration Visit (Week 6) – Elevated Risk Subjects Randomized to Carvedilol only 
Subjects will be asked to come in after 6 weeks on study medication to check vitals (if vitals not available 
in the medical record for this time point).  Study team will also assess for compliance and AEs/SAEs.  
Whenever possible, this will be combined with a clinic or infusion visit in the Perelman Center. 
 
Dose will be increased to 25mg twice daily if all below conditions are met: 
• 
SBP > 110mmHg (if multiple blood pressures available since last visit, average SBP will 
be considered); 
• 
HR > 50bpm (if multiple heart rates available since last visit, average HR will be 
considered); 
• 
No AEs/SAEs which are possibly, probably, or definitely related to the intervention are 
reported; and 
• 
Compliance between 80% and 120% 
 
If one or more of the above conditions is not met, the PI will determine whether to continue at current dose, 
titrate to next higher dose level, or titrate to next lower dose level. 
 
6.2.5 
Unscheduled Titration Visit  
If excessive (SBP < 90mmHg) and symptomatic hypotension and/or excessive (HR < 40bpm) and 
symptomatic bradycardia occurs, the patient will be asked to come in for an unscheduled titration visit.  At 
this visit, study team will check vitals, review compliance and AEs/SAEs.  
 
The PI will determine whether to continue at current dose or titrate to next lower dose level, and will 
determine timing of next titration visit (1-3 weeks).   
 
6.2.6 
Study Visit (On Intervention) 
In general, study visits will occur every 3 months for approximately one year.  However, the exact timing of 
the study visits on intervention will depend on patients’ treatment regimen.  Visits should be completed 
within +/- 28 days of targeted time point.   
 
For subjects in the doxorubicin and trastuzumab/trastuzumab-anns cancer treatment group, the visit 
between doxorubicin and trastuzumab/trastuzumab-anns should be completed after final treatment with 
doxorubicin and before first treatment with trastuzumab/trastuzumab-anns (or vice versa).   
 
During Study Visits on intervention, the following study activities will be completed: 
• 
Collect clinical data (including images from standard of care echocardiogram if done) 
• 
Symptoms Questionnaires 
• 
Research blood draw (12 mL) 
• 
AE Assessment  
• 
Compliance Assessment (for Elevated Risk Subjects randomized to carvedilol only) 
• 
Research echocardiogram if no standard of care echocardiogram at this time point (typically this 
will only apply to doxorubicin subjects) 
 
 

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6.3 
Follow Up Phase of the Study  
 
6.3.1 
Off-Intervention Follow-up - Elevated Risk Subjects Randomized to Carvedilol Only 
A final AE assessment will be conducted 30-40 days following the final dose of study medication, for 
AEs/SAEs that occur within 30 days following final dose.  This may be done over the phone or in person, 
and will also involve medical record review. 
 
A final compliance assessment may also be done at this time point, if not already completed.  In this case, 
subject will be asked to come to the Perelman Center. 
 
6.3.2 
Study Visit (Off Intervention) 
The exact timing of these visits will depend on patients’ treatment regimen.  After the first year, all patients 
will undergo an additional visit at two years (post cancer therapy initiation). Visits should be completed 
within +/- 28 days of targeted time point.   
 
Subjects in the doxorubicin + trastuzumab/trastuzumab-anns cancer treatment groups will also have an off 
intervention study visit at the end of trastuzumab/trastuzumab-anns therapy (approximately 14 months 
following start of chemotherapy). 
 
For 
subjects 
in 
the 
trastuzumab/trastuzumab-anns 
cancer 
treatment 
group, 
the 
end 
of 
trastuzumab/trastuzumab-anns study visit will be completed after final dose of study medication whenever 
possible.   
 
The following study activities will be completed at these visits: 
• 
Collection of clinical data (including images from standard of care echocardiogram if done) 
• 
Symptoms Questionnaires 
• 
Research blood draw (12 mL) 
• 
Research echocardiogram if no standard of care echocardiogram at time point (will apply to most 
subjects at 24 Month Visit) 
 
6.4 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care.  They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to intervention or 
study procedures or visit schedules, or because of AEs/SAEs.  The Investigator may also withdraw subjects 
who violate the study plan, or to protect the subject for reasons of safety or for administrative reasons.  It 
will be documented whether or not each subject completes the clinical study. Subjects assigned to 
intervention with carvedilol and who withdraw early will have one final visit to collect investigational product 
and to follow up regarding adverse events.  Subjects may withdraw or be withdrawn from treatment, but 
continue to participate in the observational portion of the study.   
 
6.4.1 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects assigned to intervention with carvedilol who withdraw consent to participate in the study during 
the study intervention will be seen for one final visit to collect the investigational product. During this visit 
they will be asked for permission to have the study team contact them approximately 30 days after their 
final dose of the study drug to assess for adverse events.   
 
Subjects may be withdrawn from treatment, but choose to continue to participate in other study activities.  
In this case, subjects will continue study visits as if they were in the low risk group. 
 
For subjects in the low risk group or elevated risk subjects assigned to usual care  who withdraw, and for 
all subjects who withdraw during follow-up, there will be no final visit and no data will be collected following 
withdrawal. 
 

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7 
Study Evaluations and Measurements  
 
7.1 
Clinical Covariates 
Detailed clinical covariates will be obtained from questionnaires and medical record review including: 
• 
Date of birth 
• 
Height (baseline only) 
• 
Weight (all visits when clinical data is collected) 
• 
Any history of disease, and in particular history of cardiac disease (collected at baseline, and 
updated at each visit when clinical data is collected) 
• 
Blood pressure and heart rate (all visits when clinical data is collected) 
• 
Medication Use (all visits when clinical data is collected) 
• 
Clinical lab results not drawn specifically for this study, including pregnancy test, metabolic panel, 
CBC and hem profile, BNP/proBNP/NTproBNP, Troponin I/Troponin T, and other cardiac 
biomarkers if drawn (all visits when clinical data is collected) 
• 
Results of cardiovascular testing, including electrocardiogram, echocardiogram, MUGA, stress 
tests (all types), cardiac MRI, and cardiac catheterization (all visits which include either clinical data 
collection or AE assessment) 
• 
BRCA status, if known (at baseline, updated at 2YFU visit) 
• 
Stage and grade of cancer (at baseline) 
• 
Cancer therapy (including surgery, chemotherapy, non-chemo systemic therapies, and 
radiotherapy) (at all visits where clinical data is collected) 
• 
Details of hospitalizations and procedures (at all visits where clinical data is collected or AE 
assessment is performed) 
• 
Family history of cancer and cardiac disease (at baseline) 
• 
Tobacco use (at screening) 
 
7.2 
Vital Signs 
Blood pressure and heart rate may be taken at the 1st, 2nd, and 3rd titration visits (if not available in the 
medical record).  Blood pressure and heart rate will be taken at any unscheduled titration visits.  
Blood pressure will be taken sitting after 5 minutes of rest.  If patient reports symptoms of orthostatic 
hypotension, blood pressure may also be taken standing to evaluate for orthostatic vital signs.  
 
