Assessment of the Reproducibility and Accuracy of a Portable System for Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors
Phase: NA
Conditions: Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm
Sponsor: City of Hope Medical Center

 
IRB #21466 
 
06/30/22 
Packet : 08 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF Population Sciences 
 
 
TITLE:  
Assessment of the reproducibility and accuracy of a portable system for early detection of 
cardiac dysfunction in childhood cancer survivors 
 
CITY OF HOPE PROTOCOL NUMBER: 
IRB # 21466  
 
PROTOCOL DATE: 06/30/2022 
 
 
 
 
 
 
 
 
 
 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
COH Initial Approval 
Protocol Dated 08/31/21 
Packet: 00 
COH Amendment 01 
Protocol Dated 06/30/22 
Packet: 01  
COH Amendment 02 
Protocol Dated 06/30/22 (tp) 
Packet: 02 
COH Amendment 03 
Protocol Dated 06/30/22 (tp) 
Packet: 03 
COH Amendment 04 
Protocol Dated 06/30/22 (tp) 
Packet: 04 
COH Amendment 05  
Protocol Dated 06/30/22 (tp)  
 
 
 
      Packet: 05 
COH Amendment 06  
Protocol Dated 06/30/22 (tp)  
 
 
 
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COH Amendment 07   
Protocol Dated 06/30/22 (tp)  
 
 
 
      Packet: 07 
COH Amendment 08   
Protocol Dated 06/30/22 (tp)  
 
 
 
      Packet: 08 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Saro Armenian, DO, MPH 
 
C0-INVESTIGATOR: 
Faizi Jamal, MD 
Rusha Bhandari, MD 
 
COLLABORATING INVESTIGATOR(S): 
 
Bonnie Ky, MD (UPenn) 
Morteza Gharib, PhD (CalTech) 
Hari Narayan, MD (UCSD) 
Derek Lance 
Caitlyn Estrada 
 
BIOSTATISTICIAN(S): 
 
Lennie Wong, PhD 
Sitong Chen 
Xinyi Du 
 
 
 
PARTICIPATING CLINICIANS: 
 
 
Biraj Bista, MD 
Deniz Urgun, MD 
 
Non-Physician Consenters: 
Claudia Herrera  
Meagan Echevarria 

 
IRB #21466 
 
06/30/22 
Packet : 08 
Stephanie Rodarte 
 

This document is confidential and for research purposes only. Distribute and use ONLY as authorized.  
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
 
Assessment of the reproducibility and accuracy of a portable system for 
early detection of cardiac dysfunction in childhood cancer survivors  
 
Version Date: 06/30/2022 
Protocol Version: 01  
 
City of Hope #: 21466 
Funding Support: National Cancer Institute  
NCT Number: 1R21CA261797-01 
Short Title Remote cardiac monitoring in CCS 
  
 
Principal Investigator 
Saro Armenian DO, MPH 
City of Hope National Medical Center 
Dept. of Population Sciences 
T: (626) 218-7320 
Email: sarmenian@coh.org 
 
 

 
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PROTOCOL TEAM 
Biostatistician 
Lennie Wong, PhD 
City of Hope National Medical 
Center 
Dept. of Population Sciences 
T: (626) 218-5204 
Email: lenniewong@coh.org 
 
Co-Investigator 
Faizi Jamal, MD 
City of Hope National Medical 
Center 
Dept. of PS MEDICINE 
T: (626) 218-2491 
Email: fjamal@coh.org 
 
Co-Investigator 
Rusha Bhandari, MD 
City of Hope National Medical 
Center 
Dept. of Population Sciences 
T: (626) 841-2394 
Email : rbhandari@coh.org 
 
 
 
Co-Investigator 
Bonnie Ky, MD 
Children's Hospital of 
Pennsylvania 
Dept. of Cardiology 
T: (215) 573-6606 
Email: 
bonnie.ky@uphs.upenn.edu 
 
Co-Investigator 
Morteza Gharib, PhD 
California Institute of Technology 
Division of Engineering and 
Applied Sciences 
T: (626) 395-4450 
Email: mgharbib@caltech.edu 
 
Co-Investigator  
Hari Narayan, MD 
Rady’s Children’s Hospital,  
San Diego 
Dept. of Cardiology 
T: (858) 966-5855 
Email: hnarayan@health.ucsd.edu 
 
 

 
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PROTOCOL SYNOPSIS 
Protocol Title 
Assessment of the reproducibility and accuracy of a portable system for early detection of cardiac 
dysfunction in childhood cancer survivors  
Study Detail 
Population/Indication(s): Childhood Cancer Survivors (Cancer diagnosis prior to 22 years of 
age) 
Phase: N/A 
Sample Size: 200 
Estimated Accrual 
Duration: 1 Year 
Estimated Study Duration 2 Years 
Participant Duration: Approximately 1 week 
  
  
Study Design 
This is a cross-sectional evaluation of 200 childhood cancer survivors who previously underwent a 
one-time assessment of cardiac function by echocardiogram (echo) and Cardiac Magnetic Resonance 
(CMR) Imaging between November 2014 and May 2017 (IRB# 14154). We plan to evaluate the 
reliability and cost-effectiveness carotid pulse-wave based measurement of cardiac ejection fraction 
using tonometry-based systems in clinical (SphygmoCor® Xcel) and home based (Oscar 2™) settings.  
Objectives 
Primary Objective(s) 
 
Validate the accuracy of ejection fraction, as measured using a tonometry-based system 
(SphygmoCor® Xcel), in the clinic setting, and determine the reproducibility (Oscar 2™) at 
home. 
Secondary Objective(s) 
 
Determine the cost-effectiveness of tonometry-based screening in the clinic setting and at 
home. 
Methods Description 
Study participants will undergo repeat measurement of ejection fraction by echo, CMR and a one-time 
measurement of carotid pulse wave in the clinical setting (SphygmoCor® Xcel) and will be taught how 
to obtain BP measurements by the portable Oscar 2™  device in the home setting. Participants will be 
asked to perform their home-based measurements within 1-5 days of the clinical assessment, allowing 
us to directly compare measurements obtained by survivors to those by research personnel. 

 
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Main Eligibility Criteria 
Main Inclusion Criteria 
 Previously enrolled in IRB# 14154.  
Main Exclusion Criteria 
 Participants cannot be actively receiving cancer-directed therapy. 
 Standard exclusion for CMR will be incorperated, and these include implated pacemaker or 
defibrillator, insulin pump, cochlear implant, central nervous system aneurism clips, implanted neural 
stimulator, occular foreign body (metal), other implanted medical devices (e.g. drug infusion ports).  
 
