Community Hospital Identification of High CV Risk Patients During Cancer Treatment (CHI)
Phase: NA
Conditions: Breast Cancer
Sponsor: Wake Forest University Health Sciences

1 
Amendment 6: Wake Forest NCORP Research Base  01115 
 
NCI Protocol #:  
 
 
 
 
WF 01115 
 
WF Protocol #: 
 
 
01115 
 
IND # (If applicable): 
 
 
 
 
 
Protocol title: 
Community Hospital Identification of High CV Risk Patients during Cancer 
Treatment (CHI) 
 
Research Base Name: 
 
 
Wake Forest NCORP Research Base (WF NCORPRB) 
Name of RB   
 
 
Glenn Lesser, MD 
Director: 
       
Dept. of Hematology Oncology 
 
Wake Forest University School of Medicine 
 
2000 West First Street, Suite 101 
 
Winston-Salem, NC  27104 
 
Telephone (336) 716-0891 
 
Fax (336) 716-6275 
 
E-mail address: glesser@wakehealth.edu 
 
 
Organization Name: 
 
    Wake Forest University Health Sciences 
Protocol Principal Investigator: 
W. Gregory Hundley, MD 
 
Departments of Internal Medicine-Cardiology and Radiology 
 
Wake Forest University Health Sciences 
 
1 Medical Center Blvd. 
 
Winston-Salem, NC 27157 
 
Telephone (336) 716-0607 
 
Fax (336) 716-9188 
 
E-mail address: ghundley@wakehealth.edu 
 
 
Organization Name:   
 
 
Albus Imaging LLC 
Project Principal Investigator   
Holly Goodwin, MBA 
 
 
116 Lowes Food Drive, Suite 217 
 
Lewisville, NC  27023 
 
Telephone (336) 776-0821 
 
E-mail address: holly@albusimaging.com  
 
 
Organization Name: 
 
 
Wake Forest University Health Sciences 
Protocol Co-Investigator:  
Dalane W. Kitzman, MD 
Departments of Internal Medicine-Cardiology and Geriatrics 
 
1 Medical Center Blvd. 
 
Winston-Salem, NC 27157 
 
Telephone (336) 716-3274 
 
E-mail address: dkitzman@wakehealth.edu  
 
Organization Name:  
 
University of North Carolina, Charlotte 
Protocol Co-Investigator:  
Yaorong Ge, PhD 
College of Computing and Informatics Department of Software and 
Information Systems  
Woodward Hall 343-B 
Charlotte, NC  28223 
Phone: 704-687-1951 
Email: yge@uncc.edu 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
Protocol Statistician: 
Wake Forest University Health Sciences 
 
Ralph D’Agostino, Jr., Ph.D 
 
Biostatistics Core Director 
 
Department of Biostatistical Sciences 
 
Division of Public Health Sciences 
 
Wake Forest University Health Sciences 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-9410 
 
Fax:  (336) 716-5425 
 
Email address:  rdagosti@wakehealth.edu 
 
 
Organization Statistician: 
Wake Forest University Health Sciences 
 
Doug Case, Ph.D 
 
Department of Biostatistical Sciences 
 
Division of Public Health Sciences 
 
Wake Forest University Health Sciences 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-1048 
 
Fax:  (336) 716-5425 
 
Email address:  dcase@wakehealth.edu 
 
RB Administrator: 
 
Gina Enevold, MSN, GNP 
 
 
Wake Forest University Health Sciences 
 
 
Department of Hematology Oncology 
 
 
2000 West First Street, Suite 101 
 
 
Winston-Salem, NC 27104 
 
 
Telephone:  (336) 716-4035 
 
 
Fax:    
   (336) 716-6275 
 
 
Email:  genevold@wakehealth.edu 
 
RB Clinic Nurse: 
 
Robin Rosdhal, RN, OCN 
 
 
Wake Forest University Health Sciences 
 
 
Department of Hematology Oncology 
 
 
Outpatient Comprehensive Cancer Center 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
 
 
Telephone:  (336) 713-6519 
 
 
Fax: 
 
   (336) 713-6476 
                                                     Email:  rosdhal@wakehealth.edu 
 
 
Grant: 
1 R43 HL 127878-01  
 
National Heart Lung Blood Institute 
6130 Executive Blvd., Room 2117 
Bethesda, MD  20892 (For FedEx, use Rockville, MD  20852) 
(301) 496-8563 
 
 
 
3U10CA081851-12 
 
 
NCI/Division of Cancer Prevention 
 
 
Community Oncology & Prevention Trials Research Group 
 
 
9609 Medical Center Drive, Room 5E502 
 
 
Rockville, MD  20850 
 
(240) 276-7050  
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
 
 
 
Agent(s)/Supplier: 
    
 
Protocol Version Date: 
12-01-15 
 
 
Approval Dates: 
 
PRC: 03-12-15 
 
NCI:   08-31-15 
 
 
 
 
FDA:  
 
 
IRB:   04-10-15 
 
 
 
 
 
Activation Date: 
 
WF:   
 
 
 
 
Sites:   
 
 
NCI Version Date: 
 
10-06-2015 
 
 
Renewal Dates: 
 
 
 
 
Amendment/Update # & Date:   
                                                    Amend 1:     10-07-2015     WF Personnel Change 
                                                    Amend 2:     10-27-2015     WF Personnel Change  
                                                    Amend 3:     12-01-2015  
 
Amend 4: 
02-29-2016 
(WF Change only) 
 
Amend 5: 
03-09-2016 
(WF Personnel Change) 
 
Amend 6: 
07-28-2016 
          

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Amendment 6: Wake Forest NCORP Research Base  01115 
SCHEMA 
 
Community Hospital Identification of High CV Risk Patients during Cancer Treatment (CHI) 
 
 
 
 
 
 
** Must receive baseline MRI scan & 3-D ECHO 
Stratification Factors: Will be determined by the PREVENT study (WF 98213).  
Study Sample: N=30 
Study Duration: 6 months per subject 
Brief Eligibility Criteria: 
 
Stage I-III breast cancer (including inflammatory and newly diagnosed recurrent breast cancer) or 
lymphoma Stage I-IV with a > 2 year life expectancy. Females and males are eligible to participate.  
 