7.3 
Laboratory Evaluations 
Blood samples will be obtained for research purposes at baseline and at all study visits. 16mL (4mL SST 
and 12 mL EDTA) will be obtained at baseline and 12mL (4mL SST and 8mL EDTA) at the subsequent 
visits.  Samples will be immediately processed and from these samples, plasma, serum, and buffy coat will 
be banked for future use.  This protocol encompasses the measurement of specific biomarkers, but the 
objective is also to include these samples in our biobank for future research in cardiotoxicity of cancer 
therapies and risk-guided interventions, and patients will be consented to have their blood used for the 
testing of additional novel biomarkers.  Blood sampling for research purposes will occur in conjunction with 
clinical blood draws when possible.  Blood sampling will be done in the usual fashion with standard 
phlebotomy precautions.  These specimens will be banked for future use (see Attachment for Blood 
Processing Protocol). 
 
All assays will be performed posthoc, in batches, to minimize the effects of confounding.  These assays will 
be performed in the Translational Core Lab, in the lab of Dr. Ky in the Smilow Translational Research 
Center, or in the lab of collaborators. We plan on testing for hsTnT and NT-proBNP, as well as other cardiac 
biomarkers to be determined as knowledge advances. 
 
7.4 
Pregnancy Testing 
If a pregnancy test is not available in the medical record within 10 days prior to enrollment, a serum or urine 
pregnancy test will be performed for subjects of reproductive potential (defined as having had menses at 
any time in the preceding 12 consecutive months) as part of the screening visit. 

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7.5 
Other Evaluations, Measures 
 
7.5.1 
Transthoracic Echocardiogram:  
Resting echocardiograms (Vivid E9 or E95, GE Healthcare) with conventional measures of systolic and 
diastolic function, in conjunction with posthoc quantitation of novel measures of strain and strain rate will 
be obtained at study visits when subjects do not have a standard of care, clinically ordered echocardiogram. 
In addition to the standard echocardiographic protocol used in clinical practice, we will obtain additional 
imaging, including a more comprehensive assessment of longitudinal and radial measures of cardiac 
function and contractility via ascertainment of myocardial velocities, strain, and strain rate using high frame 
rate 2D and color tissue Doppler which will be used for research purposes only.  For strain imaging, views 
over 5 cardiac cycles will be obtained from the 2-, 3-, and 4-chamber LV apical views, as well as via the 
parasternal short and long axis.  These additional research images will add approximately 10 minutes to 
the total acquisition time.  Off-line strain analyses will be performed on the EchoPAC system (EchoPAC, 
GE Healthcare, and Milwaukee, WI) or Tomtec System (Cardiac Performance Analyses). Results of the 
echocardiogram, according to current clinical standards, will be conveyed to the patient and entered in the 
patient’s chart.  Any clinically relevant findings will also be conveyed to the treating provider.  In particular, 
findings that represent a significant cardiac event (such as LVEF reduction to less than 50%) will be 
conveyed to the treating provider (see Attachment for Echo Protocol).  At times, clinical echocardiograms 
may be obtained as part of standard clinical practice and these studies will be obtained and used for 
quantitative analysis.   
 
All echocardiograms will be rigorously analyzed by the Penn Center for Quantitative Echocardiography 
(blinded to clinical characteristics, arm assignment, and treatment assignment). The echocardiographic 
characterization will generate a rich dataset of measures of systolic function (LVEF, longitudinal and 
circumferential strain), structure (volumes, mass), diastolic function (E/e’), and VA coupling (Ea/Ees, Ea). 
 
 
7.5.2 
LVEF for Calculation of Risk Score 
A value for LVEF from the report of the pre-chemotherapy echocardiogram is required for calculation of the 
risk score.  In general, this is documented in the EMR.  If the echo report provides a range rather than a 
value (e.g. “LVEF 55-60%”), the mean will be used in the calculator, consistent with our practice in the Penn 
CCT Cohort.  If no echo report is available in the medical record, an office note signed by attending 
physician or APP will be considered acceptable source documentation of LVEF, provided it specifies the 
study date, modality, and a value (or range) for LVEF.  
 
In some cases, we may perform an echocardiogram at screening.  This will only be done if the study team 
is not able to obtain documentation of pre-chemotherapy LVEF by echocardiography in time for patient to 
be enrolled on study.  The PI will read the screening echo and document her clinical assessment of LVEF 
for use in the calculator.  Results of this screening echocardiogram, based on current clinical standards, 
will be entered into the EMR and will be shared with the patient.  Any significant findings, based on current 
clinical standards, will be reported to the treating provider.   
 
In some cases, we may perform a research echocardiogram at baseline in order to ensure that baseline 
3D and strain echo data is available for all patients.  If clinical LVEF is available from both the clinical pre-
chemo echo and the baseline research echo, the Risk Score will be calculated using the clinical pre-chemo 
LVEF.  This is consistent with the derivation of the Risk Score. 
 
A member of the study team will use a REDCap module to calculate CTX risk score using race, 
hypertension, tobacco use, diabetes, SBP, planned treatment, and LVEF from clinical echo report.   
 

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7.5.3 
Electrocardiogram 
An electrocardiogram (EKG) will be checked as part of screening.  The study team will perform one if there 
is none available in the medical record within 28 days of enrollment.  Any clinically significant findings will 
be shared with the patient and provider and recorded in the medical record.   
 