 

 
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TABLE OF CONTENT 
SECTION………………………………………………………………………………………………………………PAGE 
Protocol Team .......................................................................................................................................... 2 
Protocol Synopsis ..................................................................................................................................... 3 
Table of Content ....................................................................................................................................... 5 
Abbreviations ............................................................................................................................................ 7 
1.0 
Objectives ..................................................................................................................................... 8 
1.1 
Primary Objective 
8 
1.2 
Secondary Objective 
8 
2.0 
Background ................................................................................................................................... 9 
2.1 
Disease Indication and Unmet Need 
9 
2.2 
About the Current Study 
10 
2.3 
Study Rationale 
10 
3.0 
Eligibility Criteria .......................................................................................................................... 11 
3.1 
Inclusion Criteria 
11 
3.2 
Exclusion Criteria 
11 
4.0 
Participant Enrollment ................................................................................................................. 11 
4.1 
Screening and Recruitment 
11 
4.2 
Informed Consent Process 
11 
5.0 
Methods ...................................................................................................................................... 12 
5.1 
Study Overview 
12 
5.2 
Study Procedures 
12 
5.3 
Duration of Study Participation 
14 
6.0 
Study Calendar ........................................................................................................................... 15 
7.0 
Human subjects Issues ............................................................................................................... 16 
7.1 
Potential Benefits 
16 
7.2 
Potential Risks 
16 
8.0 
Statistical Considerations ............................................................................................................ 16 
8.1 
Sample Size, Accrual Rate and Study Duration 
16 
8.2 
Statistical Analysis Plan 
16 
9.0 
Data Handling, Data Management, Record Keeping .................................................................. 18 
9.1 
Source Documents 
18 
9.2 
Data Capture Methods and Management 
18 
9.3 
Data Entry 
18 
9.4 
Regulatory Records 
18 
10.0 
Reporting of Adverse Events, Unanticipated Problems & Other Events of Interest .................... 19 
10.1 
Assessment of Adverse Events 
19 
10.2 
Routine AE Collection and Reporting Guidelines 
19 
10.3 
Expedited Reporting 
19 
11.0 
Adherence to the Protocol & Reporting of Protocol Deviations ................................................... 20 
11.1 
Reporting by COH 
20 
12.0 
Study Oversight, Quality Assurance, & Data and Safety Monitoring .......................................... 21 
12.1 
All Investigator Responsibilities 
21 
12.2 
Study Principal Investigator Responsibilities 
21 
12.3 
Protocol Management Team (PMT) 
21 
12.4 
Quality Assurance 
21 
12.5 
Risk Determination 
21 

 
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12.6 
City of Hope Data and Safety Monitoring Committee 
21 
13.0 
Ethical and Regulatory Considerations ....................................................................................... 22 
13.1 
Ethical Standard 
22 
13.2 
Regulatory Compliance 
22 
13.3 
Institutional Review Board 
22 
13.4 
Informed Consent 
22 
13.5 
Participant Withdrawal 
23 
13.6 
Special and Vulnerable Populations 
23 
13.7 
Participant Confidentiality 
23 
13.8 
Conflict of Interest 
24 
13.9 
Financial Obligations, Compensation, and Reimbursement of Participants 
24 
13.10 Publication/ Data Sharing 
24 
14.0 
References .................................................................................................................................. 26 
 
 
 

 
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ABBREVIATIONS  
 
Abbreviation 
Meaning 
2D 
Two-dimensional 
AE 
Adverse Event 
BLE 
Bluetooth Low Energy 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CMR 
Cardiac Magnetic Resonance  
CMS 
Centers for Medicare & Medicaid Services 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMC 
Data & Safety Monitoring Committee 
DSMP 
Data & Safety Monitoring Plan 
Echo 
Echocardiography 
EKG 
Electrocardiogram 
EF 
Ejection Fraction 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
LoA 
Limits of Agreement 
LV 
Left Ventricular  
mHealth 
Mobile Health 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
PCP 
Primary Care Provider 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
UP 
ABPM 
PWV 
Unanticipated Problem 
Ambulatory Blood Pressure Monitor 
Pulse Wave Velocity 
 

 
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1.0 OBJECTIVES 
1.1 Primary Objective 
o Validate the accuracy of ejection fraction, as measured using a tonometry-based system 
(SphygmoCor® Xcel), in the clinic setting, and determine the reproducibility (Oscar 2™) at 
home. 
1.2 Secondary Objective 
o Determine the cost-effectiveness of tonometry-based screening in the clinic setting and at 
home. 

 
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2.0 BACKGROUND 
2.1 Disease Indication and Unmet Need 
2.1.1 Risk of Congestive Heart Failure in Childhood Cancer Survivors  
Anthracyclines are among the most effective antineoplastic therapies and are used in nearly 60% of 
childhood cancer patients. One of the most widely-recognized side-effects of anthracyclines is dose-
dependent heart failure that usually develops years after completion of cancer treatment.1 Overall, 
childhood cancer survivors are at a 4-fold increased risk of heart failure when compared to age-matched 
sibling controls,2,3 and it is estimated that 1 in 10 children treated with high-dose (≥250 mg/m²) 
anthracyclines will eventually develop heart failure.4 Improvements in treatment and supportive care have 
resulted in a rapid increase in the number of childhood cancer survivors. These survivors are expected 
to constitute a significant proportion of the US population at risk for preventable heart disease in adult 
life.5,6 
2.1.2 Natural History of Cardiotoxicity 
Anthracycline cardiotoxicity is thought to be related to a combination of free-radical and topoisomerase 
IIB-mediated direct myocardial injury.7 If enough myocardial injury occurs, the heart expands in size and 
the chamber walls become thinner, creating a clinical picture similar to dilated cardiomyopathy.8 The 
characteristically delayed manifestation of heart failure after anthracycline exposure is likely related to 
the eventual failure of a reduced number of unhealthy cardiomyocytes in response to the increase in 
myocardial wall stress.9,10 Importantly, it is well-recognized that there is a variable period of asymptomatic 
cardiac dysfunction that precedes symptomatic disease, which offers a window for early detection and 
improved management of cardiac dysfunction.9 Asymptomatic cardiac dysfunction can be identified as 
abnormalities of cardiac function on imaging studies (e.g. abnormal left ventricular [LV] ejection fraction), 
allowing for initiation of pharmacologic therapy to delay or prevent the onset of symptomatic heart failure. 
Echo is the most widely available platform to assess EF, and current survivorship guidelines recommend 
lifelong echo-based screening for all anthracycline-exposed survivors. However, survivorship care 
providers and researchers have increasingly questioned the role of echo for population-based screening 
due to the wide inter- and intra-observer variability of echo-based EF.11 More accurate platforms such as 
cardiac magnetic resonance (CMR) imaging can overcome the limitations of echo, but the use of CMR 
is limited due to its significant cost and lack of wide availability. Thus, there is an urgent need to identify 
accurate as well as accessible screening strategies for at-risk survivors. 
2.1.3 Novel accessible and accurate strategies for cardiac function assessment 
A research team at California Institute of Technology (Co-I M. Gharib) recently developed a novel 
algortihm that utilizes a systems-based approach to evaluate cardiac function by using the measurements 
obtained from the carotid pulsewave. In brief, the platform relies on the concept 
that LV and arterial vasculature act as a coupled hemodynamic system before 
the aortic valve closes, expressed as a dominant frequency (ω1); Figure 1.12,13 
After valve closure, they become decoupled from one another, and the resultant 
frequency (ω2) reflects the dynamics inside the aorta and its branches.12,13 Using 
non-invasive data capture, we are able to extract metrics that correlate with a 
person’s cardiac function via analysis of hemodynamic waveforms using 
cardiovascular intrinsic frequency.13,14 This strategy has been successfully 
utilized in non-oncology populations, but has not been prospectively validated in 
a prospective cohort setting.  

