Clinical trial NCT02674204
Conditions: Breast Cancer Heart Disease Cardiotoxicity Myocardial Dysfunction
Keywords: Statin therapy trastuzumab
Sponsor: Cedars-Sinai Medical Center
Start date: 2016-05-05; Completion date: 2018-05-25
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to to examine the effects of atorvastatin, a type of statin, on changes to the heart among women undergoing breast cancer treatment. Atorvastatin may reduce or eliminate the harmful effects of chemotherapy treatment to the heart tissue of breast cancer patients.

Detailed description:
This is a placebo-controlled study. It will compare the effects of atorvastatin against the effects of a placebo (an inactive substance, such as, a sugar pill) on changes to the heart before and during breast cancer treatment. Participants will be in the study for approximately a year and a half, and the study will enroll up to 60 patients. During that time, there will be six visits that may coincide with standard of care visits. Participants will also receive telephone calls from study staff during the study intervention and a follow-up phase to check-in with them.

Arms: arm 1: One atorvastatin 20 mg oral capsule per day arm 2: One matching placebo daily
Interventions: intervention 1: Atorvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: Atorvastatin calcium, a synthetic lipid-lowering agent, is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. intervention 2: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
IIT2015-12-Goodman-STOP 
 
Statin Therapy Operates to Prevent (STOP) Heart Disease in Breast Cancer Survivors Trial 
 
Principal Investigator: 
Marc T. Goodman, Ph.D., M.P.H. 
Director, Cancer Prevention and Control 
Samuel Oschin Comprehensive Cancer Institute 
Cedars-Sinai Medical Center 
8700 Beverly Boulevard, 1S37 
Los Angeles, CA 90048 
Telephone: (310) 423-6188 
Fax: (310) 423-7182 
E-mail: marc.goodman@cshs.org 
 
Sub-Investigator(s): 
 
 
Name 
Department/Division 
Janet Wei, M.D. 
Cardiology 
C. Noel Bairey Merz, M.D. 
Cardiology 
Debiao Li, Ph.D. 
Biomedical Imaging Research 
Michael Nelson, Ph.D. 
Cardiology 
Louise E. Thomson, M.D. 
Cardiac Imaging 
Philomena F. McAndrew, M.D. 
Hematology/Oncology 
Monica M. Mita, M.D., MSc. 
Hematology/Oncology 
Michael B. Van Scoy-Mosher, M.D. 
Hematology/Oncology 
Mary El-Masry, M.D. 
Hematology/Oncology 
Heather McArthur, M.D., M.P.H. 
Hematology/Oncology 
Reva K. Basho, M.D. 
Hematology/Oncology 
Christine Pacheco Claudio, M.D. 
Cardiology 
Panteha Rezaeian, M.D. 
Cardiology 
 
Biostatistician: 
Andre Rogatko, Ph.D. 
 
Study Agent: 
Atorvastatin calcium 
 
Funding Source:  
California Breast Cancer Research Program (CBCRP) 
 
Protocol Version: 
Protocol Version 3.1, November 29, 2017 
 
Initial Protocol Version: 
Protocol Version 1.0, September 1, 2015 
 
 
 


 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:   Marc T. Goodman, Ph.D., M.P.H. 
 
 
 
Signature:  
  
Date:  
  
 
 
 
Biostatistician Name:  
 
 
 
 
Signature:  
 
Date:  
  
 
 
 
Clinical Reviewer Name:  
 
 
 
 
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Department or Division Chair:  
 
 
 
 
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IIT2015-12-Goodman-STOP 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................................................. 1 
LIST OF ABBREVIATIONS ....................................................................................................................... 3 
STUDY SCHEMA ........................................................................................................................................ 5 
STUDY SUMMARY .................................................................................................................................... 6 
1.0 
BACKGROUND AND RATIONALE ............................................................................................ 7 
1.1 
Study Disease .................................................................................................................................................. 7 
1.2 
Study Agent ..................................................................................................................................................... 7 
1.3 
Rationale .......................................................................................................................................................... 7 
2.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 13 
2.1 
Primary Objectives ........................................................................................................................................ 13 
2.2 
Secondary Objectives .................................................................................................................................... 13 
2.3 
Primary Endpoint .......................................................................................................................................... 14 
2.4 
Secondary Endpoints ..................................................................................................................................... 14 
3.0 
PARTICIPANT SELECTION ....................................................................................................... 14 
3.1 
Inclusion Criteria ........................................................................................................................................... 14 
3.2 
Exclusion Criteria .......................................................................................................................................... 14 
3.3 
Inclusion of Women and Minorities .............................................................................................................. 15 
4.0 
STUDY PLAN ............................................................................................................................... 15 
4.1 
Recruitment ................................................................................................................................................... 15 
4.2 
Study Treatment Protocol .............................................................................................................................. 17 
4.3 
Study Measurements ..................................................................................................................................... 18 
5.0 
AGENT ADMINISTRATION ....................................................................................................... 19 
5.1 
Dose Regimen and Dose Groups ................................................................................................................... 19 
5.2 
Study Agent Administration and Duration of Therapy.................................................................................. 19 
5.3 
Run-in Procedures ......................................................................................................................................... 19 
5.4 
Contraindications ........................................................................................................................................... 19 
5.5 
Concomitant Medications .............................................................................................................................. 20 
5.6 
Dose Modification ......................................................................................................................................... 20 
5.7 
Adherence/Compliance ................................................................................................................................. 20 
6.0 
PHARMACEUTICAL INFORMATION ...................................................................................... 21 
6.1 
Study Agent ................................................................................................................................................... 21 
6.2 
Reported Adverse Events and Potential Risks ............................................................................................... 21 
6.3 
Agent Availability, Packaging, and Labeling ................................................................................................ 22 
6.4 
Storage ........................................................................................................................................................... 22 
6.5  
Agent Accountability..................................................................................................................................... 22 
6.6 
Blinding and Unblinding ............................................................................................................................... 23 
7.0 
CLINICAL EVALUATIONS AND PROCEDURES .................................................................... 23 
7.1 
Schedule of Time and Events ........................................................................................................................ 23 
7.2 
Pre-Study Evaluation ..................................................................................................................................... 24 
7.3 
Baseline Testing and Evaluation During the Study Intervention ................................................................... 26 
7.4 
Evaluation at Completion of the Study Intervention ..................................................................................... 29 
7.5 
Post-intervention Follow-up Procedures ....................................................................................................... 29 
7.6 
Removal of Subjects from Study ................................................................................................................... 30 
7.7 
Methods for Clinical Procedures ................................................................................................................... 30 
8.0  
MEASUREMENT OF EFFECT AND CRITERIA FOR EVALUATION ................................... 32 
8.1 
Prevention of Cardiotoxicity Due to Breast Cancer Treatment ..................................................................... 32 
8.2 
Methods for Evaluation of Cardiac Function ................................................................................................ 32 
8.3 
Off-Agent Criteria ......................................................................................................................................... 33 
8.4 
Off-Study Criteria .......................................................................................................................................... 33 
9.0 
CORRELATIVE/SPECIAL STUDIES .......................................................................................... 34 
9.1 
Rationale for Methodology Selection ............................................................................................................ 34 
9.2 
Laboratory Correlates and Biomarkers .......................................................................................................... 34 
9.3 
Specimen Banking ......................................................................................................................................... 35 
10.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 35 
10.1 Study Design/Description .............................................................................................................................. 35 


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10.2 Sample Size and Accrual ............................................................................................................................... 36 
10.3 Randomization and Intervention ................................................................................................................... 36 
10.4 Endpoints/Statistical Considerations ............................................................................................................. 36 
10.5 Statistical Analysis Plan ................................................................................................................................ 36 
10.6 Contamination (Cross-Over) and Drop-Outs ................................................................................................. 37 
10.7 Evaluation of Toxicity ................................................................................................................................... 37 
10.8 Evaluation of Response ................................................................................................................................. 37 
10.9 Interim Analysis ............................................................................................................................................ 37 
11.0 
ADVERSE EVENTS ..................................................................................................................... 37 
11.1 Experimental Therapy ................................................................................................................................... 37 
11.2 Adverse Event Monitoring ............................................................................................................................ 38 
11.3 Definitions ..................................................................................................................................................... 38 
11.4 Steps to Determine If an Adverse Event Requires Expedited Reporting....................................................... 39 
11.5 Reporting Requirements for Adverse Events ................................................................................................ 39 
11.6 Stopping Rules .............................................................................................................................................. 40 
12.0 
STUDY MANAGEMENT ............................................................................................................. 40 
12.1 Conflict of Interest ......................................................................................................................................... 40 
12.2 Institutional Review Board (IRB) Approval and Consent ............................................................................. 40 
12.3 Registration Procedures ................................................................................................................................. 41 
12.4 Record Keeping and Data Management ........................................................................................................ 42 
12.5 Data and Safety Monitoring Board (DSMB) ................................................................................................. 42 
12.6 Executive Committee and Internal Advisory Board (IAB) ........................................................................... 42 
12.7 Adherence to the Protocol ............................................................................................................................. 43 
12.8 Amendments to the Protocol ......................................................................................................................... 43 
12.9 Record Retention ........................................................................................................................................... 43 
12.10 Obligations of Investigators........................................................................................................................... 44 
REFERENCES ............................................................................................................................................ 45 
APPENDIX A ............................................................................................................................................. 50 
APPENDIX B .............................................................................................................................................. 51 