7.5.4 
Symptoms and Activity Questionnaires 
At baseline and at each study visit (on and off Intervention), we will collect symptoms data from all patients 
based on the MD Anderson Symptoms Inventory – Heart Failure, FACIT Fatigue, FACIT Dyspnea on 
Exertion, and exercise data using the Godin Leisure Time Exercise Questionnaire.  All questionnaires are 
standardized and validated instruments,41-43 commonly used in cardio-oncology and oncology research, as 
well as in other disciplines.  
  
7.5.5 
SDOH Measures  
Using the National Institute of Minority Health and Health Disparities’ PhenX Measures for SDOH 
Collections, we will perform comprehensive phenotyping of individual (race and ethnicity, gender 
identity, sexual orientation, educational attainment, employment status, occupational prestige, 
annual family income, health insurance coverage, health literacy, food insecurity, language 
barrier, access to health services, access to health technology, discrimination and disparate 
health care quality) and structural (air quality, concentrated poverty, racial/ethnic residential 
segregation, community educational attainment, food environment and social vulnerability) 
SDOH. We will additionally collect data on distress using the National Comprehensive Cancer 
Network (NCCN) distress thermometer and problem list.56 We will also collect data on financial 
distress based on a commonly used questionnaire developed by the National Health Interview 
Survey.57 All measures of SDOH will be obtained at baseline, prior to the initiation of cancer 
therapy.  
 
7.5.5.1 Individual SDOH 
Table 4 presents the specific instruments and modes of administration for the collection of 
measures of individual SDOH. These encompass existent and widely established, validated and 
reliable instruments for the collection of measures of individual and structural SDOH developed 
by the National Institute of Minority Health and Health Disparities with the goal of establishing a 
“common currency” of measurement protocols to inform effective interventions to reduce health 
disparities (www.phenxtoolkit.org/collections/sdoh).58-61 The individual SDOH questionnaires will 
be primarily collected using the paper and pencil method. Trained clinical research coordinators 
will administer the interviewer-administered questionnaires in a face-to-face interview. 
Participants will be asked to complete the self-administered questionnaires. To improve 
compliance, participants who prefer to complete the self-administered questionnaires at home will 
be given the option to complete questionnaires digitally via email survey. Any clinically actionable 
patient responses (e.g. evidence of significant distress) will be relayed to the clinical oncologist 
and the Abramson Cancer Center social work services for appropriate follow-up once the 
participant agrees to sharing of this information with the clinical team (oncology and social work). 
Table 4: National Institute of Minority Health and Health Disparities PhenX Instruments for 
measurements of individual SDOH  
Measures of 
Individual SDOH 
Protocol/Instrument 
Mode of Administration 

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Race and ethnicity 
US Census Bureau, Census 2020, 
Questionnaire 
Self-administered 
Educational 
attainment 
National Health and Nutrition Examination 
Survey 
Self-administered 
Employment status 
Panel Study of Income Dynamics 
Self-administered 
Occupational prestige 
American Community Survey and General 
Social Survey Codebook 
Self-administered 
Gender identity  
All of Us Research Program Participant 
Provided Information 
Self-administered 
Sexual orientation 
All of Us Research Program Participant 
Provided Information 
Self-administered 
Distress 
National Comprehensive Cancer Network 
Distress Thermometer and problem list 
Self-administered 
Language barrier  
(English proficiency) 
California Health Interview Survey 2018 
Adult Questionnaire  
Interviewer-administered 
Annual family income 
National Health Interview Survey Family 
Questionnaire 
Interviewer-administered 
Health insurance 
coverage 
Health Reform Monitoring Survey 
Interviewer-administered 
Access to health 
services 
National Health Interview Survey, Adult 
Access to Health Care and Utilization 
Module 
Interviewer-administered 
Health literacy 
Short Assessment of Health Literacy-
English Questionnaire 
Interviewer-administered 
Access to health 
technology 
National Cancer Institute’s Health 
Information National Trends Survey 
Interviewer-administered 
Discrimination 
Major Experiences and Everyday 
Discrimination Scales 
Interviewer-administered 
Disparate health care 
quality 
California Health Interview Survey 2018 
Adult Questionnaire 
Interviewer-administered 
Food insecurity  
Short form of U.S. Department of 
Agriculture Economic Research Food 
Security Survey  
Interviewer-administered 
Financial distress 
National Health Interview Survey 
Interviewer-administered 
 
7.5.5.2 Structural SDOH 
As part of the PhenX tool, and as developed by the National Institute of Minority Health and Health 
Disparities with the goal of establishing a “common currency” of measurement protocols to inform 
effective interventions to reduce health disparities (www.phenxtoolkit.org/collections/sdoh), 
structural SDOH measures will also be obtained from existent resources such as the 5-year 
American Community Survey estimates by geocoding participant’s current address to local 
geographic area (e.g. county, census tract). Participant’s current address will be extracted from 
medical records. Thus, there will be no additional participant burden for the collection of structural 
SDOH measures. Table 5 summarizes the specific structural SDOH measures and resources 
that will be used for the collection of each measure.  

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Table 5: National Institute of Minority Health and Health Disparities PhenX Instruments for 
measurements of structural SDOH  
Measures of Structural SDOH 
Protocol/Instrument 
Air quality  
US Environmental Protection Agency Air Quality Index 
report 
Concentrated poverty 
5-year American Community Survey estimates 
Racial/ethnic residential 
segregation 
5-year American Community Survey estimates 
Community educational 
attainment 
5-year American Community Survey estimates 
Food environment  
US Department of Agriculture Economic Research 
Service Food Environment Atlas 
Social vulnerability 
Agency for Toxic Substances and Disease Registry 
 
7.5.6 
Drug Diary, Compliance, and Pill Count – Elevated Risk Subjects randomized to Carvedilol 
only 
Subjects will be asked to maintain a drug diary to track doses that are taken/missed, and any symptoms 
that they experience while on study medication.  To minimize confusion regarding individualized dosing, 
the study team will customize the drug diary for each patient, at each period during the study, and will give 
patient new drug diaries whenever the dose is changed or when a refill is provided.  The drug diary template 
is attached. 
 
The compliance of elevated risk subjects randomized to carvedilol will be assessed using the Hill-Bone 
Compliance Scale and pill count at each study visit.  This is a widely used, standardized44 scale which 
provides a method for clinicians to assess patients’ self-reported compliance levels and to plan appropriate 
interventions. 
 