 
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2.1.4 The high cost of cardiac screening 
Our investigative team (S. Armenian, F.L. Wong) recently evaluated the cost-effectiveness of the current 
cardiac screening guidelines for childhood cancer survivors.15 We found that although routine cardiac 
screening is cost-effective, the cost of screening by echo is the greatest contributor to lifetime screening 
cost (>$55,000 per person)15—the lifetime cost for the estimated 300,000 childhood cancer survivors in 
the US exposed to anthracyclines is thus expected to exceed $16 billion.16 As such, it is imperative that 
accurate yet inexpensive alternatives be pursued for monitoring these patients. Concerns regarding the 
rising lifetime cost of echo-based screening are also relevant for the growing number of adult-onset 
cancer survivors (e.g. hematologic malignancy, breast cancer) treated with cardiotoxic therapies—the 
combined healthcare costs for this group of patients are expected to exceed $50 billion in the year 2020 
alone.17 
2.1.5 Urgent need for remote delivery of survivorship care 
It is well-recognized that when childhood cancer survivors transition from the cancer center to the primary 
care setting, they no longer see their oncology team on a regular basis, and rarely visit survivorship care 
specialists.18 Thus, the long-term preventive care of these survivors is scattered across hundreds of 
thousands of individual primary care providers (PCPs). Although these survivors do seek primary care—
more than 90% have seen their PCPs in the past two years—it is not in the cancer center context, where 
knowledge about the link between cancer-specific risk factors (e.g. anthracyclines) and heart disease is 
known.19 As a result, <30% of long-term childhood cancer survivors report having undergone risk-based 
cardiac screening.19 Survivors living in rural communities are especially affected by the disparities in 
access to specialized survivorship centers. Tonometry-based screening has the potential to bridge the 
gap in optimal delivery of risk-based survivorship care by allowing point-of-care cardiac assessment by 
PCPs in the community, or by facilitating home-based surveillance by specialized survivorship centers. 
2.2 About the Current Study 
This study is a cross-sectional evaluation of 200 childhood cancer survivors who previously underwent a 
one-time assessment of cardiac function by echo, CMR, and a tonometry-based system between 
November 2014 and May 2017 (IRB# 14154). Study participants will undergo repeat measurement of EF 
by echo and CMR and will have their carotid pulsewave measured by tonometry using SphygmoCor® 
Xcel in the clinical setting. The pulsewave measurements obtained from the SphygmoCor® Xcel will then 
be utilized to derive the participant EF. Participants will also be taught how to obtain pulsewave 
measurements by the portable version of the SphygmoCor® Xcel, which is the Oscar 2™, allowing them 
to use it in the home setting. Participants will be asked to perform their home-based measurements within 
1-5 days of the clinical assessment, allowing us to directly compare measurements obtained by survivors 
to those by research personnel. 
2.3 Study Rationale  
This study focuses on an emerging and critically important clinical finding—the greatly increased 
risk of heart failure in childhood cancer survivors, with its associated high burden of morbidity—and 
includes several innovative approaches to address this serious threat to survivors’ health and quality of 
life, as outlined below. 
• Our proposal builds on well-established evidence that early screening for cardiac dysfunction is 
effective and introduces a new approach to easily integrate cardiac screening in the community setting. 
• We are using a very cost-efficient and scalable approach that will provide healthcare providers 
with real-time access to vital information regarding change in cardiac function in vulnerable cancer 
survivors. 

 
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• We are responding to the demands of a relatively young population (70% are <40 years of age) 
of childhood cancer survivors who are technology-engaged and willing to consider remote mobile health 
(mHealth)-promotion programs to maintain their well-being. 
Completion of the proposed research will be a major step toward building an integrative mHealth 
platform that will allow real-time screening and management of the most common health conditions (e.g. 
cardiac dysfunction, hypertension, diabetes, overweight/obesity) in childhood cancer survivors. The 
growing population of childhood cancer survivors (>500,000 alive in the U.S. today) makes development 
of such strategy’s imperative, to ensure that these survivors live long and healthy lives well after their 
cancer treatment. 
3.0  ELIGIBILITY CRITERIA 
Participants must meet all of the following criteria on screening examination to be eligible to participate 
in the study:  
3.1 Inclusion Criteria 
1. Previously enrolled in IRB# 14154. 
2. Able to understand and sign the study specific Informed Consent Form (ICF). 
3.2 Exclusion Criteria 
1. Participants cannot be actively receiving cancer-directed therapy.  
2. Standard exclusion criteria for CMR imaging will be incorporated, and these include: implanted 
pacemaker or defibrillator, insulin pump, cochlear implant, central nervous system aneurismal 
clips, implanted neural stimulator, ocular foreign body (metal), other implanted medical devices 
(e.g.: drug infusion ports). 
4.0 PARTICIPANT ENROLLMENT 
4.1 Screening and Recruitment 
We will identify eligible individuals from an existing electronic database of long-term childhood cancer 
survivors who previously participated in IRB# 14154. A member of the study team will pre-screen all 
patients that were previously enrolled in IRB# 14154 by reviewing the medical charts and will exclude 
anyone with conditions or reasons that may prohibit study entry. All eligible participants will be sent a 
letter (mail, email, or MyChart) briefly introducing the study, with instructions detailing how to contact 
research personnel if they have any questions. A member of the study team will follow up on the letter to 
gauge the survivor’s interest.  
4.2 Informed Consent Process 
Informed consent will be obtained in person or via mail, electronic mail, or by DocuSign™ to obtain 
electronic signatures from each patient per standard practice. At the time of consent, the study will be 
reviewed with the subject either by a study investigator or clinician or by a specially trained clinical 
research personnel member who will answer any questions that the subject may have prior to signing 
consent. Informed consent will be obtained from each subject who agrees to participate. The 
investigational nature and objectives of the study, the procedures involved, and their possible risks and 
discomforts will be carefully explained while obtaining informed consent. Subjects that agree to 
participate will be given a signed copy of the consent form and experimental subjects’ bill of rights to 
keep. The Principal Investigator will be available to speak to the subject in the event that the subject asks 