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LIST OF ABBREVIATIONS  
2-D echo 
2-dimensional echocardiography 
AC 
Anthracycline and cyclophosphamide 
AC-T 
Anthracycline and cyclophosphamide followed by taxane 
AC-TH 
Anthracycline and cyclophosphamide followed by taxane and Herceptin (trastuzumab) 
ACE 
Angiotensin-converting-enzyme 
ACEi 
Angiotensin-converting-enzyme inhibitor 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
BB 
β-blocker; beta blocker 
BNP 
Brain natriuretic peptide; B-type natriuretic peptide 
BRCA 
Gene mutation that elevates the risk of breast cancer 
CABG 
Coronary artery bypass graft 
CAD 
Coronary artery disease 
CBDF 
Complete Blood Count and Automated Differential 
CHF 
Congestive heart failure 
CMPL 
Comprehensive Metabolic Panel 
CMRI 
Cardiac magnetic resonance imaging 
CO 
Cardiac output 
CPK 
Creatine phosphokinase; creatine kinase 
CrCl 
Creatinine clearance  
CRO 
Clinical Research Office 
CSd 
Diastole rate 
CSs 
Systole rate 
CSMC 
Cedars-Sinai Medical Center 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVD 
Cardiovascular disease 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
ER 
Estrogen receptor 
FDA  
Food and Drug Administration 


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Gad 
Gadolinium 
GCS 
Global circumferential strain  
GTPase 
Guanosine triphosphatase 
HDAC 
Histone deacetylase 
HER2 
Human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme a 
Hs-CRP 
High sensitivity C-reactive protein 
Hs-TnT 
High sensitivity troponin 
IAB 
Internal Advisory Board 
ICF 
Informed Consent Form 
IL-6 
Interleukin 6 
IRB 
Institutional Review Board  
IV 
Intravenous 
LV 
Left ventricular 
LVEDV 
Left ventricular end diastolic volume 
LVEF 
Left ventricular ejection fraction 
LVESV 
Left ventricular end systolic volume 
LVOT 
Left ventricular outflow tract 
MOLLI 
Modified Look-Looker Inversion Recovery 
MRS 
Magnetic resonance spectroscopy 
NADPH 
Nicotinamide adenine dinucleotide phosphate 
PFR 
Peak filling rate 
PR 
Progesterone receptor 
Rac1 
Ras-related C3 botulinum toxin substrate 1 
ROS  
Reactive oxygen species 
RCT 
Randomized controlled trial 
SAE 
Serious adverse event 
SOCCI 
Samuel Oschin Comprehensive Cancer Institute 
SSFP 
Steady-state-free-precession 
SV 
Systolic volume 
TCH 
Taxotere (docetaxel), carboplatin, and Herceptin (trastuzumab) 
TCHP 
Taxotere (docetaxel), carboplatin, Herceptin (trastuzumab), and pertuzumab 
tPFR 
Time to peak filling rate 
UTR 
Peak rate of basal to apical untwisting 
WISE 
Women's Ischemia Syndrome Evaluation 


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STUDY SCHEMA 
Statin Therapy Operates to Prevent (STOP) Heart Disease in Breast Cancer Survivors Trial 
Female patients with newly diagnosed stage 1-3 breast cancer 
 
Pre-Screen Medical Chart Review and Initial Determination of Eligibility  
Clinical research staff reviews medical charts of patients diagnosed with breast cancer and completes pre-screen eligibility 
checklist: age, HER2/ER/PR status, lab results, medical contraindications, prohibited medications, prior or current statin use 
 
Recruitment and Consent 
Oncologist introduces study to potentially eligible breast cancer patients recommended for trastuzumab treatment, 
with or without anthracycline. Patients receive study information packet; clinical research staff reviews study 
details with patient and contacts patient a few days later to answer questions. Patients who want to participate will 
be consented into the trial by one of the study physicians before any research procedures are initiated. 
 
Pre-Study Evaluations* 
Physical exam; symptom assessment; ECOG performance status; blood tests to confirm eligibility and safety of statin 
initiation; urine pregnancy test for women able to become pregnant; 2D-echocardiogram. Patients with an abnormal 
2D-echocardiogram, AST/ALT > 3x ULN, creatinine > 1.8 mg/dL, or who are pregnant will be excluded. 
 
Final Determination of Eligibility 
Research staff completes full eligibility checklist for consented patients, retrieves support documents from medical charts. 
Oncologist, study cardiologist, or other physician-investigator reviews patient’s checklist, medical history, and supporting 
documentation. Clinical Research Office designee conducts final eligibility check prior to registration and randomization.  
 
Eligible, consented patients with breast cancer registered and randomized to atorvastatin or placebo (N=60) 
Atorvastatin 20 mg, daily for 12 months  
(N=30)  
 
Placebo identical in color, consistency, and appearance to 
atorvastatin 20 mg, daily for 12 months (N=30) 
 
 
 
Visit 1^ – Baseline measurements and Initiation of the Statin Intervention (from 2 weeks before the patient starts 
systemic breast cancer treatment (trastuzumab with or without anthracycline) up to 3 weeks after starting treatment) 
Review medical history, medications, and laboratory test results; vital signs assessment; ECOG performance status; 
blood draw; urine pregnancy test for women able to become pregnant; cardiac magnetic resonance imaging (CMRI); 
interviewer-administered questionnaire; self-administered QLQ-C30 and QLQ-BR23 quality of life questionnaire; 
review eligibility criteria; dispense study drug and diary 
 
Visit 2* (1 month ± 2 weeks after initiation of the statin intervention) 
Review medical history, medications, and laboratory test results; physical exam; symptom assessment; ECOG 
performance status; clinical labs for CBDF and CMPL; collect study drug and diary; assess compliance and adverse 
events; review study diary; review eligibility criteria; dispense study drug and diary 
 
Visit 3* (3 months ± 2 weeks after initiation of the statin intervention) 
Same procedures as Visit 2 and follow-up 2D-echocardiogram 
 
Visit 4^ (6 months ± 2 weeks after initiation of the statin intervention) 
Same procedures as Visit 1 and: collect study drug and diary; assess compliance and adverse events; review study diary 
 
Visit 5* (9 months ± 2 weeks after initiation of the statin intervention) 
Same procedures as Visit 3 
 
Visit 6^ (12 months ± 2 weeks after initiation of the statin intervention) 
Same procedures as Visit 4 except no study drug dispense; collect study drug and diary 
 
Follow-up phone calls (day 30, 60, 90 ± 7 after completion of the statin intervention) to assess symptoms/adverse events 
 
Endpoints – Evaluate the effect of atorvastatin use versus placebo after 12 months of intervention on changes in: 
1) Global circumferential strain (GCS), a sensitive measure of myocardial dysfunction, measured by cardiac magnetic 
resonance imaging (CMRI) 
2) Other strain-related measures, myocardial diastolic function, and cardiac morphology, measured by cine CMRI and 
tissue tagging 
3) Myocardial fibrosis and tissue viability, edema, and inflammation measured by CMRI T1 and T2 mapping values  
*Pre-Study Evaluations and Visits 2, 3, and 5 are standard of care visits.  
^Visits 1, 4, and 6 are research visits to collect endpoint data and will coincide with standard of care visits when possible. 


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STUDY SUMMARY 
 
Title 
Statin Therapy Operates to Prevent (STOP) Heart Disease in Breast Cancer 
Survivors Trial 
Protocol Number 
IIT2015-12-Goodman-STOP 
Phase 
Phase II 
Methodology 
Randomized, double-blinded, placebo-controlled, Phase II trial of statin therapy 
to ameliorate or prevent cardiac damage in women with newly diagnosed stage 
1-3 breast cancer 
Study Duration 
3.5 years 
Study Center(s) 
Cedars-Sinai Medical Center 
Objectives 
Primary Objective: To evaluate the effect of atorvastatin intervention versus 
placebo on a 1 year change from baseline on myocardial dysfunction in breast 
cancer patients who have undergone trastuzumab treatment, with or without 
anthracycline. The primary outcome is global circumferential strain (GCS), a 
sensitive measure of myocardial dysfunction, which is predictive of future 
cardiac events. Cardiac magnetic resonance imaging (CMRI) will be used to 
measure GCS. 
Secondary Objectives: To evaluate the effect of atorvastatin intervention versus 
placebo on a 1 year change from baseline on: 1) other strain-related measures, 
myocardial diastolic function, and cardiac morphology, measured by cine 
CMRI and tissue tagging; and 2) myocardial fibrosis, edema, and inflammation 
measured by T1 and T2 mapping values during the CMRI. 
Number of Subjects 
60 
Diagnosis and Main 
Inclusion Criteria 
Newly diagnosed stage 1-3 breast cancer; histologically confirmed HER2, ER, 
and PR status; minimum 18 years of age; recommended to undergo 
trastuzumab treatment, with or without anthracycline. Patients will be eligible 
for up to 3 weeks after starting treatment. 
Study Product(s), Dose, 
Route, Regimen 
Atorvastatin 20 mg and placebo identical in color, consistency, and appearance 
to atorvastatin; oral administration daily 
Duration of Administration 
12 months 
Statistical Methodology 
Analyses will be conducted on an intention-to-treat basis on all patients who 
complete the 12-month CMRI. The non-parametric Wilcoxon-Mann-Whitney 
test will be used to test the equality of statin treatment (atorvastatin) to placebo 
in reducing or preventing LV dysfunction through comparison of change in 
GCS values (∆ length / original length, expressed as %) measured from 2 weeks 
prior to start of systemic breast cancer treatment to 1 year post-initiation of the 
statin intervention. The distribution of the covariates, including age, race, dose 
of trastuzumab treatment (and anthracycline if applicable), laterality, radiation 
dose, smoking status, BMI, baseline measures of fibrosis, hormone use, and 
comorbid conditions, will be summarized and compared between the 
intervention and control groups to assess the adequacy of the randomization. 
Chance differences between groups will be adjusted for using multiple 
regression modeling.  
 