8 
  Statistical Plan 
8.1 
Primary Endpoint 
In order to assess the safety and tolerability of carvedilol, we will quantify the incidence of adverse events 
according to NCI CTCAE v5.0 and assess medication compliance. 
 
8.2 
Secondary Endpoints  
One of our secondary outcomes of interest is maximum decline in LVEF during the first year of follow-up, 
as a continuous measure.  This is a highly clinically relevant variable. The rationale for this endpoint is as 
follows: LVEF is a valid, reproducible, and highly clinically relevant measure of cardiac function and is a 
potent predictor of all-cause and CV mortality.45 Multiple oncologic and CV treatment decisions are made 
based upon LVEF.46  
 
Other secondary outcomes of interest include: maximum LVEF decline at 2 years; time to CTX (defined by 
a decline in LVEF of ≥ 10% to <50%); clinical HF (urgent or new office or ED visit or hospitalization with HF 
signs or symptoms); changes in functional measures (E/e’; longitudinal and circumferential strain, 
ventricular arterial coupling); changes in biologic measures (high sensitivity TroponinT; NT-proBNP); and 
safety and tolerability of carvedilol. We will also assess the frequency of cancer therapy dose interruptions 
due to CTX across both treatment groups. HF will be adjudicated by a cardiologist, according to standard 
definitions. HF symptoms include dyspnea, decreased exercise tolerance, and fatigue; signs of HF include 
worse end-organ perfusion or volume overload (peripheral edema, increased abdominal distension, 
pulmonary crackles/rales, increased jugular venous pressure or S3). Initiation of CV medications will be 
recorded at each study visit. Although our primary outcome assessment is at 1 year, we will explore all 
outcome measures, including maximum change in LVEF, at 2 years.  
 

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8.3 
Sample Size and Power Determination 
Sample size estimates are based on data from the Penn CCT Cohort.  Our primary objective is to establish 
the safety and tolerability of carvedilol in the high risk population. We therefore base sample size estimates 
for this pilot study on the minimum number of patients needed to identify a statistically significant difference 
in safety outcomes between carvedilol and usual care arms. We plan a total enrolled sample of size up to 
110 (consisting of high and low risk) and assume ~10% attrition. This targeted sample size yields a target 
of 56 high risk patients, of whom 50 are expected to have complete follow-up data. With a sample of size 
50 and assuming an incidence of 3.1% for hypotension, the half-width of our 95% confidence interval for 
the incidence rate will be 4.8%. For all adverse events, assuming an incidence of 12%, we will be able to 
estimate the 95% CI for the incidence rate of all adverse events with a half-width of 9%. With 50 patients, 
we are powered to detect a 4.9% difference in LVEF between the two arms. 
 
8.4 
Statistical Methods 
The first step in statistical analysis will involve summarizing the characteristics of all patients. We will use 
standard descriptive statistics (means, standard deviations (SD), medians, interquartile ranges for 
continuous variables, counts, proportions for categorical variables) and graphical methods to summarize 
the study characteristics overall, and stratified by study arm, cancer treatment (doxorubicin, 
trastuzumab/trastuzumab-anns, doxorubicin+trastuzumab/trastuzumab-anns), and by risk.   
 
An intent-to-treat approach will be used in all analyses. The intent to treat population used for our primary 
statistical analyses will include all randomized high CV risk patients. We will use a 2-sided significance level 
of 0.05 in all our hypothesis tests. Unless noted, comparisons will report unadjusted p-values. 
 
We will quantify the recruitment and retention rates, adherence rates (pill count, study diary, Hill Bone 
Compliance questionnaire), maximum tolerated dosages of carvedilol, and rates of adverse events (CTCAE 
v5). We will define these rates across the entire study population and in the elevated risk patients, 
specifically evaluating the effect of carvedilol compared to usual care. We will compare rates between the 
carvedilol and usual care arms using chi-squared tests. Block randomization within cancer treatment strata 
will help to ensure an equal distribution of treatment groups across arms; randomization will help to ensure 
baseline characteristics and CV risk are similarly distributed across arms. Blocks of 4 will be used to 
generate the randomization scheme.  
Our secondary analyses will explore the effect of carvedilol on LVEF change; the incidence of CTX (LVEF 
decline ≥ 10% to <50%); clinical HF (urgent or new office or ED visit or hospitalization with HF signs or 
symptoms); frequency of treatment interruptions due to CTX in order to obtain effect size and variance 
estimates to inform the design of our subsequent Phase III RCT.  We will also explore changes in the 
following intermediary measures:  longitudinal and circumferential strain, E/e’, VA coupling (Ea/Ees), hsTnT 
and NT-proBNP to understand if these measures can be used as surrogate outcomes in a subsequent 
RCT. We will use t-tests to compare continuous outcomes between carvedilol and usual care groups.55-
58Analyses of time-to-event secondary outcomes (CTX, HF, treatment interruptions) will be conducted 
using log rank tests to compare treatment arms; patients will be censored at the time of death or last follow-
up. As an exploratory analysis, we will use the same approach to assess the effect of carvedilol at 24 
months.  
 
As an additional analysis, we will compare the incidence of CTX occurring within the first year of follow-up 
between high risk (in the usual care arm) and low CV risk (observational group), given our additional 
objective is to prospectively validate the performance of our risk model and the ability of our model to 
successfully identify patients in need of treatment. We will also use our biomarker and imaging measures 
to define if there are dynamic changes in these markers in low risk individuals that can be used to further 
enhance the performance of our risk prediction model in future iterations. We will also ascertain our 
outcomes according to the varying degrees of CTX risk. We will use regression models estimated via 
generalized estimating equations including time, treatment, and their interaction to estimate and compare 
trends in CTX risk over time and treatment group. 
 

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8.4.1 
Safety Analysis  
Carvedilol is safe, widely prescribed and a guideline recommended HF therapy. We will ensure the safe 
administration of study drug in the elevated CV risk group with careful oversight by PI. At each study visit, 
we will assess for adverse events using the CTCAE criteria. At study completion we will report the number 
and proportion of patients experiencing adverse events, and specifically evaluate hypotension, bradycardia, 
and fatigue, as well as treatment delays related to CV events and fatigue by risk group and treatment arm. 
Adverse events will be reported according to relevant institutional policies and FDA requirements. 
 