 
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a question that the consenter is unable to answer or if the subject requests to speak with the Principal 
Investigator. 
5.0 METHODS 
5.1 Study Overview 
Participants will be scheduled to come to City of Hope for a one-time assessment of cardiac function by 
echo, CMR, and the SphygmoCor® Xcel system. On the day of the SphygmoCor® Xcel -based 
measurement, a member of the study team will also train the participant on how to use the Oscar 2™ 
ABPM system. The participant will be asked to demonstrate that they can take accurate measurements. 
Once he/she can obtain three accurate readings, they will be sent home with an Oscar 2™ ABPM  to 
perform measurements in a home-based setting. The Oscar 2™ ABPM platform only records the Subject 
ID assigned to each participant and PI’s last name in addition to the measurements collected by the BP 
monitor and so no identifying information is captured nor stored by Oscar 2™ ABPM.  
5.2 Study Procedures 
5.2.1 Echocardiographic Evaluation  
We will assess cardiac function and mechanics using comprehensive 2D echocardiography with Doppler 
imaging. Cardiac structure and function will be quantified at rest as recommended by the American 
Society of Echocardiography and the European Association of Cardiovascular Imaging practice 
guidelines.20 We will record heart rate, quantify LV volumes in systole and diastole in the apical 4- and 2-
chamber views in triplicate using the biplane method of discs to calculate EF, as recommended by the 
ASE.21 At rest, we will estimate SV using the equation: SV = (LV outflow tract diameter/2)2 × LV outflow 
tract velocity time integral (VTI). We will also derive effective arterial elastance (Ea), end-systolic 
elastance (Ees), and Ea/Ees. Ea, which is a measure of systemic arterial stiffness, will be estimated as end-
systolic pressure (ESP)/SV, and ESP will be estimated as 0.90 x systolic pressure, obtained by blood 
pressure (BP) cuff at the time of the echo. Ees is a measure of LV contractility, and will be derived using 
a modified single-beat algorithm using BP, SV, pre-ejection and total systolic ejection timing intervals.22 
VA coupling provides insight into chamber efficiency and is also predictive of cardiac dysfunction and will 
be indexed by the ratio Ea/Ees. We will also obtain detailed measures of LV diastolic function, including 
pulsed Doppler measurement of mitral valve inflow, peak velocities of early filling (E-wave) and filling 
during atrial systole (A-wave), mitral annular myocardial e’ and a’ velocities, mitral E/A and E/e’ ratios, 
and mitral deceleration time. We will evaluate peak systolic strain using commercially available analysis 
software (EchoPAC vBT08; GE Healthcare, USA). Measurements will include peak longitudinal (global 
and all LV segments), as well as regional and global circumferential strain.23 
A de-identified copy of the digitized images will be sent to the cardiology lab where LV dimensions, 
volumes, and EF will be measured by a single cardiologist (Co-I F. Jamal) who will be blinded to clinical 
and treatment history of participants. 
5.2.2 CMR Imaging  
CMR imaging will be performed on the same day using a commercially available Vida 3T scanner 
(Siemens Healthineers USA) equipped with parallel imaging methods, electrocardiographic gating, and 
an 8-channel cardiac phased-array coil. LV volumes and EF will be obtained using breath-hold ECG-
gated 2D cine steady-state free-precession sequences in the 2-, 3-, 4-chamber, and contiguous short-
axis orientations. Computation of end-systolic and end-diastolic volumes will be performed by trained 
research personnel—we have demonstrated excellent intra- and inter-observer (research personnel: 
study cardiologist) correlations for LV volume measurements (correlation coefficient range 0.91–0.99) in 
previous studies. 

 
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As in echocardiograms, a de-identified copy of the digitized images will be sent to the CMR lab where LV 
dimensions, volumes, and EF will be measured by a single cardiologist (Co-I H. Narayan) who will be 
blinded to clinical and treatment history of participants. 
 