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the human epidermal growth factor receptor-2 (HER2/ErbB2), has become a potential cause of heart failure and 
cardiomyopathy among women treated for breast cancer, especially when given with anthracyclines [9]. 
 
Statins and Cardioprotection. The prophylactic and therapeutic use of cardioprotective agents, including statins, 
angiotensin-converting-enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), and β-blockers (BB), 
have been reported to ameliorate cancer treatment cardiotoxicity, although evidence from RCTs in breast cancer 
patients have been limited. A recent review and meta-analysis of cardioprotective therapy to reduce adverse 
cardiac outcomes in cancer chemotherapy patients found that statins showed a similar efficacy compared to other 
cardioprotective agents [3]. Statins decrease CVD-related morbidity and mortality and are widely used for 
cardiovascular disease prevention [10]. In addition to cholesterol lowering anti-atherosclerotic effects, statins also 
exert pleiotropic effects that are anti-oxidative and may be cardioprotective, and therefore relevant to 
trastuzumab-induced cardiotoxicity [11]. While observational studies suggest that statins may attenuate 
chemotherapy-induced cardiac toxicity, this outcome has not been rigorously tested in a clinical trial. We 
hypothesize that the diverse and beneficial effects of statins will help protect the heart during trastuzumab 
treatment. Our multi-disciplinary research team will randomize newly diagnosed stage 1-3 breast cancer patients 
to prophylactic statin versus placebo and evaluate longitudinal structural and functional changes to the 
myocardium using CMRI. Our RCT with a longitudinal approach to studying detailed imaging changes of the 
myocardium from baseline through 12 months of treatment will elucidate pathophysiological pathways of 
myocardial damage and could lead to a new cardioprotection strategy in breast cancer treatment. 
 
Hypotheses. We anticipate that trastuzumab treatment, with or without anthracycline treatment, will impair 
global circumferential strain (GCS) and diastolic function, and increase markers of fibrosis, edema, and/or 
inflammation. We hypothesize that after 12 months of intervention, participants randomized to atorvastatin will 
experience: 
1)  Less GCS impairment compared to the placebo group; 
2) Less diastolic dysfunction compared to the placebo group; and 
3) Less myocardial fibrosis, edema, and inflammation compared to the placebo group. 
 
Chemotherapy-Induced Cardiotoxicity. Adverse cardiac events, including heart failure, myocardial ischemia, 
venous thromboembolism, and bradycardia may result from common breast cancer treatments [12]. The focus of 
our RCT is on the subacute cardiotoxic effect of trastuzumab therapy that has long-term consequences, especially 
diastolic LV dysfunction and subsequent risk of heart failure [5]. Cardiac risk is particularly elevated in breast 
cancer patients treated with a combination of anthracycline and trastuzumab. Early clinical trials showed that the 
addition of trastuzumab to anthracycline treatment for breast cancer led to a synergistic increase in cardiac 
symptoms from 13% to 27% compared to 2-8% of patients receiving trastuzumab or anthracyclines alone [13]. A 
recent analysis of a population-based cohort study of 12,500 women with invasive breast cancer demonstrated 
hazard ratios for heart failure and cardiomyopathy during treatment of 1.4 (1.1-1.8) in patients on anthracycline 
alone, 4.1 (2.3-7.4) in patients treated with trastuzumab alone, and 7.2 (5.0-10.4) in patients treated with both 
agents as compared to patients who received no chemotherapy [14]. 
 
Trastuzumab. Trastuzumab (Herceptin) targets the HER2/neu receptor which is overexpressed in 25% of breast 
cancer [15]. This receptor is also expressed at low levels in the heart and can be upregulated under stress [16]. 
Inhibition of the HER2 receptor contributes to cardiac injury in patients receiving trastuzumab, although 
mechanisms are still unclear. HER2 signaling is fundamental to cardiomyocyte development and survival [17]. 
HER2-knock out mice develop dilated cardiomyopathy progressing to systolic dysfunction, suggesting an 
important role for HER2 expression in maintaining cardiac function [18]. Trastuzumab is capable of inhibiting 
autophagy in human cardiomyocytes, leading to increased production of reactive oxygen species [19]. 
Trastuzumab down-regulation of the HER2 pathway has been linked to asymptomatic cardiac dysfunction and 
symptomatic congestive heart failure (CHF) [20]. A recent meta-analysis of five RCTs, found a RR of 5.8 (3.6-
9.3) for the association of trastuzumab and all-grade CHF with a number needed to harm of 9 (for every 9 patients 
treated with trastuzumab one additional case of CHF will occur compared to placebo) [21]. While trastuzumab-
related cardiac dysfunction was initially thought to be reversible with no frank ultra-structural changes, advanced 
CMRI data shows myocyte damage with fibrosis and scarring [22]. In spite of the increased cardiac monitoring 


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included to ensure patient safety in HER2-positive breast cancer patients, LV dysfunction occurs in up to 23% of 
patients receiving trastuzumab alone [15,20]; and in a joint analysis of two large clinical trials, 4.1% of patients 
receiving trastuzumab experienced  CHF or cardiac death [15]. In a recent trial, 7% of women with HER2-
positive breast cancer had a decrease in LV ejection fraction (LVEF) >10% at 2 years, with CHF in 0.8% of 
patients [23]. A meta-analysis of three RCTs found a RR of 6.7 (4.9-9.2) for the association of trastuzumab with 
high grade decreased left ventricular ejection fraction (number needed to do harm was 3) [21]. These sequelae 
were amplified by the fact that cardiotoxicity was the leading cause of trastuzumab interruption: 5% of clinical 
trial participants in year 1 and 9% of participants in year 2 discontinued trastuzumab treatment, which has serious 
consequences for control of HER2-positive breast cancer [15]. Moreover, the cardiotoxic effects of trastuzumab 
will likely be greater in the community setting where the presence of comorbidities is higher than in carefully 
selected clinical trial patients. Indeed, a Medicare-based study found that the incidences of cardiomyopathy and 
heart failure were increased by >10% among elderly patients treated with trastuzumab compared to non-
trastuzumab / non-anthracycline based therapy [24]. In another Medicare study [25], the 41% of patients who 
discontinued trastuzumab early - usually due to cardiovascular complications - were at higher risk of heart failure 
/ cardiomyopathy, atrial fibrillation, and other cardiovascular events than were women who were able to tolerate 
the full course of trastuzumab. 
 
Anthracyclines. Anthracyclines cause dose-dependent irreversible LV dysfunction likely resulting from oxidative 
stress and mitochondrial damage associated with myofibrillar disarray and necrosis [26]. Irreversible 
cardiotoxicity may progress to heart failure and death in breast cancer survivors [27]. It is thought that the acute 
decline in cardiac contractility caused by anthracyclines is dose-dependent, and that onset cardiomyopathy may 
occur in up to 5% of patients in the year following anthracycline therapy. The cardiotoxic effects of anthracycline 
(doxorubicin) treatment are dose-responsive, with heart failure noted in 26% of patients given the maximum 
lifetime cumulative dose of 550 mg / m2 [12]. The BCIRG-006 trial compared doxorubicin plus 
cyclophosphamide followed by docetaxel (AC-T); AC-T plus one year trastuzumab (AC-TH); and a non-
anthracycline-containing arm, docetaxel, carboplatin, and one year trastuzumab (TCH) among 3,222 HER2-
positive women with early breast cancer [28]. While the 10-year follow-up results suggested no difference in 
overall survival for the AC-TH compared with the TCH patients, the AC-TH patients experienced 5-fold more 
cardiac deaths and CHF events (p=0.0005) in the AC-TH arm (21 events) compared with the TCH arm (4 events) 
[9]. We are especially interested in the subgroup of women treated with both trastuzumab and anthracycline.  
 
Mechanisms for Treatment-Associated Cardiotoxicity. Mechanisms for trastuzumab-induced cardiotoxicity 
are still being clarified, but it is thought that trastuzumab leads to heart failure by blocking the physiological 
actions of HER2 in the heart [29,30]. HER2 is essential for normal fetal cardiac development and cardiac-specific 
deletion of HER2 leads to cardiomyopathy in mice [20,31]. HER2 is present in cardiomyocytes and, in the 
presence of the ligand neuregulin-1, HER2 upregulates phosphoinositide-3-kinase (PI3K) signaling, AKT 
activation, and the extracellular signal-regulated kinase (ERK1/2) mitogen-activated pathway; and HER2 
suppresses apoptotic signaling. In the absence of HER2 signaling, cardiac dysfunction develops, characterized by 
mitochondrial dysfunction, excessive production of reactive oxygen species (ROS), opening of the mitochondrial 
permeability transition pore, and cell death [32,33]. Anthracyclines likely cause myofibrillar loss and cellular 
necrosis through direct injury and oxidative stress [34]. Anthracyclines target cellular topoisomerase-2α and DNA 
to form a cleavage complex that triggers apoptosis in tumor cells [35]. The inhibition of topoisomerase-2β by 
anthracycline causes double-stranded breaks and death of cardiomyocytes. Topoisomerase-2β inhibition also 
reduces p53 activation of the apoptotic pathway, and decreases expression of uncoupling proteins that regulate 
NADPH oxidase-mediated mitochondrial ROS production [4]. NADPH oxidase, an important cause of 
cardiovascular disease, consists of several protein components, including Rac1, a Rho guanosine triphosphatase 
(GTPase). Inhibition of Rac1 was found to protect mice from doxorubicin-induced myocardial dysfunction, while 
Rac1 overexpression led to decreased activity of histone deacetylases (HDAC), mimicking the effects of 
doxorubicin on p53-mediated apoptosis [36]. 
 