8.5 
Subject Population(s) for Analysis 
An intent to treat approach will be used in all analyses; the intent to treat population used for our primary 
statistical analyses will include all randomized high CV risk patients. 
 
9 
Safety and Adverse Events 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
For FDA regulated studies the FDA defines an adverse event as the following:  
 
Adverse event means any untoward medical occurrence associated with the use if a drug in humans 
whether or not considered drug related.  
 
9.1.2 
Serious Adverse Event 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
For the purpose of this study, planned procedures and hospitalizations (such as for mastectomy) will not 
be considered to be AEs/SAEs.  Events that occur to complicate and prolong such hospitalizations will be 
considered to be AEs/SAEs, as appropriate.   
 

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9.2 
Recording of Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for 
defining and grading AEs/SAEs.  We will record cardiovascular AEs (Table 4), expected AEs regardless of 
attribution, unexpected AEs which are at least possibly related to the study intervention, incidental findings 
from the research echocardiogram, and all AEs ending in death.  Only events Grade 2 and higher will be 
recorded, unless resulting in hospitalization for ≥24 hrs. 
 
Table 4: CTCAE v5 Cardiovascular Terms 
Cardiac Disorders 
Vascular Disorders 
Other CV Related Terms 
Aortic Valve Disease 
Arterial thromboembolism 
Cardiac troponin I increased 
Asystole 
Capillary leak syndrome 
Cardiac troponin T increased 
Atrial Fibrillation 
Flushing 
CPK increased 
Atrial Flutter 
Hematoma 
Ejection fraction decreased 
Atrioventricular Block 
Hot flashes 
Electrocardiogram QT corrected 
interval prolonged 
Atrioventricular Block first 
degree 
Hypertension 
Electrocardiogram T wave 
abnormal 
Cardiac Arrest 
Hypotension 
Localized edema 
Chest pain – cardiac 
Lymph leakage 
Pulmonary hypertension 
Conduction disorder 
Lymphedema 
 
Cyanosis 
Lymphocele 
 
Heart Failure 
Peripheral ischemia 
 
Left Ventricular Systolic 
Dysfunction 
Phlebitis 
 
Mitral Valve Disease 
Superficial thrombophlebitis 
 
Mobitz (type) II atrioventricular 
block 
Superior vena cava syndrome 
 
Mobitz type I 
Thromboembolic event 
 
Myocardial Infarction 
Vasculitis 
 
Myocarditis 
Vascular disorders – other, 
specify 
 
Palpitations 
 
 
Paroxysmal atrial tachycardia 
 
 
Pericardial effusion 
 
 
Pericardial tamponade 
 
 
Pericarditis 
 
 
Pulmonary valve disease 
 
 
Restrictive cardiomyopathy 
 
 
Right Ventricular dysfunction 
 
 
Sick sinus syndrome 
 
 
Sinus bradycardia 
 
 
Sinus tachycardia 
 
 
Supraventricular tachycardia 
 
 
Tricuspid Valve disease 
 
 
Ventricular arrhythmia 
 
 
Ventricular fibrillation 
 
 
Ventricular tachycardia 
 
 
Cardiac disorders – other, specify 
 
 
 

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At each contact with the subject during the intervention phase and for 30 days following the final dose of 
study medication, the investigator will seek information on adverse events by review of the medical record, 
specific questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should be 
recorded in the documentation, though should be grouped under one diagnosis. 
 
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study intervention or participation is not the cause.  Serious adverse events that are 
still ongoing at the end of the intervention period will be followed up to determine the final outcome.  Any 
serious adverse event that occurs within 30 days following the final dose of study medication and is 
considered to be possibly related to the study intervention or study participation will be recorded and 
reported once the study team becomes aware of it.   
 
Once the final AE Assessment is completed (approximately 30 days after final dose of study medication) 
the study team will no longer document expected events.  All cardiovascular AEs (Table 4) and AEs related 
to study activities will continue to be documented.  A description of the event, including its date of onset 
and resolution, whether it constitutes an SAE or not, any action taken, outcome, and the investigator’s 
assessment of causality (relationship to study activity) and determination of severity will be included in the 
record.  
 
9.2.1 
Toxicity Grading of Potentially Expected Respiratory Disorders 
For rales and status asthmaticus, use CTCAE Category, “Respiratory, other”. 
 
9.3 
Relationship of AE to Study and Expectedness 
The PI will be responsible for determining the relationship of an AE to the study intervention or study 
activities.  Events will be classified as unrelated, possibly, probably, or definitely related. If an AE is not 
unrelated, the PI will also determine if the AE is expected (known adverse effect of carvedilol) or 
unexpected.  Known adverse effects of carvedilol are listed in Table 4 (Section 12.1) and described in the 
consent form.  Finally, the PI will characterize the event’s relatedness to underlying conditions; events will 
be characterized as not related to underlying condition, related to condition studied, or related to other co-
morbidity.   
  
9.4 
Reporting of Adverse Events and Unanticipated Problems 
 
The investigators will conform to the adverse event reporting timelines, formats and requirements of the 
various entities to which they are responsible, including the FDA, Penn IRB, and the Abramson Cancer 
Center. 
 
At a minimum, the below information will be provided at the time of the initial report 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study intervention was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study intervention 
 
 
Additionally all other events (unanticipated problems, adverse reactions, and subject complaints  will be 
recorded and reported with respect to institutional and federal policies as described in the Penn Manual 
and below.  
 

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9.4.1 
Follow-up report 
If an SAE has not resolved at the time of the initial report or new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) should be submitted to the IRB. The investigator 
will ensure that all SAE are followed until either resolved or stable.  
 
9.4.2 
Investigator Reporting to Penn Entities  
AE/SAEs 
will 
be 
reported 
to 
the 
Penn 
IRB 
in 
accordance 
with 
IRB 
policy 
(http://www.upenn.edu/IRB/mission-institutional-review-board-irb/reportable-events).   
 
All events meeting the DOCM reporting requirements will also be entered into the PennCTMS AE/SAE form 
(http://www.ctsrmc.org/sae.php).  
 
As much as possible, events will be reported as a diagnosis, not as a list of symptoms.  Symptoms that led 
to the diagnosis will be included in the event description, but will not be reported as the actual event.   
 