5.2.3 SphygmoCor® Xcel and Oscar 2™ ABPM -based Capture of Cardiac Function 
Description: The SphygmoCor® Xcel and Oscar 2™ ABPM devices use a standard brachial cuff 
to measure brachial systolic and diastolic pressures as well as tonometry while capturing brachial 
waveform. Additionally, the device uses a thigh cuff to capture aortic pulse wave velocity (PWV) 
measurements using the aid of a carotid tonometer. During the visit, the Xcel device will first be used with 
a BP cuff to obtain routine blood pressure measurements of systolic and diastolic pressure before the 
cuff partially re-inflates to capture the brachial waveform. Afterwards, the study staff will switch to thigh 
cuff and carotid tonometer to capture blood pressure waveforms at the carotid and femoral sites. These 
data points are then analyzed by the SphygmoCor® Xcel software, deriving ascending aortic waveform 
and PWV using a validated mathematical transfer function, and displaying the calculated data alongside 
other noninvasive central blood pressure measurements recorded. SphygmoCor® Xcel and Oscar 2™ 
ABPM system has 510(k) U.S. FDA clearance as a medical device to perform non-invasive 
cardiovascular measurements as an adjunct to manage various cardiovascular conditions. 
On the day of examination: Research personnel will place the SphygmoCor® Xcel cuff over the 
participant’s maximum brachial pulse, after palpation of the course of the brachial artery. Afterwards, the 
research personnel will switch to thigh cuff and carotid tonometer to capture blood pressure waveforms 
at the carotid and femoral sites. The procedure of collecting the brachial pulse will then be redone using 
the Oscar 2™ ABPM and cuff. Research personnel will instruct the participant on how to properly put on 
the cuff and take accurate measurements. The participant will be allowed to demonstrate understanding 
by taking measurements on themselves until 3 successful measurements are performed. The time of 
application is defined as the time needed to collect 20-30 good quality arterial waveforms, not to exceed 
BP cuff inflation time of <180 seconds at one time. Measurements will be obtained from the left (preferred) 
or right brachial arteries. The SphygmoCor® Xcel and Oscar 2™ ABPM data capture procedures are 
non-invasive. Measurements made from both systems will be relayed via wired connection to the study 
laptop that is disconnected from all networks. Recordings will ideally be performed on the same day as 
the echo and CMR, and research personnel will be blinded to both the echo and CMR results. After the 
waveforms are collected, cardiac cycles will be selected by a researcher blinded to study participant 
clinical history, echo, and CMR data. We will use the selected cycles to calculate EF via a specialized 
algorithm called the Intrinsic Frequency.13,24,25 In brief, the intrinsic frequency algorithm computes the two 
dominant dynamic frequencies present within a cardiac cycle before and after the closure of the aortic 
valve (see A.3, Figure 1). Due to the high nonlinearity of the dynamics of both the LV and arterial systems, 
we will apply a linear regression model to calculate EF. 13,24,25 Our research team recently automated 
real-time measurement of EF from these waveforms using artificial-intelligence machine-learning 
algorithms,13,24,25 and we will use this approach in addition to previously employed retrospective linear 
regression techniques. 
Instruction for home-based measurement: Study personnel will guide participants on proper 
anatomic placement of the Oscar 2™ ABPM cuff. To demonstrate competency, participants will be asked 
to obtain at least three correct measurements in the clinic. In addition, they will be given an instructional 
brochure that details the proper self-measurement technique. Participants will be asked to take the Oscar 
2™ ABPM and associated cuff home with them and perform measurements that day over the interval of 
4 hours. The data from at home measurements will be imported into the secure study laptop after the 
Oscar 2™ ABPM and cuff are returned to research personnel. Research personnel will be available to 
troubleshoot technical difficulties. Once the participants complete the measurements, they will return the 
devices back to City of Hope using a pre-paid shipping label and box given to them at their clinic visit. A 

 
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member of the research personnel will follow-up to confirm the measurements were completed and the 
devices were returned. 
 
Receiving, Storage, System Use and Return: Research personnel are responsible for the 
shipment, receipt, storing, charging, and testing the Oscar 2™ ABPM device. The Oscar 2™ ABPM 
device components will be cleaned using 70% alcohol wipe upon receipt.  
5.2.4 Other Study Procedures 
5.2.4.1 Measurement of Blood Pressure, Heart Rate, Body Weight and Height 
Blood pressure, heart rate, body height and weight will be measured the day of the clinic 
visit. Sitting/supine blood pressure and heart rate should be measured after the subject 
has been sitting quietly for at least 5 minutes. Body height and weight should be measured 
without shoes, using the same equipment for each study participant whenever possible. 
5.2.4.2 Questionnaires 
Self-reported and CRA/CRN administered questionnaires will be used to obtain baseline 
data on demographics, family history, and other CV risk factors.  
1. 
Demographics, 
and 
CV 
risk 
factors 
information 
(Demographics 
and 
Cardiovascular Risk  Factors Form) 
2. 
Family history (COH DPS Family History Form) 
The salient domains captured by these questionnaires include date of birth, gender, 
race/ethnicity, socioeconomic status, and both familial and environmental CV risk factor. 
5.3 Duration of Study Participation 
The clinic portion of the study will take approximately 4 to 6 hours, while the home-based measurement, 
including the return of the Oscar 2™ ABPM, is expected to take no more than 1 week.  
 

 
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6.0 STUDY CALENDAR 
All assessments may increase in frequency as clinically indicated. 
  
 
 
Screening 
Clinic Visit 
At Home 
 
Remote or City of 
Hope 
At City of 
Hope 
At Participant’s 
Home 
Screening  
X 
 
 
Consent 
X 
 
 
Vital Signs (Blood Pressure. 
Heart Rate, Height, Weight)  
 
X 
 
Echo 
 
X 
 
CMR 
 
X 
 
Oscar 2™ ABPM Training 
 
X 
 
Oscar 2™ ABPM Device 
Measurements 
 
X 
X 
Return Oscar 2™ ABPM 
Device 
 
 
X# 
Questionnaires@ 
 
X 
 
# A prepaid return shipping label and box will be given to the participant for shipment back 
to City of Hope. 
@Questionniares will be completed electronically or at the clinic visit. 

 
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7.0 HUMAN SUBJECTS ISSUES 
7.1 Potential Benefits 
Subjects will not receive any additional benefit from participating in the current protocol. The knowledge 
gained from the current study may be used to develop more comprehensive screening strategies in at-
risk populations. 
7.2 Potential Risks 
The eligibility criteria for the current study have been established to exclude individuals for whom this 
study is not appropriate. The risks of this study are minor. Some of the questions in the questionnaires 
may make the participant uncomfortable or anxious. The questionnaires that are being used for this 
research study have been used before in previous studies. To the best of our knowledge they have not 
caused anyone serious problems. Furthermore, participants may skip any questions they are not 
comfortable answering. 
Additional protection against risk: In order to protect patients from any potential risks associated with 
the current study, the following assurances will be adhered to: (1) participation is voluntary and consent 
to participate can be withdrawn at any point within the study without penalty, (2) prospective patients who 
do not wish to volunteer for the current study will not lose their access to medical services at the City of 
Hope, (3) all patients will be informed of foreseeable benefits and risks, (4) all data collected from patients 
or via medical chart review will be stored in a secure computer network folder and/or locked file cabinet(s). 
In addition, patients will be informed that they have the right to refuse to continue their participation 
without penalty if they experience significant emotional discomfort, or for any other personal reason. If 
significant distress is evident during the study, patients will be encouraged to seek appropriate treatment, 
and a list of referrals will be provided as needed. 
 