Scheduled to receive chemotherapy with any anthracycline. 
 
  > 21 years of age 
 
Enrollment in WF 98213 
Recruitment and Screening 
Baseline 
Self- Report Questionnaires 
Fast MRI** 
3D ECHO 
Enrollment and Randomization 
 in PREVENT study 
(WF 98213) 
 2 Month 
Fast MRI 
3D ECHO 
Troponin-I  
      Self-Report   
 Questionnaires 
6 Month 
Self-Report Questionnaire 
Fast MRI 
3D ECHO 
12, 18, 24 Month 
Follow-up via PREVENT study 
(WF 98213) 

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Amendment 6: Wake Forest NCORP Research Base  01115 
INDEX 
 
 
COVER PAGE 
 
SCHEMA 
 
1. OBJECTIVES ...................................................................................................................6 
  
2. BACKGROUND................................................................................................................7 
 
 
3. SUMMARY OF STUDY PLAN..………………………………………………………………… 8 
 
4. PARTICIPANT SELECTION .............................................................................................8 
 
5. AGENT ADMINISTRATION ............................................................................................10 
 
6. PHARMACEUTICAL INFORMATION .............................................................................10 
 
7. CLINICAL EVALUATIONS AND PROCEDURES ...........................................................10 
 
8. PROTOCOL SPECIFIC TRAINING REQUIREMENTS ....................................................13 
 
9. SPECIMEN MANAGEMENT...........................................................................................13 
 
10.  REPORTING ADVERSE EVENTS .................................................................................14 
 
11. STUDY MONITORING....................................................................................................16 
 
12. STATISTICAL CONSIDERATIONS ................................................................................17 
 
REFERENCES 
 
Consent Form 
  
 
APPENDICES 
 
 
1. Data Submission Checklist 
2. Eligibility Checklist-Registration 
3. Flow Sheet – TAS Sheet - Addendum 
4. MRI Patient Information 
5. Lab Instructions 
6. Early Withdrawal Form 
7. Screening Form 
8. PROMIS Fatigue Short Form 
9. RAND 36 Item Short Form Health Summary 
 
 
 
 
 
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
1. 
OBJECTIVES 
The overall of this proposal is to test in community hospitals the utility of a 10-min magnetic resonance 
imaging (MRI) scan protocol combined with proprietary image analysis algorithms for detecting early 
cardiovascular (CV) injury during receipt of chemotherapy for breast cancer (BrC) and lymphoma. This 
technology provides health-care delivery systems with a time-efficient method to identify those at risk of a 
future CV event so that prevention can be implemented to prolong survival and reduce morbidity in cancer 
survivors. Over 280,000 patients are diagnosed with BrC in the U.S. each year, and nearly 20% experience a 
serious, premature CV event.i,ii,iii  In addition, each year 80,000 patients are diagnosed with Hodgkin’s 
disease & non-Hodgkin’s lymphoma who are also susceptible to CV injury based on their treatment 
regimensiv,v ,v i,v ii,v iii. These CV events are the long-term consequences of acute cardiotoxic effects of the 
chemotherapy and could be prevented. Unfortunately, over 80% of BrC and lymphoma patients are treated in 
community hospitals that lack protocols to detect acute cardiotoxicity and intervene when the CV injury may 
be reversible Albus’ focus is to decrease CV related morbidity and improve the quality of life of BrC & 
lymphoma survivors by creating a strategy for detection, early risk stratification, and intervention for 
chemotherapy-related cardiotoxicity.  
 
While recent research indicates that conventional MRI, advanced echocardiography (global longitudinal 
strain and 3D) and serum biomarkers can detect CV injury early after receipt of Chemotherapy, these 
methods require lengthy and difficult examinations that are not routinely executed in community hospitals 
where the majority of patients with BrC & lymphoma are treated. Yet, 1-month deteriorations in traditional 45-
min MRI measures are known to forecast 6-month subclinical deteriorations in left ventricular ejection fraction 
(LVEF) that are associated with CV events. At the same time, new observational data indicate therapy with 
HMG-CoA reductase inhibitors/statins administered early during receipt of Chemotherapy may prevent 
subsequent cardiac dysfunction and CV events. Our MRI fast scanning techniques remedy these community 
hospital implementation obstacles.  
 
In this proposal, we propose to test the utility of these fast scans within an existing funded randomized 
clinical trial R01HL118740 of generic atorvastatin that is researching methods to prevent cardiotoxicity in 
patients treated with Chemotherapy for BrC and lymphoma (taking advantage of significant existing clinical 
trial resources). This study allows us to address our over-arching goal: to determine the optimal 
implementation (alone or in combination with other tests) of our proprietary MRI processes for forecasting CV 
injury in patients treated with Chemotherapy in community hospitals through performance of a Phase II 
comparative effectiveness study within an ongoing clinical trial.  
 
Primary Objectives 
Specific Aim 1: To determine if baseline to 2-month measures of left ventricular (LV) volumes, T1/T2 times, 
and/or aortic pulse wave velocity (all acquired within 10 minutes) can predict baseline to 6-month post 
Chemotherapy deteriorations in LVEF, as measured by a typical 45-min MRI.  
 
Specific Aim 2: To compare the Albus 10-min MRI metrics with both ECHO (including PWV) and cardiac 
serum biomarkers (TnI) for predicting baseline to 6 month deteriorations in LVEF.  
 
Specific Aim 3: To use exploratory algorithmic modeling to obtain optimal strategies for determining the 
combination of metrics (10-min MR, ECHO, serum biomarkers) at 2-months that predict the 6-month post 
Chemotherapy deteriorations in CV function. 
 