9.4.3 
Investigator Reporting to the FDA 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND/ IDE safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and associated type 
of event: 
 
• Within 7 calendar days 
Any study event that is all: 
– associated with the use of the study drug, and 
– unexpected, and  
– fatal or life-threatening, 
 
• Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, and 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
 
Additional reporting requirements 
Sponsors are also required to identify in IND/IDE safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Applicable events can be reported to the FDA using Form FDA3500A or in narrative format. The report 
must be sent to the correct division. Specific information that must be included in the reports can be found 
in 21 CFR 312.32 or in 21 CFR 812.150. 
 
Reports should be submitted to the Center for Drug Evaluation and Research (CDER) at 1-800-FDA-1088 
 
Central Document Room 
Center for  Drug Evaluation and Research 
Food and Drug Administration 

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5901-B Ammendale Rd 
Beltsville, MD 20705-1266 
 
9.5 
Medical Monitoring 
 
9.5.1 
Data and Safety Monitoring Plan 
The monitoring of a clinical trial is an essential element of study processes designed to ensure the protection 
of subjects’ rights, the safety of subjects enrolled in the trial, and the integrity and quality of the resulting 
data.  The study shall adhere to the requirements described in the protocol, the International Conference 
on Harmonization (ICH) and FDA Good Clinical Practices (GCP) and SOPs.  In addition to PI oversight, the 
protocol will be subject to review and oversight be the Abramson Cancer Center Clinical Trials Scientific 
Review and Monitoring Committee (CTSRMC) and Department of Operations, Compliance, and Monitoring. 
 
10 Study Administration, Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
10.2 Data Collection and Management  
Each subject will be assigned a unique identifier upon signing consent.  Any information linking the subject 
to his or her subject ID will be maintained locally in a password protected shared-drive hosted on the UPHS 
network and managed by UPHS IS; access to this drive will be controlled by the PI.   
Paper copies of study records (including Case Report Forms (CRFs) and source documents) will be stored 
in a locked cabinet accessible to the study team only.   
 
Enrollment and adverse event data will be recorded in PennCTMS.  All research data will be maintained in 
a HIPAA compliant study database on REDCap.   
 
Blood samples will be identified by subject ID, visit number, and date collected.  
 
Echocardiographic images and a clinical report of the echocardiogram will be generated and linked with the 
patient’s EMR.  Quantitated echocardiographic data will be labeled with the subject ID, visit number, and 
date of echocardiogram only and entered into the REDCap database.   
 
10.3 Records Retention  
All study records will be maintained as described above for the duration of the study and until the last 
banked specimen has been exhausted or for at least one year following the final study-related publication 
or for at least seven years after the close out of the study (whichever is latest).  After this time, financial 
records, source documentation, and paper CRFs may be appropriately destroyed.  All versions of the 
protocol and all signed consent form/HIPAA authorizations will be retained permanently, in keeping with 
the University of Pennsylvania Records Retention Schedule.  
 
Records in PennCTMS will be retained according to PSOM/UPHS policy. 

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There may be future questions of interest related to the study of the cardiovascular effects of doxorubicin 
and/or trastuzumab/trastuzumab-anns and risk-guided cardioprotective strategies.  The de-identified data 
or samples collected from this study may be shared with academic collaborators both within and across 
institutions.  In so doing, they will help to answer questions of mutual interest that are related to the overall 
aims of this study.  To that end, subjects will be asked to opt in to allow the future use of their data and 
future use of their remaining blood samples. If they agree, their blood samples or data may be kept (as 
described above) indefinitely. 
 
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
The investigator will allocate adequate time for all monitoring activities.  The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all the above noted 
study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 
adequate space to conduct the monitoring visit. 
 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the CTSRMC, IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities.  
 
12 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB concerning the conduct of the study will be made in writing to the investigator and 
a copy of this decision will be provided to the sponsor before commencement of this study. 
  
12.1 Risks 
 
12.1.1 Risks of Carvedilol 
 
Refer to the current FDA-approved package insert for the most comprehensive and up to date information 
on adverse reactions.  Table 4 lists adverse effects that have been reported with carvedilol. 
 
Table 4: Adverse Effects of Carvedilol 
 
Common, May be Serious 
Occasional, May be Serious 
Rare and Serious 
(> 20%) 
(4-20%) 
(≤ 3%) 
Tiredness 
Asthenia (weakness or lack of energy) 
Syncope (fainting) 
Dizziness 
Edema (swelling) 
Angina (chest pain) 
 
Bradycardia (low heart rate) 
Atrioventricular Block  
 
Hypotension (low blood pressure) 
Erythema multiforme  
 
Hypertension (high blood pressure) 
Stevens-Johnson Syndrome  
 
Heart Failure 
Toxic Epidermal Necrolysis  
 
Headache 
Aplastic Anemia  
 
Diarrhea 
Intraoperative Floppy Iris Syndrome 
 
Nausea 
Visual Changes 
 
Vomiting 
Status Asthmaticus (severe asthma) 
 
Hyperglycemia (low blood sugar) 
 
 
Hypercholesterolemia (high cholesterol) 
 
 
Arthralgia (joint pain) 
 
 
Cough 
 

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Rales 
 
 
 
Reproductive risks: Pregnancy category C.  Animal (rats and rabbits) reproduction studies have shown 
adverse events.  There is no adequate data on the use of carvedilol in pregnant women.  It is not known 
whether carvedilol is excreted in human milk and infant risk cannot be ruled out.  Study will obtain a 
pregnancy test as part of screening (if subject is able to become pregnant and one is not available in the 
medical record).  Subjects in the Elevated Risk Group assigned to intervention with carvedilol and who are 
of potential child-bearing status will be instructed to use adequate birth control and will be offered 
counseling on what this entails.  Such subjects will be instructed to notify the study doctor immediately if 
they are or think they may be pregnant while on study drug.  If a patient becomes pregnant while on 
carvedilol, patient will be taken off of study drug; if appropriate, the PI will coordinate transition to other 
antihypertensive regimen with patient’s clinical care team. 
 
Drug interactions:  Refer to the current FDA-approved package insert for the most comprehensive and up 
to date information on drug interactions.  Due to potential drug interactions, a complete patient medication 
list will be reviewed and recorded prior to initiation and at all study visits.  Investigational carvedilol will be 
recorded in subject’s EMR at current dose.  Subject will be given a wallet card with information on the study 
drug and potential drug interactions and study contact information (see Wallet Card attachment) to share 
with clinical care team.   
 