8.0 STATISTICAL CONSIDERATIONS 
8.1 Sample Size, Accrual Rate and Study Duration  
o Total accrual: We will accrue up to 200 participants (180 evaluable participants - we estimate 
10% of participants will have inevaluable cardiac measurements due to technical difficulty). 
Accrual is expected to be completed in 1 year.  
o Study duration is expected to be about 2 years (1-year complete accrual + 1 year for data 
analysis and manuscript preparation). 
o Participant duration will be about 1 week. 
8.2 Statistical Analysis Plan  
We will generate descriptive statistics for participants’ demographics, lifestyle behaviors (physical activity, 
tobacco use), family history of CVD, history of cardiovascular risk factors and other comorbidities (e.g. 
hypertension, diabetes, dyslipidemia, thyroid disease), including relevant cancer and non-cancer CVD 
Risk Scores, and cancer treatment-related exposures. We will assess participation bias by comparing 
demographics (age, gender, race/ethnicity) and treatment-related exposures among participants and 
non-participants. We will use a two-sided Type I error=0.05, 

 
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Specific Aim 1: Validate the accuracy of ejection fraction, as measured using a tonometry-based 
system (SphygmoCor® Xcel), in the clinic setting, and determine the reproducibility (Oscar 2™) 
at home..  
Our working hypotheses are that: 1.1) In-clinic SphygmoCor® Xcel-derived mean EF will be comparable 
to that obtained using CMR, but lower than that obtained using echo; and 1.2) Home-based, self-
measured Oscar 2™ ABPM EF will be comparable to Oscar 2™ ABPM EF obtained by research 
personnel. 
Analytic plan for clinic-based assessment: We will compare EF across the three diagnostic platforms and 
will generate Bland–Altman plots to evaluate agreement between echo and CMR, SphygmoCor® Xcel  
and CMR, and echo and the SphygmoCor® Xcel system. The distribution of the difference between two 
screening approaches will be checked for normality, and 1-sample t-test will be used to test if the mean 
difference (D) varies from 0. Limits of agreement (LoA) will be computed as the usual 95% upper and 
lower confidence limits based on D and its standard deviation (SD). The lower and upper confidence 
limits of LoA will be calculated and compared against the maximum allowable limits to determine if the 
approaches are in agreement or not. Maximum allowable limits for SphygmoCor® Xcel  vs. CMR, echo 
vs. CMR, and SphygmoCor® Xcel vs. echo will be 5%,10%, 20%. Regression analysis will be performed 
to examine proportional bias by the magnitude of the mean measured EF. We will calculate Pearson 
correlation coefficients between EF obtained from echo, CMR, and SphygmoCor® Xcel. We will also 
compare previously obtained (IRB# 14154) tonometry-based EF to that from the current study, allowing 
us to describe correlations and change over time. Sensitivity, specificity, false-negative rate, and false-
positive rates will be calculated to assess the accuracy of SphygmoCor® Xcel  as well as echo for 
detection of abnormal EF compared to CMR (gold standard). The selected cutoff for abnormal (EF <45%) 
will be per established thresholds in oncology (refs) and non-oncology populations (refs), as it is a clear 
indicator for referral to a cardiologist for clinical assessment. We will perform similar analyses to explore 
the accuracy of SphygmoCor® Xcelfor detecting cardiac dysfunction at higher EF thresholds (e.g. <50%, 
<55%), given the emerging data on the prognostic value of less pronounced (EF 46%–54%) 
abnormalities in childhood cancer survivors. Analytic plan for home-based assessment: We will generate 
Bland–Altman plots to evaluate agreement between clinic-(SphygmoCor® Xcel) and home-based (Oscar 
2™ ABPM) measurements; 1-sample t-test will be performed to examine whether the mean difference 
between the two approaches differs from 0. LoA and the upper and lower confidence limits of LoA will be 
computed, with the latter limits compared to x as the maximum allowable limits. Linear regression analysis 
will be performed to examine for proportional bias by the magnitude of EF. 
Power calculations: We conservatively estimate that of the 221 participants enrolled on IRB# 14154, 200 
will agree to participate in the current study. Based on our previous experience, we anticipate that a 
minimum of 180 out of 200 study participants (90% of the cohort) will have a measurable EF from all 
(echo, CMR, SphygmoCor® Xcel) modalities. In Bland–Altman analysis, measurements from two 
methods will be considered in agreement if the confidence intervals of the LoA are within the maximum 
allowable difference. LoA and its confidence intervals depend on D and SD of the pair of approaches 
compared. Based on our prior study, we assumed D and SD to be 0.24 and 7.7 for tonometry-based vs. 
CMR, 4.93 and 10.9 for Echo vs. CMR, and 5.19 and 13.0 for tonometry-based vs. Echo comparisons. 
Given a confidence level of the LoA of 0.95, 180 participants will provide 80% power to detect agreement 
when the maximum allowable difference for SphygmoCor® Xcel vs. CMR comparison is 18.4, Echo vs. 
CMR is 30.2, and SphygmoCor® Xcel vs. Echo is 35.4. Anticipating challenges of implementing home-
based measurement of EF, we estimate there will be a minimum of 170 study participants (85% of the 
cohort) who will have both clinic- and home-based EF available for review. The confidence level of the 
LoA and its confidence intervals are assumed to be 0.95. For D ranging from 0 to 5 and SD from 5 to 7.7, 
170 participants will provide 80% power to detect agreement when the maximum allowable mean 
difference between clinic- and home-based EF measurement ranges from 12.0 to 23.0. 