To achieve these aims, we will study 30 subjects from community hospitals that also enroll in another study 
(funded through a NIH R01 mechanism) who are scheduled to receive Chemotherapy for Stage I-III BrC or 
lymphoma. Each participant will receive the new 10-minute Fast MRI, a conventional 45-min MRI (previously 
proven), a 3D ECHO/PWV, and cardiac serum biomarkers. The results of this pilot study will gauge the merit 
for funding a continued initiative to replace existing lengthy community hospital based scans with a rapid 
imaging solution. Ultimately, the desire is to expand this process to include those with heart failure, or other 
high CV risk profiles (e.g., hypertension, diabetes) to assess CV risk and direct therapy in community 
hospitals.  
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
2. 
BACKGROUND 
This study is significant in that it:   
1) Creates a new, easy-to-implement, clinically viable process for community hospitals to identify the early 
 
evidence of CV injury throughout receipt of Chemotherapy for BrC & lymphoma that was previously  
 
only available in academic centers. This study will incorporate a 10-minute MRI scan (a dramatic   
      reduction from the current 45-minute cardiac MRI procedures). Reduced acquisition times allow  
      community hospitals to perform these new procedures with minimal disruption to existing clinical  
      workflow. Our proposed study will be conducted in community hospitals, where >80% of patients  
      currently receive treatment for breast cancer and lymphoma in the US. Therefore, the processes and  
      procedures developed from this proposal will readily translate into clinical practice and be useful for the  
      majority of US patients with BrC or lymphoma.  
2) Allows identification of optimal combination of methods (MRI, ECHO) to detect myocardial injury 
 
upon receipt of chemotherapy. This will provide the ability to utilize data from these various modalities 
 
to develop and patent new predictive models that can direct the early detection of myocardial injury for  
      the purpose of preventing future CV events in breast cancer and lymphoma survivors.  
3) Directly compares the utility of our 10-min scan for those that are treated versus not treated with 
 
potentially cardioprotective therapy as they receive Chemotherapy.  
 
2.1. Preliminary Data: 
The research will be conducted by a highly experienced academic team. During the last 10 years, the 
assembled team has published 7 peer-reviewed manuscripts regarding the evolution of CV disease in 
individuals receiving chemotherapy.  
2.1.1. Performance of a high-quality, 10-minute cardiac MR scan: Our 10-minute scan was 
developed to greatly reduce the scan time 
while maintaining the temporal resolution             
of the sequences so that strain analysis  
could be performed without a separate set 
 
of tagged scans. These goals were 
accomplished by utilizing higher parallel 
imaging acceleration factors, combining 
pairs of scans into single breath holds, and 
eliminating localizers for which other scans 
could be used. We have successfully 
refined and repeated the 10-minute 
protocol for acquiring data for LV 
 
volumes/ mass/ EF/ strain, T1/T2  
mapping and aortic stiffness measures 
(Figure 1). The protocol is performed on 
widely available 1.5T scanners and is thus 
suitable for translation into community hospitals.  
2.1.2. Our MRI analytic measures of signal intensity within the left ventricle indicate myocellular 
injury in animals and are abnormal in patients receiving Chemotherapy.ix,x In animals and humans, 
we demonstrated that T1 changes identify myocellular injury that precede and forecast LVEF 
deterioration after Anthracyclines. We observed similar findings in a cohort of 63 human subjects 
followed longitudinally for 8 months. Our analytic methods allow segmentation of the LV myocardium, 
measurement of myocardial tissue characteristics indicative of injury and fibrosis, and then display this 
information in a format interpretable by physicians.  
2.1.3. Atorvastatin attenuates declines in LVEF and is associated with few CV events after 
Chemotherapy. In a recent study of 40 patients scheduled to receive Anthracyclines, those randomized 
to receive atorvastatin (40 mg per day before and during Anthracyclines) had no decrease in LVEF at 6 
months, but those randomized to receive Anthracyclines without statins had an 8% reduction in LVEF.19 
We observed fewer admissions for CHF among 628 breast cancer survivors receiving statins compared 
to those not prescribed a statin for secondary diagnosis of CVD.  
Figure 1. Middle short axis slices from fast 10-min scan (L) & Standard 
MR scan (R) have comparable spatial resolution (2x2mm), w hile the 
fast scan provides improved temporal resolution (28ms versus 44ms), 
permitting strain analysis w ith no need for a separate tagging 
acquisition. 

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Amendment 6: Wake Forest NCORP Research Base  01115 
2.1.4. Baseline to 1-month changes in LV 
performance during chemotherapy forecast future 
LVEF measures 6 months after initiating 
Anthracyclines. In 44 individuals receiving 
Anthracyclines, 25 experienced a 10% drop in LVEF at 6 
months and the remaining 19 patients had a preserved 
LVEF (Figure 2). As shown, early imaging detects those 
that are/are not at risk for future CV events.  
2.1.5. Within 3 months, Chemotherapy increases 
PWV, a predictor of CV events.xi In 40 individuals who 
received chemotherapy for BrC, lymphoma, or leukemia 
(and 13 age & sex-matched comparators), there was an 
increase PWV, which is a known independent predictor of adverse CV events. The magnitude of 
increase of PWV and aortic stiffness was equivalent to aging the CV system by 15–20 years.xii 
 
3. 
SUMMARY OF STUDY PLAN 
3.1 Study Design/Timeline and Integration with another Study: We propose to work with another 
double-blinded, 
placebo-controlled, 
randomized 
clinical trial of 250 
patients = or > 21 
years scheduled to 
receive 
Chemotherapy for 
Stage I-III BrC 
breast cancer or 
lymphoma, (R01-
HL118740: 2/1/14-
8/31/18) whose 
overall goal is to 
determine if statin 
administration reduces the 2-year incidence of LV dysfunction and early manifestations of heart failure.  
 
The current study proposes a 10-min MRI scan, an ECHO, measures of serum troponin and other data 
captures at 2-months, as well as, a 10-min MRI scan and ECHO at 6-months (Figure 3). The baseline 
to 2-month measurement period is  selected to correspond to the clinical time point after the 
patient will have received Chemotherapy.  
 
  
3.2. The Wake Forest NCORP Research Base (WF NCORP RB) will recruit from NCORP sites with 
appropriate MRI facilities that treat modest numbers of breast cancer and lymphoma patients with 
anthracycline-based therapy. Importantly, the PI has visited and conducted interviews with all 
participating NCORP sites to verify their MRI, ECHO, and breast cancer and lymphoma recruitment 
capabilities. 
 