Radiation-Induced Cardiotoxicity. Cardiovascular toxicity resulting from radiotherapy for mostly left-sided 
breast cancer has been well-documented, especially among women receiving whole heart doses of ≥ 5 gray, as 
was common in the past [37]. Radiation-related injury may include structural damage to the heart, such as 
fibrosis, pericardial adhesions, microvascular damage and valvular stenosis, as well as damage to the coronary 


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arteries [38]. Despite this, radiation to left-sided breast tumor was not found to be associated with congestive heart 
failure in a national population of elderly women with breast cancer [39]. The radiation dose to the heart has 
decreased substantially during the past decade, driven by medical advances such as accelerated partial breast 
irradiation [40]. Although tangential radiation treatment for left-sided breast cancer is now computed tomography 
(CT)-guided, delivering the lowest dose of radiation for the shortest duration, coronary arteries in the field can be 
affected [41]. The degree to which improved radiotherapeutic technologies have ameliorated long-term risk of 
heart failure in breast cancer patients is unknown. We expect that randomization of patients to statin and placebo 
will balance the frequency of left-sided breast cancer and the relative radiation exposure to the heart. If by chance 
the radiation dose to the heart is imbalanced between the two groups, we will conduct a sensitivity analysis 
following our primary intention-to-treat analysis to investigate if variations in radiation dose affected the results 
of statin. 
 
Statins (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)) Inhibitors and Breast Cancer. Statins, used 
primarily to reduce LDL-cholesterol by inhibiting the conversion of HMG-CoA to mevalonate, are well-tolerated 
with few serious side effects [6]. Statin use reduces the incidence of major vascular events, such as myocardial 
infarction, stroke and coronary revascularization, as well as overall mortality [10]; and this risk reduction extends 
to healthy individuals at low baseline risk of cardiovascular disease. Emerging evidence implicates an imbalance 
of angiogenic and antiangiogenic factors in hypertension and coronary artery disease [42,43] that can be 
normalized by statin treatment  [44]. A key mechanism whereby statins can inhibit cardiotoxicity includes the 
reduced production of isoprenoid (e.g., farnesyl pyrophosphate, geranyl pyrophosphate), a necessary post-
translational modifier of the RAS superfamily of GTPase proteins, including Rac. Rac is an important activator of 
the NADPH oxidase [45]. When prenylated, Rac tethers co-activator p67 to the membrane and induces a 
conformational change leading to the assembly of NADPH oxidase complex and production of O2 [46]. By 
inhibiting the prenylation of Rac1, statins have been shown to decrease ROS production, attenuating cardiac 
hypertrophy [47]. Statins also promote mitochondrial turnover, attenuating ROS production and accumulation of 
mtDNA mutations [48,49]. Statins may alter the expression of vascular growth factors, thereby improving the 
capillary network and reversing the anti-angiogenic effects of trastuzumab in the heart [50]. Taken together, these 
studies provide compelling evidence that statins regulate, either directly or indirectly, several signaling pathways 
implicated in cardiomyocyte damage. We hypothesize that the diverse and beneficial effects of statins will help 
protect the heart during cancer chemotherapy. 
 
Not all statins are expected to have a specific local effect on cardiomyocytes, as they vary in hepatoselectivity. 
Hydrophilic statins, such as rosuvastatin, accumulate in the liver, as they are taken into liver cells by carrier-
mediated transporters that are expressed in hepatocytes. Lipophilic statins such as atorvastatin enter cells in the 
hepatic and extrahepatic tissue via passive diffusion and do not accumulate in the liver, thus making it more 
available to other organs [51]. Congruent with this property, lipophilic statins were found to be associated with 
reduced recurrence of cancer in a large cohort of Danish women with stage I-III breast cancer, while hydrophilic 
statins did not have any impact on outcome [52]. Given these observations, we decided to select a lipophilic statin 
for our intervention. Among several lipophilic statins on the market, including atorvastatin, simvastatin, 
fluvastatin, and lovastatin, we have chosen atorvastatin not strictly for its greater lipid-lowering efficacy when 
compared to simvastatin [8], but also because of its anti-inflammatory and anti-apoptotic properties [53,54]. 
 
Global Circumferential Strain (GCS). Global circumferential strain (GCS) is a composite measure of the strain 
and relaxation of the heart during the systole and diastole. In a prospective follow-up of 84 women with HER2-
positive breast cancer treated with anthracyclines, taxanes and trastuzumab, both peak systolic longitudinal 
myocardial strain < 19% and ultrasensitive troponin I measured at the completion of therapy were the most 
predictive of subsequent cardiotoxicity, as defined by Cardiac Review and Evaluation Committee criteria [55]. In 
support of this finding, results from a study of 81 women undergoing trastuzumab and anthracycline treatment 
showed that a ≥ 11% reduction in global strain measured by echocardiography was strongly predictive of later 
reductions in ejection fraction [56]. The clinical relevance of myocardial strain in predicting long-term cardiac left 
ventricular (LV) dysfunction is further underscored by the significant 7.7% reduction in global strain observed up 
to 6 years following cessation of anthracycline therapy in 75 asymptomatic breast cancer survivors [57]. The 
global circumferential strain was also reported to be an independent predictor of future heart failure and cardiac 
death in patients with a previous episode of heart failure [58]. A meta-analysis of 1,500 cancer patients 






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delaying diagnosis and treatment by ≥ 6 months may reduce the benefit of heart failure treatment [3]. Presently, 
there is little evidence regarding risk reduction schema to reduce myocardial injury during cancer treatment 
despite the existence of effective cardiovascular disease preventive strategies [77]. A recent meta-analysis showed 
that several medications, including statin, had efficacy for reducing the risk of cardiac injury in cancer patients 
[3]. Statins are well-accepted and well-tolerated medications [6] and have demonstrated a reduction in mortality in 
primary and secondary prevention of cardiovascular diseases [10]. Our multi-disciplinary approach will allow us 
to integrate findings regarding structural changes to the myocardium with pre- and post-therapeutic functional and 
metabolic characteristics. We focus on women undergoing trastuzumab treatment (with or without anthracycline) 
for breast cancer because they will derive the greatest benefit from an early intervention to prevent cardiac injury. 
Our short-term follow-up will facilitate an examination of initial changes in cardiotoxicity among breast cancer 
survivors. Detailed imaging changes to the myocardium from baseline through one year of statin therapy will 
ultimately inform mechanistic pathways of treatment-induced myocardial damage. 
 
Our review of the literature and ClinicalTrials.gov identified no published RCT evaluating the benefit of early 
initiation of statin specifically in breast cancer patients. However, a number of past or ongoing studies (e.g., NCT 
01022086, 00679874, 02306538, 02062983) have used CMRI to examine heart function in breast cancer patients 
treated with trastuzumab, supporting the utility of non-invasive imaging in the proposed RCT. Randomizing 
women planning to undergo breast cancer treatment to prophylactic therapy with statin, which is known to be 
inexpensive, well-tolerated, safe, effective and approved for prevention of cardiovascular disease, is a strength as 
it may make the trial more attractive to oncologists who are enrolling patients, as well as to potential subjects. 
Presently, no consensus-based guidelines exist for post-treatment cardiovascular disease monitoring of breast 
cancer survivors [77]. Subtle injury to cardiac muscle during breast cancer treatment that fails to heal following 
cessation of therapy is a critical health and quality of life concern among breast cancer survivors. This knowledge 
gap in the cardiovascular care of breast cancer patients is understandable in that these women are generally 
excluded from cardiac clinical trials. Evidence is needed regarding the benefit of implementing measures early to 
reduce or prevent cardiac injury among women with the most aggressive molecular subtypes of breast cancer. The 
management strategies being tested are logical and consistent with present clinical care of women at risk for 
cardiac disease, yet novel for the population. This short-term trial will document the feasibility of recruiting breast 
cancer patients to statin therapy, will evaluate efficacy and safety of this preventive strategy, and will inform the 
search for key biologic mechanisms and time course through which breast cancer treatment leads to myocardial 
dysfunction with future progression to ischemia and heart failure. Future studies will include longer follow-up to 
capture longer-term cardiotoxicity and larger numbers of breast cancer patients to optimize our cardioprotection 
strategies.  
 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
 
The objective of the Statin Therapy Operates to Prevent (STOP) Heart Disease in Breast Cancer Survivors Trial 
is to examine the effect of statin use versus placebo on myocardial functional and structural changes in 60 women 
diagnosed with stage 1-3 breast cancer recommended to undergo trastuzumab treatment, with or without 
anthracycline. We will conduct a randomized, double-blinded, placebo-controlled, Phase II trial of atorvastatin to 
ameliorate or prevent cardiac damage in women with newly diagnosed breast cancer. Detailed imaging changes to 
the myocardium from baseline through 12 months of follow-up will ultimately inform mechanistic pathways of 
treatment-induced myocardial damage. Our ultimate goal is to develop strategies that will attenuate the long-term 
cardiotoxicity from trastuzumab treatment. 
 