 
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Specific Aim 2 Determine the cost-effectiveness of tonometry-based screening in the clinic 
setting and at home.  
Our working hypothesis is that home-based (Oscar 2™ ABPM) screening will be a cost-effective 
alternative to in-clinic echo or CMR-based screening.  
Analytic plan: The outcome of interest will be cardiac dysfunction detected by each screening modality 
applied at a single screening session. A Markov model will be used to compare screening approaches, 
with varying probabilities of asymptomatic cardiac dysfunction according to clinical covariables (e.g. age, 
sex, anthracycline dose) for each screening approach. We will apply the sensitivity and specificity of 
echo, CMR, and the Oscar 2™ ABPM system (clinic, home-based) to compare the number of 
asymptomatic cardiac dysfunction cases identified via each method. Screening costs for echo and CMR, 
including costs of clinical services, will be obtained from the 2020 Centers for Medicare & Medicaid 
Services (CMS). We will assume a range of costs for the Oscar 2™ ABPM system ($1,000-1,500) and 
will estimate attendant clinical services from the CMS. We will compute the cost per cardiac dysfunction 
diagnosed by each modality. In addition, we will compute the cost per additional cardiac dysfunction 
identified by a screening device relative to a comparator (e.g. Oscar 2™ ABPM vs. CMR). If the cost per 
additional cases diagnosed is less than a willingness-to-pay threshold (e.g.$100,000), the screening 
approach will be deemed cost-effective relative to the comparator. Although some study participants will 
not be Medicare beneficiaries, Medicare’s reimbursement methodology was developed to reflect true 
resource costs. This methodology has been employed in economic analyses of other cancer screening 
interventions. We will use sensitivity analysis to assess the impact of assumptions and uncertainty on 
results and conclusions. 
9.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
9.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, questionnaires) that 
are relevant to the research study. The Investigator or their designee will prepare and maintain adequate 
and accurate source documents. These documents are designed to record all observations and other 
pertinent data for each patient enrolled in this research study. Source documents must be adequate to 
reconstruct all data transcribed into data entry forms. 
9.2 Data Capture Methods and Management 
Data for this study will be collected using REDCap, a secure web application for building and managing 
online surveys and databases, that is compliant with 21 CFR Part 11. A member of the study team will 
enter data pertaining to the participant’s visits into REDCap. 
9.3 Data Entry  
The Investigator is responsible for all information collected on subjects enrolled in this study. All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy 
by the Investigator. All data entry must be completed by designated study personnel.  
9.4 Regulatory Records 
The Investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 
 

 
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10.0 REPORTING OF ADVERSE EVENTS, UNANTICIPATED PROBLEMS & OTHER EVENTS OF 
INTEREST 
The research team is responsible for classifying adverse events (AEs) and unanticipated problems (UPs) 
as defined in the relevant regulations and reporting to all applicable parties, including but not limited to 
the COH IRB, DSMC, Food and Drug Administration (FDA), National Institutes of Health (NIH) and other 
collaborators, e.g., pharmaceutical companies. The research team is responsible for the continued 
monitoring and tracking of all AEs in order to ensure non-reportable events are reviewed and monitored 
and do not rise to a reporting level. 
10.1 Assessment of Adverse Events 
The site Investigator will be responsible for determining the event name, and assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events as applicable per the City of Hope Clinical 
Research Adverse Event and Unanticipated Problem policy, Adverse events will be characterized using 
the descriptions and grading scales found in NCI CTCAE v5.0. A copy of the scale can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.  
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
o Unrelated – The event is clearly NOT related to study treatment and is clearly related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
medications administered to the participant. 
o Unlikely – The event is unlikely related to the study treatment and is most likely related to 
other factors such as the participant’s clinical state, other therapeutic interventions, or 
concomitant drugs. 
o Possible – The event may be related to study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration but could have been produced by other factors 
such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.  
o Probable – The event is most likely related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is unlikely related to the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
o Definite – The event is clearly related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is not reasonably explained by other factors such as the participant’s 
condition, therapeutic interventions, or concomitant drugs. 
10.2 Routine AE Collection and Reporting Guidelines 
AEs will be collected from the signing of informed consent until ending study participation. AEs will be 
monitored by members of the study team. AEs reported through expedited processes (e.g., reported to 
the IRB, DSMC, FDA, etc.) must also be reported in routine study data submissions. 
10.3 Expedited Reporting  
Serious Adverse Events that require expedited reporting and unanticipated problems will be reported 
according to the approved City of Hope Clinical Research Adverse Event and Unanticipated Problem 
policy. 

 
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11.0 ADHERENCE TO THE PROTOCOL & REPORTING OF PROTOCOL DEVIATIONS 
Deviations from the protocol should be avoided, except when necessary to eliminate immediate hazard(s) 
for the protection, safety, and well-being of a research participant. As a result of deviations, corrective 
actions are to be developed by the research personnel and implemented promptly.  
11.1 Reporting by COH 
All protocol deviations and planned protocol deviations will be reported in accordance with the City of 
Hope Clinical Research Protocol Deviation policy. 

 
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12.0 STUDY OVERSIGHT, QUALITY ASSURANCE, & DATA AND SAFETY MONITORING 
12.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that a research study is conducted according to the protocol, 
and applicable regulations; for protecting the rights, safety, and welfare of participants under the 
investigator's care are followed.  
12.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the research study, including overseeing 
that responsibilities are executed in accordance with federal regulations.  
12.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, collaborating investigators, 
clinical research associate/coordinator, and the study biostatistician, is responsible for ongoing 
monitoring of the data and safety of this study, including implementation of the stopping rules for 
safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) to review study status. The meeting 
is a forum to discuss study related issues including accrual, SAE/AE/UPs experienced, study response, 
deviations/violations, and study management issues. The appropriateness of further participant 
enrollment and the specific intervention for subsequent participant enrollment are addressed.  
12.4 Quality Assurance  
Clinical site auditing is conducted to ensure that the rights of human subjects are protected, that the study 
is implemented in accordance with the protocol and regulatory requirements, and that the quality and 
integrity of study data and data collection methods are maintained. This research study will be audited 
by the City of Hope Office for Safety and Data Quality. Details of clinical site auditing are documented in 
the City of Hope Institutional Data and Safety Monitoring Plan (DSMP). 
12.5 Risk Determination  
This is a low risk study, as defined in the City of Hope Institutional Data and Safety Monitoring Plan 
(DSMP), because it is a non-interventional study using non-invasive testing and therefore the risk of 
harm is low. The SphygmoCor® Xcel system SphygmoCor® Xcel system and Oscar 2™ ABPM do not 
meet the definition for a significant risk device in accordance with 21 CFR 812.2(b) (1) (ii). NSR device 
studies do not have to have an IDE application approved by FDA. The study Principal Investigator is 
responsible for monitoring protocol conduct and reporting all reportable events to the City of Hope 
(COH) Data and Safety Monitoring Committee (DSMC) and Institutional Review Board (IRB) in 
accordance with the City of Hope Institutional Deviation policy, and Clinical Research Adverse Event 
and Unanticipated Problem policy.  
12.6 City of Hope Data and Safety Monitoring Committee 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor study progress, 
compliance, safety, and accrual data from this research study via the PMT Progress Report (submitted 
by the Study Principal Investigator according to the frequency outlined in the City of Hope Institutional 
DSMP). The DSMC is composed of clinical specialists who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the Protocol 
Management Team.  
 