4. 
PARTICIPANT SELECTION 
4.1. Inclusion Criteria 
4.1.1 
Stage I-III breast cancer (including inflammatory and newly diagnosed recurrent breast cancer) 
or lymphoma Stage I-IV with a > 2 year life expectancy,   
4.1.2 
Scheduled to receive chemotherapy with an Anthracycline (doxorubicin or epirubicin)  
4.1.3 
> 21 years of age  
4.1.4 
Prior cancers allowed if no evidence of disease  
4.1.5 
ECOG 0 or 1 
4.1.6 
Enrollment in NCI Protocol #: WF 98213. Patients must receive a 3D ECHO along with Baseline 
(98213) MRI prior to first chemotherapy treatment. 
Figure 2. Change in left ventricular (LV) ejection fraction 
from baseline to 1 month during receipt of chemotherapy 
forecasts the change in LVEF from baseline to 6 months. 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
 
 4.2 Exclusion Criteria 
4.2.1 
Patients with ferromagnetic cerebral aneurysm clips or other intraorbital/intracranial metal; 
pacemakers, defibrillators, functioning neurostimulator devices or other implanted electronic 
devices.  
4.2.2 
Most breast tissue expanders are not allowed. (If uncertain, inform the MRI tech to confirm 
eligibility status.)    
4.2.3 
Unable to provide informed consent 
4.2.4 
Symptomatic Claustrophobia 
4.2.5 
Pregnant or breasting feeding. Due to unknown risks and potential harm to the unborn fetus a 
negative serum pregnancy test must have been obtained per protocol 98213 in patients with 
child-bearing potential. For this reason patients of child-bearing potential must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence (not having 
sex), oral contraceptives, intrauterine device (IUD), DeProvera, tubal ligation, or vasectomy of 
the partner (with confirmed negative sperm counts) in a monogamous relationship (same 
partner). An acceptable, although less reliable method involves the careful use of condoms 
and spermicidal foam or gel and/or cervical cap or sponge prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her study physician immediately. 
 
4.3.     Inclusion of Patients and Minorities 
Table 2:  Race/Ethnicity 
 
Gender 
White 
Black or 
African-
American 
 
Hispanic 
or Latino 
Asian or 
Pacific 
Islander 
 
Unknown 
 
Total 
Male 
3 
1 
0 
0 
0 
4 
Female 
21 
4 
1 
0 
0 
26 
Total 
24 
5 
1 
0 
0 
30 
 
4.4. Recruitment and Retention Plan 
4.4.1 
Over 300 breast and lymphoma patients should be eligible for enrollment among the NCORP 
sites, approximately 14% of whom will be males. Assuming conservatively that 17% (1 in 6) of 
the patients will consent to the study, we expect ~50 patients could be enrolled once the study 
is active at all planned sites. If enrollment is unexpectedly low, we can add additional NCORP 
sites in which study coordinators, imaging expertise, and patient populations are readily 
available.  
 
 
4.4.2. At each site, specific recruitment plans may include the following according to the site’s 
institutional policy: screening clinic charts; tumor registry data; referral sources such as patient 
advocate groups, retirement communities, churches, support organizations, community 
organizations, newspapers, radio; or patient recruitment posters and recruitment letters. 
 
 
4.4.3. The research PI or designee at each WF NCORP Research Base NCORP, which may include 
the clinic physician, resident, research nurse or research assistant, will review cancer registry 
and medical chart information to identify patients eligible for this protocol.  Patients identified 
using these methods will be asked to join the study during their next clinic visit/consultation. 
 
Accrual is expected to be 5 patients per month. Targeted accrual should be met in 
approximately 8 months for the study. A maximum of 30 patients will be enrolled on this trial. 
Patients will be followed for 6 months as part of this study.   
 
 
 
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
5. AGENT ADMINISTRATION 
 
5.1. 
A sedative may be administered to claustrophobic patients.  
 
6.  PHARMACEUTICAL INFORMATION 
 
6.1  
Sedative  
In the event a patient is claustrophobic (extreme discomfort or fear of small spaces) they may be offered an 
intravenous injection of a sedative medication to make the patient drowsy, relaxed and comfortable during 
the MRI scan. Because sedatives may decrease alertness and cause lightheadedness or dizziness, the 
patient must have another adult drive them home from the clinic if they are given a sedative. 
 
Possible risks and side effects of the sedative include: 
 
Most Common Events may occur in about 2% of patients. 
 
dizziness  
 
headache 
 
Less Common 
 
unusually fast/slow/irregular heartbeat, 
 
fainting,  
 
confusion, 
 
mental/mood changes, 
 
trouble breathing, 
 
muscle twitching and involuntary movements, 
 
Rare but Serious Events 
 
throat discomfort, 
 
skin rash and hives. 
 
6.2  
Agent Accountability    
Each participating MRI NCORP site will maintain a careful record of the inventory and disposition of the 
sedative according to institutional policy.  
  
 
 
7.     CLINICAL EVALUATIONS AND PROCEDURES 
 
         Note: Fast MRI is embedded in (98213) Baseline  and 6 month MRI. Data will be extracted for use in this  
                   protocol. Only additional Fast MRI is at 2 months and additional 3D ECHO will be required at 2 and 6  
                  months. 
 
 7.1  Schedule of Events 
At each participating Research Base site, medical charts will be screened to determine potential 
eligibility by physicians (including residents or fellows, if applicable), research nurses, or clinical 
research associates. This information should be recorded on the Screening Form. Patients identified as 
potentially eligible will then be asked to consider joining the study. Patients meeting initial eligibility 
criteria and who agree to participate in the study will sign informed consent.  Baseline Fast MRI & 3D 
ECHOs will be captured in tandem with baseline PREVENT study MRI. The acquisition of the patient’s 
clinical ECHO at baseline can be used for the CHI study so that duplication of this measurement is not 
required. Patients will be asked to complete the Self-Report Questionnaires.: At 2 months a Fast MRI, 
3D ECHO,  ultrasensitive Troponin I and Self-Report Questionnaires will be obtained. At 6 months a 
Fast MRI & 3D ECHO will be captured in tandem with PREVENT study MRI and Self-Report 
Questionnaires will be obtained.   