2.1 
Primary Objectives 
 
2.1.1 
To evaluate the effect of atorvastatin intervention versus placebo on a 1 year change from baseline in 
myocardial dysfunction in breast cancer patients who have undergone trastuzumab treatment, with or without 
anthracycline. The primary outcome is global circumferential strain (GCS), a sensitive measure of myocardial 
dysfunction, which is predictive of future cardiac events. Cardiac magnetic resonance imaging (CMRI) will be 
used to measure GCS. 
 
2.2 
Secondary Objectives  


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2.2.1 
To evaluate the effect of atorvastatin intervention versus placebo on a 1 year change from baseline in 
other strain-related measures, myocardial diastolic function, and cardiac morphology, measured by cine 
CMRI and tissue tagging; 
 
2.2.2 
To evaluate the effect of atorvastatin intervention versus placebo on a 1 year change from baseline in 
myocardial fibrosis, edema, and inflammation measured by T1 and T2 mapping values during the CMRI. 
 
2.3 
Primary Endpoint 
 
The primary endpoint is change in global circumferential strain (GCS) measured by CMRI. GCS is a composite 
measure of myocardial deformation as the heart contracts and relaxes. The equality of atorvastatin intervention to 
placebo in reducing or preventing left ventricular (LV) dysfunction will be assessed through comparison of 
change in GCS values measured from baseline (from 2 weeks before the patient starts systemic breast cancer 
treatment (trastuzumab with or without anthracycline) up to 3 weeks after starting treatment) to 12 months post-
initiation of the statin intervention. 
 
2.4 
Secondary Endpoints 
 
Secondary outcomes include additional global measures of cardiac function, diastolic function, cardiac 
morphology, and tissue viability. Differences in secondary outcomes from baseline to 12 months follow-up will 
be compared in the atorvastatin and placebo groups using a similar approach to the main outcome. 
 
2.4.1 
Changes in other strain-related measures (global longitudinal strain (GLS), peak LV twist and torsion), 
myocardial diastolic function (LV untwisting rate, diastolic strain rate) and cardiac morphology (mass, 
wall thickness, internal dimensions)  
 
2.4.2 
Changes in myocardial fibrosis and tissue viability, edema, and inflammation 
 
3.0 
PARTICIPANT SELECTION 
 
3.1 
Inclusion Criteria 
 
3.1.1 
Female patients with newly diagnosed stage 1-3 breast cancer 
 
3.1.2 
Histologically confirmed HER2, ER, and PR status 
 
3.1.3 
Recommended to undergo trastuzumab treatment, with or without anthracycline. Patients will be eligible 
for up to 3 weeks after starting treatment. 
 
3.1.4 
Age minimum 18 years 
 
3.1.5 
Able and willing to read, understand, and sign an informed consent form (ICF) and medical release form 
 
3.1.6 
Willing and able to comply with trial protocol and follow-up 
 
3.1.7 
ECOG performance status 0-1 (Karnofsky ≥ 70%; see Appendix A) 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Prior use of statin medication within the past year  
 
3.2.2 
Not using statin medication but is eligible for statin therapy based on the 2013 ACC/AHA guidelines 
(LDL cholesterol >190, or LDL <190 and ASCVD risk >7.5%; http://tools.acc.org/ASCVD-Risk-


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Estimator/) and is > 50 years old; or is eligible for statin therapy based on the 2013 ACC/AHA guidelines 
and is 40-50 years old and wishes to be placed on statin therapy 
 
3.2.3 
History of adverse effects, intolerance, or allergic reactions attributed to statin medication 
 
3.2.4 
Current use of gemfibrozil, cyclosporine, clarithromycin, itraconazole, erythromycin, the hepatitis C 
protease inhibitor telaprevir, HIV protease inhibitors, colchicine, or red yeast rice 
 
3.2.5 
Current use of any other investigational agent 
 
3.2.6 
Pregnant or intention to get pregnant during the next 18 months. Pregnant women are excluded from this 
study because atorvastatin is a lipid-lowering agent with the potential for teratogenic or abortifacient 
effects, and MRI is contraindicated in pregnant women. 
 
3.2.7 
History of diabetes, severe lung disease, renal disease (creatinine > 1.8 mg/dL or CrCl ≤ 50 mL/min), or 
hepatic disease (AST and ALT > 3 times upper normal limits) 
 
3.2.8 
Abnormal baseline echocardiogram or cardiac MRI (detection of congenital heart disease; ischemic heart 
disease; moderate or severe valvular heart disease; cardiomyopathy; EF < 55%) 
 
3.2.9 
Previously known or diagnosed heart disease (e.g. congenital; valvular; coronary artery disease; history of 
myocardial infarction or acute coronary syndrome; cardiomyopathy, including infiltrative, hypertensive, 
hypertrophic, dilated, constrictive pericarditis, or other cardiomyopathy) 
 
3.2.10 Left ventricular dysfunction (EF < 55%) 
 
3.2.11 Prior non-cardiac illness with an estimated life expectancy < 4 years 
 
3.2.12 Known active infection with HIV 
 
3.2.13 Allergy or contraindication to MRI testing, including metallic parts in the body prohibiting MRI, prior 
gadolinium contrast reaction, or uncontrolled moderate hypertension (sitting blood pressure >160/95 mm 
Hg with measurements recorded on at least 2 occasions) 
 
3.2.14 Has metallic breast expanders in place at the time of screening 
 
3.2.15 Concurrent illness which in the opinion of the investigators would compromise either the patient or the 
integrity of the data 
 
3.3 
Inclusion of Women and Minorities 
 
Women and members of all races and ethnic groups are eligible for this trial. Men are excluded from the study 
because there are very few cases of male breast cancer. 
 
4.0 
STUDY PLAN 
 
4.1 
Recruitment 
 
Women with newly diagnosed stage 1-3 breast cancer will be recruited from the Brandman Breast Center at 
Cedars-Sinai Medical Center (CSMC), the Tower Hematology Oncology Medical Group, and the offices of 
CSMC affiliated oncologists. Between January and June 2016, 61 women with breast cancer were recommended 
to undergo trastuzumab treatment at Cedars-Sinai. The number of women who received trastuzumab treatment 
may be greater because data collection guidelines do not require the Cancer Registry to collect individual agent 
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potentially eligible patients may not be seen again by the treating oncologist until after they are no longer eligible 
for the study. In such cases, women who have had all their questions about the trial answered on the day they first 
learn about the study, and who wish to volunteer for the trial, may be consented to participate in the study the 
same day they are first informed of the research.  
 
After consent has been obtained, clinical research staff will complete a full eligibility checklist and compile the 
support documents from patient medical records, including laboratory reports, medical history, physician notes, 
and current medications list. The oncologist, study cardiologist, or other physician-investigator will review the 
patient’s eligibility checklist, medical history, and supporting documentation. Patients with a history of heart 
disease or cardiomyopathy and patients > 50 years old who are eligible for statin therapy based on the 2013 
ACC/AHA guidelines (LDL cholesterol >190, or LDL <190 and ASCVD risk >7.5%; 
http://tools.acc.org/ASCVD-Risk-Estimator/) will be excluded from the trial. Patients 40-50 years old who are 
eligible for statin therapy based on the 2013 ACC/AHA guidelines and want to be placed on statins will also be 
excluded.  
 
A Clinical Research Office (CRO) designee will conduct a final eligibility check prior to registration. Consented 
patients who qualify for the study after the pre-study eligibility evaluations and CRO confirmation of eligibility 
will be registered for the trial, enrolled in the study, randomized to the intervention (atorvastatin or placebo), and 
scheduled for Visit 1, the baseline testing. 
 
4.2 
Study Treatment Protocol 
 
All women will receive their usual care under the guidance of their oncologist. Importantly, this will include 2-D 
echo to allow us to compare current screening practice with the innovative CMRI. Breast cancer patients 
scheduled for systemic breast cancer treatment are recommended to undergo a 2D-echocardiogram prior to 
starting treatment, and 3 months and 9 months after initiation of treatment for standard of care monitoring. 
 
There will be three research study visits (Visits 1, 4, and 6) to collect endpoint data: baseline measurements and 
initiation of the statin intervention, from 2 weeks before the patient starts systemic breast cancer treatment 
(trastuzumab with or without anthracycline) up to 3 weeks after starting treatment; and follow-up visits 6 and 12 
months after initiation of the statin intervention. Each research visit will include a medical history, medications, 
and laboratory test results review; vital signs assessment and measurement of weight; ECOG performance status; 
blood draw; pregnancy test for women who are able to become pregnant (during the pre-study evaluations visit 
and at each research visit; see 4.3 Study Measurements for pregnancy test details); cardiac magnetic resonance 
imaging (CMRI); interviewer-administered questionnaire; quality of life assessments, QLQ-C30 and QLQ-BR23; 
eligibility criteria review; dispensing the study drug (atorvastatin or placebo, no dispense at 12-month visit; 
compliance and adverse events assessment; and review of the study diary.  
 
There will be three additional encounters during standard of care oncologist visits (1 month, 3 months, and 9 
months after initiation of the statin intervention) that include a medical history, medications, and laboratory test 
results review; physical exam; symptom assessment; ECOG performance status; clinical labs for a Complete 
Blood Count and Automated Differential (CBDF) and a Comprehensive Metabolic Panel (CMPL); eligibility 
criteria review; compliance and adverse events assessment; review of the study diary; and dispensing the study 
drug. See Section 7.0 Clinical Evaluations and Procedures for a detailed description of the study treatment 
protocol. 
 