 
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13.0 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
13.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 Title 21 Part 11 – Electronic Records; Electronic Signatures  
 Title 21 Part 50 – Protection of Human Subjects  
 Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 Title 21 Part 56 – Institutional Review Boards  
 Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 Health Insurance Portability and Accountability Act of 1996  
 Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not limited 
to State of California Health and Safety Code, Title 17 
o Applicable NIH policies and procedures 
o Applicable institutional research policies and procedures 
13.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 
50, 56 and State of California Health and Safety code, Title 17, must review and approve this protocol, 
informed consent form and any additional documents that the IRB may need to fulfill its responsibilities 
(Investigator’s Brochure, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) prior to initiation of the study. Revisions to approved 
documents will require review and approval by the IRB before the changes are implemented in the study. 
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
The IRB’s written unconditional approval of the study protocol and the informed consent document must 
be in the possession of the investigator before the study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and unanticipated 
problems occurring during the study, and any additional adverse experiences in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely the 
safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
13.4 Informed Consent 
The Principal Investigator or IRB approved named designee will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document. In addition, they will review the experimental subject’s bill of rights if 
applicable, and the Health Insurance Portability and Accountability Act (HIPAA) research authorization 
form. Prospective participants will be informed that they may withdraw from the study at any time and for 

 
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any reason without prejudice, including as applicable, their current or future care or employment at City 
of Hope or any relationship they have with City of Hope. Prospective participants will be afforded sufficient 
time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The method 
of obtaining and documenting the informed consent and the contents of the consent must comply with 
the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the investigator and available for 
inspection by regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
13.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies.  
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
13.6 Special and Vulnerable Populations 
13.6.1 Women and Minorities and Other Underrepresented Populations 
The study is open to anyone regardless of gender, race or ethnicity. Efforts will be made to extend the 
accrual to a representative population impacted by the disease under study and among populations with 
the City of Hope catchment area. If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully.   
13.6.2 Vulnerable Populations 
Per 45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant 
women, mentally incapacitated persons, and economically or educationally disadvantaged persons as 
vulnerable populations.  
Economically/educationally disadvantaged persons are not actively targeted for participation, nor are 
they excluded from participation. This study does not pose additional risks for economically/educationally 
disadvantaged persons than for the general population. 
13.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators and the research personnel. This 
confidentiality is extended to cover testing of biological samples in addition to any study information 
relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and Accountability 
Act of 1996. HIPAA regulations require a signed subject authorization informing the subject of the nature 
of the PHI to be collected, who will have access to that information and why, who will use or disclose that 
information, and the rights of a research participant to revoke their authorization for use of their PHI. In 

 
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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 participants 
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. 
Release of research results should preserve the privacy of medical information and must be carried out 
in accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of participants will be securely maintained in the strictest confidence, according to current 
legal requirements. Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The Investigator/Institution will permit direct access to source data and documents by the FDA, and other 
applicable regulatory authorities. The access may consist of study-related monitoring, including remote 
monitoring, audits, IRB reviews, and FDA/regulatory authority inspections. The patient’s confidentiality 
will be maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
13.8 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study. All City of Hope investigators will follow the City of Hope conflict of interest policy. 
13.9 Financial Obligations, Compensation, and Reimbursement of Participants 
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope to the injured participant. There are no plans for City of Hope 
to provide financial compensation in the event of physical injury to a participant.  
13.9.1 Compensation 
The research participant will receive $100 gift card at completion of the clinic visit and an additional $100 
gift card upon receipt of their devices and tablet at the end of the study. 
13.10 Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the City of Hope PI. Any investigator involved 
with this study is obligated to provide City of Hope with complete test results and all data derived from 
the study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement between City of Hope. The 
publication or presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov; it is City of Hope 

 
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policy to register the trial prior to enrollment of the first patient. Results will be reported on 
ClinicalTrials.gov generally within 12 months after the primary completion date unless criteria to delay 
submission are met per the final rule. 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
 

 
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14.0 REFERENCES 
 
1. 
Lipshultz SE, Adams MJ, Colan SD, et al: Long-term cardiovascular toxicity in children, 
adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, 
management, prevention, and research directions: a scientific statement from the American Heart 
Association. Circulation 128:1927-95, 2013 
 
2. 
Oeffinger KC, Mertens AC, Sklar CA, et al: Chronic health conditions in adult survivors of 
childhood cancer. N Engl J Med 355:1572-82, 2006 
 
3. 
Mulrooney DA, Yeazel MW, Kawashima T, et al: Cardiac outcomes in a cohort of adult 
survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer 
Survivor Study cohort. BMJ 339:b4606, 2009 
 
4. 
van Dalen EC, van der Pal HJ, Kok WE, et al: Clinical heart failure in a cohort of children 
treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42:3191-8, 2006 
 
5. 
Barry EV, Lipshultz SE, Sallan SE: Anthracycline-induced cardiotoxicity: natural history, 
risk factors, and prevention., American Society of Clinical Oncology. Chicago, IL, 2008, pp 448 
 
6. 
Lipshultz SE, Colan SD: Cardiovascular trials in long-term survivors of childhood cancer. 
J Clin Oncol 22:769-73, 2004 
 
7. 
Horenstein MS, Vander Heide RS, L'Ecuyer TJ: Molecular basis of anthracycline-induced 
cardiotoxicity and its prevention. Mol Genet Metab 71:436-44, 2000 
 
8. 
Adams MJ, Lipshultz SE: Pathophysiology of anthracycline- and radiation-associated 
cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer 44:600-6, 
2005 
 
9. 
Lipshultz SE, Alvarez JA, Scully RE: Anthracycline associated cardiotoxicity in survivors 
of childhood cancer. Heart 94:525-33, 2008 
 
10. 
Lipshultz SE, Lipsitz SR, Sallan SE, et al: Chronic progressive cardiac dysfunction years 
after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 23:2629-36, 
2005 
 
11. 
Monsuez JJ: Detection and prevention of cardiac complications of cancer chemotherapy. 
Arch Cardiovasc Dis 105:593-604, 2012 
 
12. 
Pahlevan NM, Gharib M: Aortic wave dynamics and its influence on left ventricular 
workload. PLoS One 6:e23106, 2011 
 
13. 
Pahlevan NM: A Systems Approach to Cardiovascular Health and Disease with a Focus 
on Aortic Wave Dynamics, Doctoral dissertation, California Institute of Technology, 2013 
 
14. 
Pahlevan NM, Gharib M: A wave dynamics criterion for optimization of mammalian 
cardiovascular system. J Biomech, 2014 
 
15. 
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