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
 
 
7.2.   Baseline Evaluations 
     
 MRI Variables -  
The primary cardiac and vascular outcome measures include LVEF and PWV. LVEF was selected as 
our primary cardiac outcome because clinically it has been used for >30 years to guide the 
administration of potentially cardiotoxic chemotherapy.xiii,xiv Also, we will measure LV end diastolic 
volume, LV end systolic volume, myocardial strain and strain rate, and mass according to published 
standards and treat them as continuous variables.xv ,xv i,xv ii Since vascular stiffness is associated with CV 
events,xv iii we will measure PWV because it measures aortic stiffness without reliance on measures of 
central aortic pressure, is highly reproducible, and it can be very accurately measured with MRI 
because it does not require external marking of central landmarks. xix,xx,xxi Finally, we will acquire T1 and 
T2 maps of the LV myocardium that have been shown in other studies to be associated with myocardial 
injury.xxii,xxiii The fast MRI protocol is short (10 mins.). All MRI scans will be performed after a formal 
evaluation of the physical performance parameters of the CMR scanner, completed daily using 
standard manufacturer-recommended evaluation methods with calibration phantoms to ensure 
consistent measures over time. Each MRI assessment will be blinded to patient identifiers, the 
corresponding MRI exam, and prior MRI exams of the same measure (a blinded, unpaired read). A 
complete double reading on 15% of the CMR cases will be performed for quality control. All study 
participants will be offered benzodiazepines to assist in easing any claustrophobia concerns. 
 
ECHO Variables - A standardized ECHO-Doppler examination with 2D and 3D ultrasound and spectral 
Doppler will be performed according to American Society of Echocardiography (ASE) 
guidelinesxxiv xxv xxv iand as previously described by Dr. Kitzman and colleagues in multiple clinical 
trials.,xxv ii,xxv iiixxix,xxx The exam will be focused on evaluation of LV volumes and EF (in 2 and 3D), mass, 
global longitudinal strain (GLS), diastolic function, and pulse wave velocity and is designed to produce 
variables of interest to patients with BrC & lymphoma and to match key variables from the cardiac MRI 
exams. All field sites have current model Philips iE33 instruments, enabling standardized, uniform, 
efficient acquisition of all variables in a single exam. Exams will be performed by registered cardiac 
diagnostic sonographers. Analysis: For 2D LV volumes, endocardial borders will be traced in end-
diastolic and end-systole in the apical 4 and 2 chamber views and calculated by the modified Simpson’s 
technique. 3D echo has the potential for more accurate LV volumes and EF because it uses all voxels 
in the acquired 3D, full-volume dataset and is relatively independent of geometric assumptions. Global 
3D LV volumes will be analyzed with semi-automated border detection over full cardiac cycles using Q-
lab (Philips) software. LVEF will be calculated by the standard formula. Circumferential and longitudinal 
strain will be measured from the short axis and apical views, respectively. Doppler mitral flow and 
annular displacement (septal and lateral) velocities will be traced from the apical 4 chamber view for 
peak early, atrial, and systolic velocities, early deceleration time, and arterial PWV will be assessed 
from carotid and femoral pulse Doppler, ECG, and measured distance. xxxi All measures will be 
performed in triplicate. Overall image quality will also be graded as good, fair, poor, unevaluable.  
 
 Quality of Life 
    
 Self-Report Questionnaires: 
The Self-Reported questionnaires are a collection of well-validated, brief, fee-free instruments 
assessing key patient reported outcomes related to this study. For this study, we will include the short 
forms for quality of life. The total administration time for these questionnaires is 5 minutes.   
 
 
7.3. Evaluations During Study Intervention 
 
Self-Report questionnaires will be obtained at 2 months 
 
As part of this study, an additional measurement of ultrasensitive Troponin I will be collected at 2-months, 
as well as, a Fast MRI and 3D ECHO.  
 
 
  
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
7.4. Evaluations at Completion of Study Intervention 
At 6-months, all study participants will complete Self-Report questionnaires, have a Fast MRI and 3D 
ECHO.   
 
 
7.5.  Post-intervention Follow-up Period. N/A 
 
 
7.6 Methods for Clinical Procedures   
Processes for obtaining the Self-Report questionnaires, fast MRI, and ECHO are provided in the 
Appendices. 
 
 Fast MRI & 3D ECHO invoices should be emailed to Albus Imaging  at clinicaltrials@albusimaging.com 
 or mailed 116 Lowes Food Drive, Suite 217, Lewisville, NC 27023 (Email is preferred.) 
 
      7.7. Study Parameters Table   
              Enrollment in PREVENT study should be documented. Fast MRI is embedded in (98213) Baseline and 6  
              month MRI. Data will be extracted for use in this protocol. PREVENT study data will be made available to  
              the CHI research team.   
 
(A) Must be obtained prior to first chemotherapy treatment 
 
 
Evaluation 
Procedure 
Baseline 
2  
Months 
6 
Months 
Description 
Informed Consent 
X 
 
 
 
Fast MRI (A) 
X 
X 
X 
LV Volumes (incl LV end diastolic volume, LV 
end systolic volumes), Pulse Wave Velocity, 
myocardial strain & strain rate, mass, T1 and T2 
maps. 
Fast MRI Encounter Form 
X 
X 
X 
 
3D ECHO (A) 
X 
X 
X 
LV Volumes, Ejection Fraction (in 2 and 3D), 
mass, global longitudinal strain (GLS), diastolic 
function, and pulse wave velocity. 
ECHO Encounter Form 
X 
X 
X 
 
Lab –  
ultrasensitive Troponin-I  
 
X 
 
 
Self-Report Questionnaires 
X 
X 
X 
 
Flow Sheet/ Addenda 
X 
X 
X 
 
Toxicity Assessment Sheet 
(TAS)  
 
 
 
If applicable any time during study. 
Early Withdrawal  
Treatment/Consent 
 
Submit this form when a participant withdraws from active treatment or 
withdraws consent prior to study completion. 
Screening Form 
 
Submit this form every month. 