Research visits will coincide whenever practicable with usual care clinic appointments to reduce travel time and 
increase compliance with the study protocol. The study visit will be scheduled as early in the morning as possible. 
Each subject will be offered $100 at the completion of each research study visit as reimbursement for their time, 
transportation, parking, and other expenses related to the study. Participants who complete all three research study 
visits will receive $300. A packet of material, including an appointment letter, a map, and parking instructions for 
the visit will be provided to the subject prior to the scheduled study visit. A day or two prior to the scheduled 
study visit, the participant will be contacted by telephone to confirm or reschedule her visit. If a subject misses her 
study visit, she will be called promptly to reschedule. The study coordinator will have a database which tracks 


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active participants who do not have a scheduled visit or who have missed their targeted visit date. Study visits will 
be rescheduled for up to 3 months until the participant is considered lost to follow-up. 
 
4.3 
Study Measurements 
 
Following is a brief description of study measurements. See Section 7.7 for a more detailed description. 
 
Cardiac magnetic resonance imaging (CMRI). CMRI will be performed at baseline and at the 6-month and 12-
month research visits (Visits 1, 4, and 6). CMRI will be used to measure the primary outcome, global 
circumferential strain (GCS) and the secondary outcomes, myocardial diastolic function, and fibrosis. CMRI is a 
non-invasive, non-radiation imaging modality that is the gold standard cardiac imaging technique for cardiac 
structure (atrial and ventricular size and volume, valves, pericardium, edema, fibrosis) and function (myocardial 
blood flow quantification, systolic and diastolic function). CMRI can also detect myocardial fibrosis with late 
gadolinium enhancement and T1 mapping. Patients with claustrophobia may pre-medicate as needed prior to the 
CMRI. Women who have breast reconstruction surgery after enrollment/completion of the baseline visit that 
includes metallic breast expanders prohibiting MRI will not be required to do the CMRI while the breast 
expanders are in place. 
 
Blood specimen. A blood specimen will be collected from each participant at every research visit. Less than 1 
mL of blood will be drawn for measurement of hematocrit and creatinine levels used for CMRI calculations, and 
5 mL will be drawn for laboratory blood tests to monitor for potential adverse effects of the intervention. An 
additional (optional) 28 mL blood sample will be collected from subjects who consent to have their blood samples 
banked for future studies of blood biomarkers. 
 
Pregnancy test. Because statins are known to be teratogenic and MRI is contraindicated in pregnant women, 
women < 60 years of age who have not had a menstrual period in the last 30 days will be required to have a urine 
pregnancy test during the pre-study evaluations and at every research visit. However, women who have had a 
hysterectomy, both ovaries removed, or a tubal ligation will not be required to have a pregnancy test. 
 
Physical assessment. Participants will have a physical assessment at every standard of care and research study 
visit. Each assessment will include vital signs, including blood pressure, heart rate, and temperature; measurement 
of weight; and ECOG performance status. The oncologist will perform a physical exam and an interval symptom 
history at every standard of care visit. 
 
Medical record review. Medical history, concomitant medications, and laboratory test results will be reviewed at 
every standard of care and research study visit. Specific information regarding the type of treatment regimen and 
dose received will be obtained through the electronic medical record, including Taxotere (docetaxel), carboplatin, 
and trastuzumab (TCH); TCH with pertuzumab (TCHP); and anthracycline and trastuzumab regimen doxorubicin 
(or epirubicin), cyclophosphamide, and taxane followed by trastuzumab (AC-TH). Information regarding breast 
or chest wall radiation, including right vs. left sided radiation, total dose, and number of fractions of radiation, as 
well as technique and dosimetry will be collected. BRCA mutation information will also be collected. 
 
Baseline and follow-up questionnaires. A structured interview, developed for this investigation and including 
risk factor and clinical assessment, will be administered by the research staff at Visit 1 (baseline). The 
questionnaire will obtain information regarding race/ethnicity; education; anthropometry including weight at 
different decades of life; medical history, including history of cancer and BRCA testing; menstrual and pregnancy 
histories; use of oral contraceptives and hormones; adult recreational physical activity; tobacco smoking history; 
and history of alcoholic beverage consumption. A shorter questionnaire will be administered at the 6 and 12 
month visits to assess changes in exposures and behaviors between visits. 
 
Quality of life and symptoms assessment. We will measure quality of life and symptoms using the QLQ-C30 
and QLQ-BR23. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is a 30-
item measure developed to assess the quality of life of cancer patients [78]. The measure includes three scales: 
global health status, functional status (physical, role, emotional, cognitive, and social), and physical symptoms. 


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The EORTC QLQ-BR23 is a 23-item measure specifically for patients with breast cancer that assesses disease 
symptoms and emotional problems related to breast cancer [79,80]. Participants will self-administer the QLQ-C30 
and QLQ-BR23 assessments. 
 
5.0 
AGENT ADMINISTRATION 
 
Intervention will be administered on an outpatient basis. Reported agent adverse events (AEs) and potential risks 
are described in Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
• 
Agent(s): Atorvastatin calcium and placebo 
• 
Daily dose(s) and regimen(s) for each agent: One capsule atorvastatin calcium 20 mg or placebo per day 
 
Sixty participants with newly diagnosed stage 1-3 breast cancer will be randomized into one of 2 groups: 30 
participants will receive 20 mg atorvastatin and 30 participants will receive a placebo identical in color, 
consistency, and appearance to atorvastatin. Atorvastatin 20 mg and matching placebo will be supplied as over-
encapsulated capsules for oral administration.  
 
The recommended starting dose of atorvastatin is 10 to 20 mg once daily. The dosage range of atorvastatin 
calcium tablets is 10 to 80 mg once daily.  
 
5.2 
Study Agent Administration and Duration of Therapy 
 
Patients will self-administer one capsule of atorvastatin 20 mg or placebo daily. Atorvastatin calcium can be 
administered as a single dose at any time of the day, with or without food. Patients will be instructed to take the 
study agent at bedtime or with an evening meal. In the absence of treatment delays due to adverse events, 
treatment for each agent will extend for 12 months. 
 
5.3 
Run-in Procedures  
 
None. 
 
5.4 
Contraindications 
 
Patients are advised not to consume grapefruit while on atorvastatin. Grapefruit contains one or more components 
that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit 
juice consumption (> 1 liter per day). Participants enrolled in the study will be instructed to avoid all forms of 
grapefruit (e.g., juice, fruit, grapefruit seed extract, dietary supplements containing grapefruit) during the trial. 
 
The combined use of atorvastatin with gemfibrozil, cyclosporine, lipid-modifying doses of niacin, azole 
antifungals, or strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, erythromycin, the hepatitis C 
protease inhibitor telaprevir, or combinations of HIV protease inhibitors), and fibric acid derivatives) is 
contraindicated due to an increased risk for myopathy. Patients will be screened for contraindications to 
atorvastatin prior to enrollment in the study. Patients with known active infection with HIV will be excluded from 
the study. Patients will be advised not to use contraindicated medications during the study and will be excluded if 
use of any contraindicated medication is unavoidable. Concomitant medications will be reviewed at study visits 
and during follow-up telephone calls. Participants will be closely monitored for symptoms and side effects to the 
study drug and will be instructed to call the study doctor immediately if they have a serious adverse reaction. 
 


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5.5 
Concomitant Medications 
 
Medications known to interact with atorvastatin will be documented on the concomitant medication case report 
form (CRF) and will include start and stop date, dose and route of administration, and indication. Taking these 
medications would exclude the patient from study participation. These medications include: gemfibrozil, 
cyclosporine, clarithromycin, itraconazole, erythromycin, the hepatitis C protease inhibitor telaprevir, HIV 
protease inhibitors, colchicine, and red yeast rice. Any medications taken by the patient that are deemed clinically 
significant in relation to the study, including medications started, stopped, or dose-modified to treat AEs 
considered at least possibly related to the study drug, will also be recorded on the concomitant medication CRF. 
 
5.6 
Dose Modification 
 
The study agent will be stopped in the event of an AE ≥ grade 3 considered possibly, probably, or definitely 
related to the study agent. The study agent will be restarted after resolution. One of the common side effects of 
statin medication is myalgia (muscle pain with normal CPK level), and rarely this is associated with statin 
myopathy (muscle weakness or other muscle injury with or without elevation in CPK level). In randomized 
controlled trials of standard dose statin therapy (including atorvastatin 20 mg), the risk is very low. We will 
measure levels of creatine phosphokinase (CPK) in the blood drawn at the first study visit to establish a patient-
specific reference for this indicator of muscle toxicity. During the trial, if the participant reports unexplained 
muscle pain or weakness, CPK will be tested again to check for elevation. The cardiologist on trial will determine 
whether the symptoms or an elevation in CPK warrants the participant to discontinue taking the study drug. The 
study agent will be permanently discontinued in subjects who experience grade 3 or greater myopathy 
(unexplained muscle symptoms and CPK > 5 times ULN) or persistent hepatotoxicity (ALT or AST > 3 times 
ULN) that is considered possibly, probably, or definitely related to the study agent. 
 