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 during the intervention phase for subjects in the elevated risk group who are randomized 
to carvedilol.   
 
 
 

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1. NOT ALLOWED DURING INTERVENTION 
Strong CYPD6 Inhibitors: 
• 
buproprion (Wellbutrin) 
• 
fluozetine (Prozac) 
• 
paroxetine (Paxil) 
• 
quinidine (Quinidex) 
 
Clinically Significant Moderate CYPD6 Inhibitor 
• 
duloxetine (Cymbalta) 
 
2. SHOULD BE AVOIDED DURING INTERVENTION 
 
Other Moderate CYP2D6 Inhibitors: 
• 
sertraline (Zoloft) 
• 
terabinafine (Lamisil) 
 
Weak CYPD6 Inhibitors: 
• 
amiodarone (Cordarone) 
• 
cimetidine (Tagamet) 
• 
thioridazine (Mellaril) 
  
3. WILL BE TRACKED DURING INTERVENTION 
Other Possible CYP2D6 Inhibitors: 
• 
celecoxib (Celebrex) 
• 
chlorpheniramine* 
• 
chloropromazine (Thorazine) 
• 
citalopram (Celexa) 
• 
clemastin (Tavist)* 
• 
clomipramine (Anafranil) 
• 
diphenhydramine (Benadryl)* 
• 
doxepin (Sinequan) 
• 
doxorubicin (Adriamycin) 
• 
escitalopram (Lexapro) 
• 
halotantrine (Halfan) 
• 
haloperidol (Haldol) 
• 
hydroxyzine (Vistraril, Atarax)* 
• 
levomepromazine (Noxinan) 
• 
lopinavir (Kaletra) 
• 
methadone 
• 
metoclopramide (Reglan) 
• 
midodrine (ProAmantine) 
• 
moclobemide (Aurorix, Manerix) 
• 
ranitidine (Zantac)* 
• 
ritonavir (Norvir) 
• 
ticlopidine (Ticlid) 
• 
tipranavir (Aptivus) 
• 
tripelennamine (Pyribenzamine) 
• 
other histamine H1 receptor antagonists** 
 
Possible CPY2D6 Inducers 
• 
dexamethasone (Decadron, Hexadrol) 
• 
rifampin (Rifadin, Rimactane) 
* available over the counter 
**Examples: cetirizine (Zyrtec), dimenhydrinate (Drammamine), doxylamine (included in NyQuil), fexofenadine 
(Allegra), loratidine (Claritin), meclizine (Antivert, Drammamine), pheniramine (Avil) 

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Patients on strong or clinically significant CYPD6 inhibitors (1) will be excluded at screening.  Patients in 
the elevated risk group randomized to carvedilol will be asked to notify the study team immediately if they 
are prescribed one of these drugs while taking study medication.  When the study team becomes aware 
that patient has been prescribed one of the drugs in (1), the PI will be notified.  The PI will contact treating 
provider to recommend possible alternatives prior to the patient’s starting the new medication.  If there is 
no clinically acceptable alternative to a drug in (1), patient will stop carvedilol.  Patient will continue on study 
and complete all study visits.   
 
If a subject is on a drug in (2) at screening and is in the elevated risk group randomized to carvedilol, the 
PI will contact the treating provider as soon after consent as possible to recommend possible alternatives.  
Patient may start study medication while this is occurring.  If a subject in the elevated risk group randomized 
to carvedilol is prescribed a drug in (2) during the intervention, they are asked to notify the study team 
immediately.  When the study team becomes aware that the patient has been prescribed one of the drugs 
in (2), the PI will be notified and will contact the treating provider to recommend possible alternatives.  If 
there is no clinically acceptable alternative to a drug in (2), the subject will stop carvedilol.  Patient will 
continue on study and complete all study visits. 
 
Of note, detailed correspondence with oncology PharmD at Penn do not indicate that the interaction with 
doxorubicin is clinically relevant, and patients have been safely treated with these agents in combination, 
both in clinical practice and in randomized clinical trials (Kalay et al, Avila et al).39,40  In addition, although 
both dexamethasone and diphenhydramine are commonly used in this population as pre-medication for 
chemotherapy, the potential interaction with carvedilol is not believed to be clinically significant.  We do not 
intend to restrict concomitant use of either agent in subjects on study intervention. 
 
Carvedilol may mask symptoms of hypoglycemia or worsen hyperglycemia.  Subjects with diabetes in the 
elevated risk group assigned to the intervention arm will be reminded to follow-up with their PMD or 
endocrinologist on a regular basis and to notify them that they are on carvedilol. 
 
12.1.2 Risk of Study Procedures 
Echocardiography is a safe and non-invasive imaging modality.  There are no serious risks associated with 
transthoracic echocardiography.  The additional strain imaging acquired during this study poses no 
foreseeable serious risks to subjects.  Strain imaging prolongs acquisition time by approximately 15 
minutes, which does not pose any foreseeable serious risks to subjects.  It is possible that subjects may 
experience mild, temporary discomfort from the ultrasound probe being pressed against the chest or from 
lying in the recumbent position for the duration of the study. 
 
Blood draws: Participants in this study will undergo blood sampling for biomarker assessment.  Blood may 
also be drawn as part of screening (if results are not available within the medical record). 
Occasionally there are risks associated with blood draws such as bruising, swelling, black and blue marks, 
fainting and/or infection at the site.  Subjects may also experience a decrease in hemoglobin and hematocrit 
(red blood cell number, called anemia) from having blood drawn frequently. To minimize discomfort and 
inconvenience, blood sampling will be combined with a routine clinical blood draw whenever possible.  
Approximately 16mL (1tbs) of blood will be collected at baseline for research purposes and approximately 
12mL (2tsp) of blood will be collected at subsequent visits (see Table 3 for timepoints when blood will be 
collected).  We do not propose collecting more that 50mL in an 8-week period for the purposes of this study.   
 
Symptoms Survey:   There are no medical risks associated with answering survey questions.  However, a 
patient may become uncomfortable providing personal information.  Any question that makes a patient 
uncomfortable can be skipped. 
 