13 
Amendment 6: Wake Forest NCORP Research Base  01115 
 
     . 
  
 
7.8. Off Treatment Criteria  
Participants may stop participating for the following reasons: adverse event or serious adverse event, 
concomitant medications, medical contraindication, or interruption of chemotherapy due to adverse 
events or death. 
Participants will continue to be followed, if possible, for safety reasons and in order to collect endpoint 
data according to the schedule of events.  The study is designed to account for dropouts due to poor 
health or death; thus, there will be no replacement of subjects that must drop out of the study after 
enrollment. 
Patients who are unable to have an MRI or ECHO at baseline will not be allowed to continue 
participation in the study.      
 
 7.9 Off-Study Criteria 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, adverse event/serious adverse event, lost to follow-up, 
concomitant medication, medical contraindication, withdraw consent, or death.   
 
8. PROTOCOL SPECIFIC TRAINING REQUIREMENTS 
 
8.1 MRI Training 
 The study PI presented the MRI protocol for review and discussion with the MRI technologists 
 
and associated study coordinators during the Investigator meeting held at the 2013, 2014 and  
      2015 Annual Research Base NCORP Meeting. 
 Prior to the start of participant enrollment into the study, Wake Forest University Medical Center   
 cardiology imaging specialists observe and continue MRI training at each of the study locations.   
 
Each site will be required to submit two satisfactorily performed studies to the image 
coordinating center at Wake Forest before initiating the study per protocol 98213 requirements. 
 
 
8.2 ECHO Training 
 For ECHOs, the field site sonographers will be trained in the study protocol by the Wake Forest 
 
Echo Core Lab Director (Dr. Kitzman) and chief sonographer (Ms. Stewart, RDMS) prior to study 
 
launch using written, illustrated sonographer instructions, a teaching video, didactic sessions, 
 
practice patients, field site visits, and 2 final qualifying test cases. 
 
 
9. SPECIMEN MANAGEMENT  
 
 
9.1 Lab Corp: Troponin-I at 2 months  
 
Lab Corp will be utilized for all labs. LabCorp couriers will deploy to each site from local LabCorp 
facilities for specimen pick-up as samples are drawn. All specimens should be collected in containers 
provided by LabCorp. Note storage times and temperature instructions for each test.       
                                                
 
9.2 Collection and Handling Procedures 
 
Refer to Appendix Lab Instructions. 
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
10. REPORTING ADVERSE EVENTS   
    
 A list of adverse events/serious adverse events that have occurred or might occur that are related to 
this study intervention can be found in Section 6.2. 
 Adverse Event/Serious Adverse Event reporting begins after the informed consent is signed. 
 Serious Adverse Events occurring within 30 days of study completion must be reported via FDA Form 
3500 (MedWatch). 
 
10.1 Protocol Specific Reporting for Adverse Events (AEs) 
 
 DEFINITION: An adverse event (AE) is any untoward medical occurrence in a study participant.   
 
 Grades 1, 2, and 3 expected (solicited) and unexpected (unsolicited) AEs that meet the above 
definition for an AE and are ONLY definitely related, possibly related or probably related to 
this study intervention should be reported to the RB DMC using the Toxicity Assessment 
Sheet. 
 
10.2 Protocol Specific Reporting for Serious Adverse Events (SAEs) 
 
 
 
DEFINITION: ICH Guideline E2A and Fed. Reg. 62, Oct. 7, 1997 define serious adverse events as 
those events that meet any of the following criteria? 
 Results in death 
 Is life threatening (Note: the term life threatening refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe). 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 Is a congenital abnormality/birth defect. 
 Events that may not meet these criteria, but which the investigator finds very unusual and/or 
potentially serious, will also be reported in the same manner. 
 
 Grades 3, 4, and 5 expected (solicited) and unexpected (unsolicited) SAEs that meet the 
above definition for SAEs and/or regardless of attribution (i.e. regardless of whether they are 
related to this study intervention or not) should be reported to the RB DMC using the FDA 
Form 3500 (MedWatch).  
 Site staff and/or Principal Investigators will report to the RB Data Management Staff within 24 hours 
of discovering the details of all unexpected severe, life threatening (grade 4) and/or fatal adverse 
events (grade 5) if there is reasonable suspicion that the event was definitely, probably, or possibly 
related to the study intervention.  
 
Otherwise, the MedWatch should be sent to the NCORPRB DMC by fax or email within 10 working 
days of discovering the details of the SAE. 
 
Hospitalizations that are scheduled for routine treatments and procedures unrelated to study 
intervention do not need to be reported. 
 
 
 
 
                   Data Elements to include on the MedWatch are: 
 
SAE reported date 
 
CTCAE Term (v4.03) 
 
Event onset date and event ended date 
 
Severity grade (use table provided in Section 10.1.3 below) 
 
Attribution to study intervention (relatedness) 
 
Action taken with the study participant and intervention 
 
Outcome of the event 
 
Comments 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
10.3 Guidelines to determine grade and severity of AEs and/or SAEs 
 
 
 
Identify the adverse event using the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03.  The CTCAE provides descriptive terminology and a grading scale for each adverse event 
listed.  A copy of the CTCAE can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
AEs will be assessed according to the CTCAE grade associated with the AE term.  AEs that do not 
have a corresponding CTCAE term will be assessed according to the general guidelines for grading 
used in the CTCAE v4.03. as stated below. 
 
 
 
          
                         
Activities of Daily Living (ADL) 
 
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
The Research Base Grant PI, Safety and Toxicity Review Committee and/or Study Chair will take 
appropriate action to inform the membership and statistical personnel of any protocol modifications and/or 
precautionary measures, if this is warranted. 
 
The RB DMC is responsible for communicating AEs/SAEs to the FDA,  WF IRB, the WF Safety and 
Toxicity Review Committee (STRC) and/or other regulatory agencies as appropriate per agency reporting 
requirements. 
 