If a participant experiences elevated liver enzymes (AST/ALT > 3x ULN), we will continue the study agent and 
repeat the liver function tests (LFTs) 7-10 days later. If AST/ALT values resolve (≤ 3x ULN), the participant will 
continue on the study agent. If AST/ALT values are still elevated (> 3x ULN), the participant will discontinue the 
study agent. We will measure LFTs 4 weeks later. If AST/ALT values are still elevated (> 3x ULN), the study 
agent will be permanently discontinued. If AST/ALT values resolve (≤ 3x ULN), we will restart the study agent at 
half the dose, atorvastatin 10 mg or placebo, and continue to closely monitor all clinically obtained LFTs. 
 
5.7 
Adherence/Compliance 
 
Compliance will be measured by pill (capsule) counts and patient diaries. Compliance is defined as 85% of the 
total dose with all doses of the study agent taken during the week before Visit 6 (the final visit). A patient diary 
will be used to monitor daily compliance (Appendix B). Participants will be instructed to record the time the study 
drug was taken each day in the diary, as well as any missed doses and potential side effects. Diaries will be 
reviewed and compliance will be assessed at every study visit. 
 
Phone calls will be made to study participants every four weeks (± 7 days) to monitor compliance. Participants 
will be asked if they missed any doses of medication, and the dates of all missed doses will be recorded. The 
study agent diary will be reviewed with participants at every visit. Participants who report having taken < 85% of 
the study drug doses between phone calls, or whose pill count at a study visit reveals < 85% compliance, will be 
called every two weeks (± 3 days) to monitor compliance until compliance resolves to at least 85%. 
 
The participant will be asked at registration if they would like to receive reminder emails or text messages 
regarding the study medication. Messages will be sent daily for the first week; in following weeks, messaging will 
be targeted to participants having difficulty remembering their dose. Since agent compliance is very important 
during the final week of the intervention, text/email messages will be sent to all study participants who opt to 
receive these reminders. In addition, phone calls will be made to all study participants during the week before 
their final visit (Visit 6) to remind them to take the study drug every day until the visit. Participants will also be 
reminded to bring any leftover study drugs and the study diary with them to every visit. 
 


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Pill counts will be performed at Study Visits 2, 3, 4, 5, and 6 to assess compliance. If less than 85% of the dose 
has been consumed during the study period, the subject will be considered non-compliant. All participants that 
receive a study agent for any period of time will be evaluable for toxicity. 
 
6.0 
PHARMACEUTICAL INFORMATION 
 
6.1 
Study Agent  
 
Atorvastatin calcium, a synthetic lipid-lowering agent, is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A 
(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-
limiting step in cholesterol biosynthesis. 
 
The empirical formula of atorvastatin calcium is (C33H34 FN2O5)2Ca•3H2O and its molecular weight is 1209.42. 
Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and 
below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; 
slightly soluble in ethanol; and freely soluble in methanol. Atorvastatin calcium tablets for oral administration 
contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate; candelilla 
wax, FCC; croscarmellose sodium; hydroxypropyl cellulose, NF; lactose monohydrate; magnesium stearate; 
microcrystalline cellulose; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); 
polysorbate 80; and simethicone emulsion.  
 
6.2 
Reported Adverse Events and Potential Risks 
  
The most common (incidence ≥ 5.0% in patients) reported adverse events (AEs) are nasopharyngitis, arthralgia, 
diarrhea, pain in extremity, and urinary tract infection. Other AEs reported in clinical trials (< 5%) were 
dyspepsia, nausea, musculoskeletal pain, muscle spasms, myalgia, insomnia, and pharyngolaryngeal pain. 
 
Persistent increases in serum transaminases (to more than 3 x ULN) have occurred in 0.7% of patients who 
received atorvastatin calcium tablets in clinical studies (0.2% for atorvastatin 20 mg). One patient in clinical trials 
developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or 
other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels 
returned to or near pretreatment levels without sequelae [7]. It is recommended that liver function tests be 
performed before initiating therapy with atorvastatin calcium, and thereafter when clinically indicated. 
 
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in 
conjunction with increases in creatine phosphokinase (CPK) values above 10 x ULN. Myopathy sometimes takes 
the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities 
have occurred. Predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled 
hypothyroidism, and renal impairment. The concomitant use of higher doses of atorvastatin with certain drugs 
such as fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, and strong CYP3A4 inhibitors (e.g., 
clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. Cases 
of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, 
and caution should be exercised when prescribing atorvastatin with colchicine. 
 
The risk of myopathy, including rhabdomyolysis, is dose related. The risk of myopathy and rhabdomyolysis is 
increased by high levels of statin activity in plasma. Atorvastatin is metabolized by the cytochrome P450 isoform 
3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the plasma levels of atorvastatin 
and may increase the risk of myopathy [6,81]. These include erythromycin, clarithromycin, the hepatitis C 
protease inhibitor telaprevir, and combinations of HIV protease inhibitors, including saquinavir plus ritonavir, 
lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus 
ritonavir, or grapefruit products. Combination of these drugs with atorvastatin is contraindicated [Table 2] [7]. If 
short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with atorvastatin must be suspended 
during the course of treatment.  


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Table 2. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis 
Interacting Agents 
Prescribing Recommendations 
Cyclosporine, HIV protease inhibitors (tipranavir plus 
ritonavir), hepatitis C protease inhibitor (telaprevir) 
Avoid atorvastatin 
HIV protease inhibitor (lopinavir plus ritonavir) 
Use with caution and lowest dose necessary 
Clarithromycin, itraconazole, HIV protease inhibitors 
(saquinavir plus ritonavir*, darunavir plus ritonavir, 
fosamprenavir, fosamprenavir plus ritonavir) 
Do not exceed 20 mg atorvastatin daily 
HIV protease inhibitor (nelfinavir)  
Hepatitis C protease inhibitor (boceprevir) 
Do not exceed 40 mg atorvastatin daily 
*Use with caution and with the lowest dose necessary 
 
• Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of 
niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing 
with atorvastatin calcium tablets. 
• Digoxin: Patients should be monitored appropriately. 
• Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased. 
• Rifampin should be simultaneously co-administered with atorvastatin calcium tablets. 
• Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-
administered with gemfibrozil, concomitant administration of atorvastatin calcium tablets with 
gemfibrozil should be avoided. 
 
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, 
including atorvastatin calcium. 
 
6.3 
Agent Availability, Packaging, and Labeling 
 
Atorvastatin 20 mg and matching placebo are investigational agents for oral administration supplied to 
investigators by the Cedars-Sinai Medical Center Department of Pharmacy. Generic atorvastatin 20 mg tablets 
will be over-encapsulated and the capsules will be filled with an inert excipient (generally lactose powder). The 
placebo capsules are identical looking capsules but only filled with lactose powder. The amount of lactose will 
range from 700 mg-1 g per capsule (less if the capsule contains an atorvastatin tablet). 
  
Atorvastatin and placebo will be packaged and labeled by the Cedars-Sinai Medical Center Department of 
Pharmacy Investigational Drug Service. Each bottle will be labeled with a one-part label identifying study 
specific information, such as study title, protocol number, dosing instructions, recommended storage conditions, 
the name and address of the distributor, randomization number, and a caution statement indicating that the agent 
is limited by United States law to investigational use only and the agent should be kept out of reach of children. 
 
The study agent will be dispensed to the participant five times: One bottle of 44 capsules (30-day supply + 14 
days buffer) at baseline, one bottle of 74 capsules (60-day supply + 14 days buffer) at 1 month, and one bottle of 
104 capsules (90-day supply + 14 days buffer) at 3 months, 6 months, and 9 months after initiation of the 
intervention.  
 
6.4 
Storage 
 
Study agents will be stored in a safe, secure, temperature monitored limited access drug storage area specifically 
for research medication at the Cedars-Sinai Medical Center Department of Pharmacy. Study agents shall be 
maintained at a controlled room temperature [between 15-25°C] by the Pharmacy and once dispensed, the 
subjects will be instructed to store the drug in their homes protected from light, heat, and moisture. 
 
6.5  
Agent Accountability 


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The Investigator is required to maintain adequate records of receipt, inventory, dispensing, and disposition of the 
study agent. This responsibility has been delegated to the study research pharmacist, Suwicha Limvorasak, 
Pharm.D., Investigational Drug Pharmacist at the Samuel Oschin Comprehensive Cancer Institute (SOCCI). The 
receipt record will include from whom the agent was received, date, quantity and batch or lot number. The 
dispensing record will note quantities and dates study agent was dispensed to and returned by each participant. 
 
6.6 
Blinding and Unblinding 
 
The research pharmacist will manage the investigational agent. The blind will be maintained through the effort of 
the research pharmacist, and the pharmacy. Unblinding will only occur when it is deemed medically necessary. 
The date and reason for breaking the blind will be documented by the Principal Investigator. 
 
In the event that the Principal Investigator and treating physician have determined that it is medically necessary to 
unblind the participant due to life threatening or emergent clinical issues, a summary of the clinical history and 
request for unblinding will be forwarded to Dr. Howard Sandler, Medical Director, for final review and final 
approval. Documentation of unblinding approval will be provided to the research pharmacy and maintained in 
research chart. 
 