12.1.3 Other Risks of Participating in Study 

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Risks Related to CTX Risk Calculator: We plan to tell subjects to which risk group they belong based on 
our CTX risk calculator.  For some patients, knowing this information may cause additional anxiety.  
Additionally, subjects in the elevated risk group assigned to usual care may experience anxiety related to 
the fact that they are not receiving the active intervention.  The PI will provide counseling to all patients 
about how to interpret their risk score to help them manage this anxiety.  Furthermore, all subjects 
(regardless of risk group or arm assignment) will receive the same prospective monitoring.  The PI will 
contact patients with the results of any echo done for research purposes, and we will reassure patients 
throughout the study that if there are any clinically significant findings from study procedures, we will tell 
them and their care team. 
 
The risk of incorrect assignment to the elevated risk group (a false positive from the CTX Risk Calculator) 
would result in the prescription of carvedilol or usual care.  Thus, the risks are analogous to that of being 
on carvedilol (discussed in 12.1.1).  A false negative from the CTX Risk Calculator would result in 
assignment to the current standard of care.   
 
Genetic Information:  Plasma, serum, and DNA from blood samples will be banked for future use.  Blood 
samples banked from this study may be used as part of an exploratory analysis to help generate hypotheses 
as to if there are SNP variations that are associated with an increased risk of cardiotoxicity development, 
and if there are SNP variations that are associated with deriving greater benefit from cardioprotection with 
carvedilol.  We will determine the most cost-effective approach to genotyping at the time of analysis as this 
technology continues to evolve.   
 
One possible risk is the loss of confidentiality of genetic information.  This research includes genetic testing.  
The researchers believe that the risks that a subject will be identified solely from genetic information are 
very small, but the risk may change in the future as new methods of tracing information are developed.   
 
There can be a risk to knowing genetic information.  New health information about inherited traits that might 
affect subjects or their blood relatives could be found during a research study. Although we are not able to 
know all of the risks from taking part in research on inherited traits, we believe that the risks to subjects and 
their families are very low.  Samples will be coded and results of genetic testing will not be shared with 
subjects or entered into their medical record. A related possible risk is disclosure of genetic information that 
could lead to discrimination in insurance or employment. Very rarely health or genetic information could be 
misused by employers, insurance companies, and others. For example, it could make it harder to get or 
keep a job or insurance, or life insurance companies may charge a higher rate based on this information. 
We believe the chance these things will happen is very small, but we cannot make guarantees. 
 
Time: As a result of taking part in this study, patients may lose time at work or home and spend more time 
in the doctor’s office than usual.  As much as possible, study visits will be planned on days subjects will be 
at the Perelman Center for clinical care, and scheduled so as to minimize the “extra” time patients are asked 
to spend here.   
 
Other: In addition, there may be other unforeseeable risks and inconveniences associated with participation 
in this study.     
 
12.2 Benefits 
There may be no direct benefit to being in this study. 
 
This study may benefit future breast cancer patients by furthering efforts to better predict who is at risk for 
cardiotoxicity, and is an important first step in developing risk-guided cardioprotective strategies for cancer 
patients. 
 

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12.3 Risk Benefit Assessment 
While this study does involve certain risks to subjects, the potential benefits derived from this study 
significantly outweigh the risks associated with this research. 
 
12.4 Informed Consent Process / HIPAA Authorization  
The study will use a combined Informed Consent and HIPAA Authorization Form.   
 
After the subject has been identified by the oncologist, study staff will conduct a phone or in-person interview 
(script attached) to assess subject interest in the study and review exclusion criteria.  If patient is interested 
and is found to be ineligible, study staff will describe the study in detail to make the patient aware of the 
procedures, intervention, and time commitment involved with the study.  During or immediately following 
this conversation, the subject will be given a copy of the informed consent form to review (coordinator will 
email or mail to patient with permission, or will make arrangements to meet patient at next visit at Perelman 
Center).  During this conversation, patients will be encouraged to discuss the study with their treating 
oncologist and with other providers, including primary care provider or cardiologist.  Patients will be given 
the opportunity to ask study staff questions about the study during this conversation and in follow-up 
conversations.  The will also be offered an opportunity to discuss the study with the PI on the phone or in 
person prior to the screening visit.  If interested, patients will be given the option of scheduling the screening 
visit during this conversation.  If they prefer to consider the study further before scheduling the screening 
visit, study staff will ask for permission to follow-up with the patient at a specified time to see if they would 
like to schedule the screening visit.   
 
 
Written consent will be obtained by research coordinator or attending physician investigator in person, in a 
private exam or consult room.  The person obtaining consent will review the details of the study with the 
patient, and will remind the patient that participation is voluntary and will not change the treatment they 
would otherwise receive.  Person obtaining consent will ensure all questions regarding the study are 
answered to the patient’s satisfaction. A copy of the signed consent form will be given to the patient.  No 
study procedures will be completed until written consent is obtained.  Typically, consent will be obtained at 
the screening visit.  The person obtaining consent will document consent in the electronic medical record. 
 
13 Study Finances 
 
13.1 Funding Source 
Funding for this project will come from R01 HL118018 and from departmental start-up funds. In addition, 
the study has been funded by an AHA grant, and is currently supported by an NHLBI R21. This pilot study 
is critical to the generation of preliminary data for a new R01 application. 
 
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
 
13.3 Subject Stipends or Payments 
In appreciation for their participation, subjects will receive $6 for each study visit.  If visits occur on days 
when patients are not scheduled for infusion, we will also reimburse for parking. Payment will be made 
using the Greenphire ClinCard.  Subjects will be given a FAQ on the Clincard (see attachments). 
 
14 Publication Plan 
Publication authorship will be based on the relative scientific contributions of the PI, co-Investigators, and 
key personnel and in accordance with policies of the University of Pennsylvania.  Drafting and publication 
of manuscripts will be carried out in a collaborative manner and pre-defined authorship roles will be set so 
as to avoid conflicts and disagreements.  The PI will review progress, address concerns, prioritize analysis 
plans, and discuss publications. 

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This material is the property of the University of Pennsylvania.   
 
 
 
 
15 Attachments 
• Subject drug diary template 
• Blood Processing Protocol 
• Echo Protocol 
• Hill-Bone Compliance Scale 
• MD Anderson Symptoms Inventory – Heart Failure 
• FACIT Fatigue  
• FACIT Dyspnea on Exertion 
• Godin Leisure-Time Questionnaire 
• Greenphire Clincard FAQ 
• Wallet Card 
 
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