Institutions must comply with their individual Institutional Review Board (IRB) policy regarding submission 
of documentation of adverse events. All MedWatch reports should be sent to the local IRB in accordance 
with the local IRB policies. 
 
 
 10.4 Follow-up of SAEs  
 
 
 
Site staff should send follow-up reports as requested when additional information is available.  
Additional information should be entered on the MedWatch form in the appropriate format.  Follow-up 
information should be sent to the RB Data Management Center as soon as available. 
 
SAEs (Grade 4 and/or Grade 5) for this protocol should be followed for those related to the study 
intervention.  Documentation should include: 
 
 
PID 
 
Date of SAE 
 
Description of the event  
 
Relationship of the SAE to the study intervention 
 
Severity  
 
Intervention/Resolution 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL*. 
3 
Severe 
Severe or medically significant but not immediately life-
threatening; 
Hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
4 
Life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5 
Fatal 
Death related to AE. 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
11.  STUDY MONITORING    
 
 
 11.1 Data Management Schedule 
 
The Eligibility checklist/Registration Form should be completed on-line prior to placing the patient on 
study.   Data forms will be submitted to the WF NCORP Research Base.  Mail to Suite 101 2000 W. 
1st Street Winston-Salem, NC 27104 or fax to (336) 713-6476 according to the timetable below: 
Form 
Submission Schedule 
Consent Form, Flow Sheet/Addenda, Fast MRI Encounter 
Form, ECHO Encounter Form, Self- Report Questionnaires 
Baseline – within 14 days of registration 
Self-Report Questionnaires 
Baseline (+ or - 14 days) 
Fast MRI Encounter Form, ECHO Encounter Form, 2-month 
Self Reporting Questionnaires Flow Sheet/ Addenda, TAS if 
applicable, Lab – Troponin-1 
2 months (+ or - 14 days) 
Fast MRI Encounter Form, ECHO Encounter Form, Self- 
Reporting Questionnaires, Flow Sheet/Addenda  
6 months (+ or - 14 days) 
Early Withdrawal Form 
Participants who withdraw from 
treatment or study prior to completion. 
Submit at withdraw.  
Screening Form 
Every month 
 
 
11.2 
Case Report Forms 
 
  
Participant data will be collected using protocol-specific case report forms (CRF).  
 
 
 
11.3  Source Documents 
 
Source documents are the original signed and dated records of participant information (e.g., the medical 
record, shadow chart) which may include electronic documents containing all the information related to a 
participant’s protocol participation. Source documents are used to verify the integrity of the study data, to 
verify participant eligibility, and to verify that mandatory protocol procedures were followed. An 
investigator and other designated staff are required to prepare and maintain adequate and accurate 
documentation that records all observations and other data pertinent to the investigation for each 
individual participating in the study. All data recorded in the research record (including data recorded on 
CRFs) must originate in the participant’s medical record, study record, or other official document 
sources. 
 
Source documents substantiate CRF information. All participant case records (e.g., flow 
sheets, clinical records, physician notes, correspondence) must adhere to the following standards: 
 
 
Clearly labeled in accordance with HIPAA practices so that they can be associated 
with a particular participant or PID; 
 
 
Legibly written in ink; 
 
 
Signed and dated in a real time basis by health care practitioner evaluating or treating  
the participant;  
 
 
Correction liquid or tape must not be used in source documents or on CRFs. 
 
 
Corrections are made by drawing a single line through the error. Do not obliterate the 
original entry. Insert the correct information, initial, and date the entry. 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
All laboratory reports, pathology reports, x-rays, imaging study and scans must have: 
 
 
Complete identifying information (name and address of the organization performing, 
analyzing, and/or reporting the results of the test); and 
 
 
Range of normal values for each result listed. 
 
      11.4 Data and Safety Monitoring Board 
The Data Safety Monitoring Board meets every six months to review all phase II and phase III protocols. 
The Board includes members demonstrating experience and expertise in oncology, biological sciences , 
biostatistics and ethics. The DSMB report is generated by the RB statistician. Areas of review may 
include the following: Date study Opened; Study Objectives; Patient Accrual; Patient Status and 
Retention; Study Status; Last Contact Status; Patient Compliance; Number of Biopsies/Labs as needed; 
Patient Characteristics; Summary of Observed Toxicities; Adverse Events; Date, Event briefly described, 
Relationship to Drug, Arm assigned; Summary of Primary and Secondary Measures. 
          
      11.5 Record retention  
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator in a secure  
storage facility in compliance with HIPAA, OHRP, FDA regulations and guidance, and NCI/DCP 
requirements unless the standard at the site is more stringent. 
 
 
 
11.6 CDUS Reporting 
The WF NCORP Research Base Data Management Center will submit quarterly reports to DCP/CTEP 
by electronic means using the Clinical Data Update System (CDUS) 
 
12.  STATISTICAL CONSIDERATIONS  
 
12.1. Study Design/Endpoints 
We propose to test the utility of fast MRI scans to identify cardiotoxicity in patients treated with 
Chemotherapy for BrC or Lymphoma (taking advantage of existing clinical trial resources). This  study 
allows us to address our over-arching goal: to determine the optimal implementation (alone or in 
combination with other tests) of our fast MRI processes for forecasting CV injury in patients treated with 
Chemotherapy in community hospitals through performance of a Phase II comparative effectiveness 
study within an ongoing clinical trial.  
 
Primary endpoints include LVESV, LV end diastolic volume (LVEDV), LV mid-wall circumferential strain, 
T1 & T2 Mapping, PWV, aortic wall thickness compared between fast MRI & ECHO and Troponins.  
 
  
12.2. Primary Aims 
 
Specific Aim 1: To determine if baseline to 2-month measures of left ventricular (LV) volumes, T1/T2 
times, and/or aortic pulse wave velocity (all acquired within 10 minutes) can predict baseline to 6-month 
post Chemotherapy deteriorations in LVEF, as measured by a typical 45-min MRI.  
 
Specific Aim 2: To compare the 10-min MRI metrics with both ECHO including PWV and cardiac serum 
biomarker (TnI) for predicting baseline to 6 month deteriorations in LVEF.  
 
Specific Aim 3: To use exploratory algorithmic modeling to obtain optimal strategies for determining the 
combination of metrics (10-min MRI, ECHO, serum biomarkers) at 2-months that predict the 6-month 
post Chemotherapy deteriorations in CV function. 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
12.3. Analysis Plan 
Aim 1: We will estimate the correlations between the baseline to 2-month changes in 3 measures from the 
10-min MRI (LV volumes, T1/T2 times and aortic PWV) and the baseline to 6-month changes in LVEF as 
measured by a 45- min MRI. With 30 patients available, we will have 80% power to detect a correlation of 
0.5 between each of the baseline to 2-month changes in 10-min MRI measures with the baseline to 6-
month change in LVEF. To examine whether the variability of the two MRI assessments (10-min and 45-
min) is comparable we will calculate variance ratios for different CV measures and determine their 
comparability (i.e., they will be considered comparable if they fall between 0.8 and 1.2).  
 
Aim 2: The second Aim will focus on determining the association between early changes in our 10-min 
MRI as well as changes in conventional measures of CV dysfunction including: 45-min MRI, ECHO 
(including PWV) and cardiac serum biomarker (TnI) at 2-months and 6-month deteriorations in LVEF. In 
2 fashions, we will estimate the change in each of the novel and conventional measures after 2-months 
and determine how well they predict the baseline to 6-month change in LVEF. First, we will estimate the 
correlation between the baseline to 2-month changes for each measure with the baseline to 6-month 
change in LVEF. Also, we may fit linear regression models to estimate the relationship of these early 
changes in measures with the 6-month change in LVEF adjusting for patient level characteristics. Next, we 
will dichotomize the patients into those who exhibit a drop in LVEF from baseline to 6 months (absolute 
level of EF below 50% or a 10% or greater drop in LVEF) and those who don’t. We will then perform a 
series of 2 sample t-tests to see whether the mean change after 2 months in LVEF and the other 
measures is different for patients who exhibit a drop in LVEF at 6 months.  
 
Aim 3: We will fit a series of exploratory multiple logistic regression models where the outcome measure 
will be the binary variable LVEF drop baseline to 6-months (yes/no) and each model will begin with a key 
predictor (10-min MRI measures, 45-min MRI measure or ECHO measure) and then we will add in 
additional clinical and patient level characteristics into the models to determine whether there is a 
combination of clinical and demographic characteristics that enhance the prediction of LVEF drop for each 
measure of CV dysfunction. We recognize that with a limited sample size these models will provide 
initial information about variables that may be useful in predicting the outcome of interest. In 
addition, we will consider using alternative model building strategies such as artificial neural network 
(ANN) in order to determine whether there are combinations of the measures taken at baseline and 2 -
months that predict a drop in LVEF at 6 months. For these analyses we will have over 80% power to 
detect correlations of 0.50 between the baseline to 2-month changes in each measure and the baseline to 
6 month changes in the outcomes assuming a 2-sided test with alpha=0.05 and 30 patients. In addition, 
we will have 80% power to detect a difference between groups (those with a 6-month drop in LVEF vs 
those without a 6-month drop) equal to 1.06 standard deviations for the measure of interest assuming a 2-
sided test with alpha=0.05 if roughly half of the patients exhibit a drop in LVEF after 6 months. If only 33% 
(n=10) exhibit a drop at 6-months then we will have 80% power to detect a difference of 1.12 standard 
deviations. The primary goal of this Aim for this study is to determine which measures exhibit a correlation 
with the 6-month outcome and show some predictive strength in the logistic regression models. Those 
measures that meet these criteria will then be considered in Phase II, which will allow us to directly 
compare the predictive strength of each measure with each other. In Phase II, when our sample size will 
increase to 150 patients, we will be able to fit more robust statistical models to develop predictive 
equations for identifying patients at risk for a drop in LVEF based on their initial and 2-month measures. 
With the larger sample size we will have over 80% power to detect correlations between the predictors and 
6-month change in LVEF of 0.23 or larger. In addition, we will be able to mean differences in patients with 
or without a 6-month drop in LVEF of less than 0.58 standard deviations if at least 20% (n=30 out of 150) 
of the patients exhibit a 6-month drop in LVEF.  
 
 
 
 
 
 
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
 
 
12.4. Secondary Analyses:  
 
 
 
Additional cost analyses will be performed. Costs for outpatient services will be based on the Outpatient 
Prospective Payment amounts (nationwide and specific locality) based on Healthcare Common 
Procedure Codes or Ambulatory Payment Classification groups.xxxii MRI or ECHO will be converted into 
cost using the Medicare charges. xxxiii Direct Medical Costs: Medicare diagnosis-related group 
reimbursement rates will be applied to define hospital costs (nationwide - and area-specific) using the 
PC Pricer Prospective Payment System estimator. Total procedural times including preparation and 
recovery time will also be obtained. Other cost data we will analyze includes: procedural complications 
cost, inflation/discounting, and societal perspectives.xxxivCumulative Costs: Costs will be aggregated by 
combining direct medical and indirect costs with complication and incidental finding costs to provide a 
summed follow-up cost for each study participant.  
 
 
 
12.5. Power and Sample Size considerations for the primary hypothesis 
 
This is pilot trial of 30 subjects.  Because of the budget limits of a pilot trial, we did not choose the sample 
size specifically to detect a 0.5 correlation – but felt that this was a reasonable sample size and with that 
sample size we could detect a correlation of 0.5. We aim to determine which measures exhibit a 
correlation and which also show some predictive strength in the logistic regression models.  We will use 
this for the design of our Phase II study which will show the predictive strength of each measure and will 
be sufficiently powered.   
 
 
 
  
 
12.6. Evaluation of Toxicity 
    
  All participants will be evaluable for toxicity from the time of their first MRI. 
 
 
 
  
12.7. Interim Analysis 
Interim reviews will be performed by the Data Safety Monitoring Committee every six months to assess 
accrual, retention, compliance, the incidence of AEs, SAEs, diabetes and LV function measures.  
 

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Amendment 6: Wake Forest NCORP Research Base  01115 
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