7.0 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Time and Events 
 
Study Procedures 
Pre-
Study*  
 
Visit 1^ 
(Baseline)  
From 2 
weeks before 
patient starts 
systemic 
breast cancer 
treatment up 
to 3 weeks 
after starting 
treatment:  
initiation of 
the statin 
intervention 
Visit 2*  
1 month  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 3*  
3 months  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 4^  
6 months  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 5*  
9 months  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 6^  
12 months 
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Follow-
Up  
Days 30 ±7, 
60 ±7, and 
90 ±7 after 
completion 
of the statin 
intervention 
Assess eligibility and recruitment 
X 
 
 
 
 
 
 
 
Informed Consent and HIPAA 
authorization 
X 
 
 
 
 
 
 
 
Registration and randomization to 
atorvastatin or placebo 
X 
 
 
 
 
 
 
 
Review inclusion/exclusion 
criteria and study requirements 
X 
X 
X 
X 
X 
X 
 
 
Review medical history, 
medications, and laboratory test 
results 
X 
X 
X 
X 
X 
X 
X 
 
Demographics (birth date, race, 
ethnicity, education) 
X 
X 
 
 
 
 
 
 
Physical exam and symptom 
assessment 
X 
 
X 
X 
 
X 
 
 
Vital signs, measure weight 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
2D-echocardiogram1 
X 
 
 
X 
 
X 
 
 
Urine pregnancy test2 
X 
X 
 
 
X 
 
X 
 


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Study Procedures 
Pre-
Study*  
 
Visit 1^ 
(Baseline)  
From 2 
weeks before 
patient starts 
systemic 
breast cancer 
treatment up 
to 3 weeks 
after starting 
treatment:  
initiation of 
the statin 
intervention 
Visit 2*  
1 month  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 3*  
3 months  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 4^  
6 months  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 5*  
9 months  
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Visit 6^  
12 months 
± 2 weeks 
after 
initiation of 
the statin 
intervention 
Follow-
Up  
Days 30 ±7, 
60 ±7, and 
90 ±7 after 
completion 
of the statin 
intervention 
Blood test: Complete Blood 
Count and Automated Differential 
(CBDF) 
X 
 
X 
X 
 
X 
 
 
Blood test: Comprehensive 
Metabolic Panel (CMPL) 
X 
 
X 
X 
X 
X 
X 
 
Blood test: Lipid panel3 
X 
X 
 
 
X 
 
X 
 
Blood test: Creatine 
phosphokinase (CPK) 
 
X 
 
 
 
 
 
 
Blood tests: hematocrit and 
creatinine4 
 
X 
 
 
X 
 
X 
 
Collect blood for future research5 
 
X 
 
 
X 
 
X 
 
Cardiac Magnetic Resonance 
Imaging (CMRI) 
 
X 
 
 
X 
 
X 
 
Risk factor questionnaire 
 
X 
 
 
X 
 
X 
 
QLQ-C30 and QLQ-BR23 
 
X 
 
 
X 
 
X 
 
Dispense study agent and diary 
 
X 
X 
X 
X 
X 
 
 
Collect study agent and diary 
 
 
X 
X 
X 
X 
X 
 
Review study diary 
 
 
X 
X 
X 
X 
X 
 
Assess compliance (pill count) 
 
 
X 
X 
X 
X 
X 
 
Assess adverse events 
 
 
X 
X 
X 
X 
X 
X 
Telephone contact6 
X 
X 
X 
X 
X 
X 
X 
X 
*Pre-Study evaluations and Visits 2, 3, and 5 are standard of care visits.  
^Visits 1, 4, and 6 are research visits to collect endpoint data and will coincide with standard of care visits when possible. 
1 A 2D-echocardiogram will be done for standard of care monitoring before the patient starts systemic breast cancer 
treatment, and 3 months and 9 months after initiation of treatment.  
2 Because statins are known to be teratogenic and MRI is contraindicated in pregnant women, women < 60 years of age 
who have not had a menstrual period in the last 30 days will be required to have a urine pregnancy test at the pre-study 
evaluations and at Visits 1, 4, and 6. Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will 
not be required to have a pregnancy test. 
3 Lipid panel: If lipid panel results within the past 12 months are not available, a lipid panel will be done to confirm 
eligibility prior to registration. The lipid panel will not be done at Visit 1 if a lipid panel was done at the pre-study 
evaluations or if lipid panel results within 30 days prior to the visit are available. 
4 Less than 1 mL of blood will be drawn from each participant at Visits 1, 4, and 6 for measurement of hematocrit and 
creatinine levels used for CMRI calculations. 
5 Blood collection for future research: An additional (optional) 28 mL blood sample will be collected at Visits 1, 4, and 6 
from participants who consent to have their blood samples banked for future studies of blood biomarkers. 
6 Telephone contact every four weeks (± 7 days) during the intervention to assess compliance and adverse events. Follow-
up telephone contact on days 30 ± 7, 60 ± 7, and 90 ± 7 after completion of the statin intervention to assess adverse events. 
 
7.2 
Pre-Study Evaluation 
 


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Assessments performed exclusively to determine eligibility for this study will be done only after obtaining 
informed consent. Assessments performed for clinical indications (not exclusively to determine study eligibility) 
may be used for baseline values even if the studies were done before informed consent was obtained. 
 
7.2.1  Pre-Screen Medical Chart Review and Initial Determination of Eligibility  
 
Clinical research staff will identify potential participants via a review of participating oncologist-investigator 
schedules to identify breast cancer cases that would be appropriate to screen via medical records. A protocol 
specific checklist will be used to determine initial eligibility as specified in the inclusion and exclusion criteria. 
Medical records will be reviewed for: 
1. Age 
2. Breast cancer diagnosis (stage; HER2, ER, and PR status) 
3. Medical contraindications and laboratory results that impact inclusion in the study 
4. Prior or current use of statin medication, and current use of prohibited concomitant medications 
 
Research staff will indicate if the patient appears to meet the general criteria, i.e., yes or no response, and will not 
record specific test results or other detailed data points on the checklist. The names of the patients who appear to 
meet the study eligibility criteria will be recorded along with the name of their treating physician. Research staff 
will contact the oncologist-investigator and advise that the patient has been identified as a potential research 
participant, and the eligibility checklist will be forwarded to the oncologist for review. 
 
7.2.2 
Recruitment and Consent 
 
Potentially eligible patients with newly diagnosed stage 1-3 breast cancer will be scheduled for a consult with an 
oncologist. 
• 
The oncologist will introduce the study to breast cancer patients recommended for trastuzumab treatment 
(with or without anthracycline) during the treatment planning visit after standard care options have been 
presented.  
• 
Patients will receive a study information packet to take home that includes the study information leaflet, 
the IRB approved study informed consent form and HIPAA authorization, and the Learning More about 
Research Opportunities brochure to advise them of the voluntary nature of participation. Clinical research 
staff will be present at the clinic during this visit and will be available to review the study information 
packet with the patient. 
• 
Patients will be encouraged to review the consent documents with family, friends, and/or other 
physicians. The patient will be told that the decision to join or not join the study will not affect the 
medical treatment that she receives, and that she can withdraw from the study at any time. The study 
coordinator will follow up with the patient a few days later by phone to address any additional questions. 
• 
Patients who are interested and want to volunteer for the trial will be consented to participate in the study 
by the oncologist at their next standard of care visit, or by one of the study physician-investigators present 
during the patient's baseline pre-study standard of care echocardiogram. 
 
Because there is a short window of time (1 week) for all the pre-treatment assessments before systemic breast 
cancer treatment is initiated, some potentially eligible patients may not be seen again by the treating oncologist 
until after they are no longer eligible for the study. In such cases, women who have had all their questions about 
the trial answered on the day they first learn about the study, and who wish to volunteer for the trial, may be 
consented to participate in the study the same day they are first informed of the research. 
 
7.2.3 
Pre-Study Evaluations 
 
Consented patients will undergo the following tests to confirm eligibility and safety of statin initiation: 
• 
Physical exam including vital signs assessment, measurement of height and weight  


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• 
Symptom assessment and ECOG performance status 
• 
Clinical labs for a Complete Blood Count and Automated Differential (CBDF) and a Comprehensive 
Metabolic Panel (CMPL) 
• 
Lipid panel. If lipid panel results within the past 12 months are available, the lipid panel will not be 
required. 
• 
Urine pregnancy test for women < 60 years of age who have not had a menstrual period in the last 30 
days. Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required 
to have a pregnancy test. 
• 
Baseline 2D-echocardiogram 
 
Women who are pregnant, who have an abnormal 2D-echocardiogram, or who have AST/ALT > 3x ULN or 
creatinine > 1.8 mg/dL will be excluded from the trial. 
 
7.2.4  Final Determination of Eligibility, Registration, and Randomization 
After consent has been obtained, clinical research staff will complete a full eligibility checklist and compile the 
support documents from patient medical records, including laboratory reports, medical history/physician notes, 
and current medications list. The oncologist, study cardiologist, or other physician-investigator will review the 
patient’s eligibility checklist, medical history, and supporting documentation. 
 
Patients with a history of heart disease or cardiomyopathy and patients > 50 years old who are eligible for statin 
therapy based on the 2013 ACC/AHA guidelines (LDL cholesterol >190, or LDL <190 and ASCVD risk >7.5%; 
http://tools.acc.org/ASCVD-Risk-Estimator/) will be excluded from the trial. Patients 40-50 years old who are 
eligible for statin therapy based on the 2013 ACC/AHA guidelines and want to be placed on statins will also be 
excluded. 
 
A Clinical Research Office (CRO) designee will conduct a final eligibility check prior to registration. Consented 
patients who qualify for the study after the pre-study eligibility evaluations and CRO confirmation of eligibility 
will be registered for the trial, randomized to the intervention (atorvastatin or placebo), and scheduled for Visit 1, 
the baseline testing.  
 
7.3 
Baseline Testing and Evaluation During the Study Intervention 
 
7.3.1  Visit 1 – Baseline Testing and Initiation of the Statin Intervention 
 
Visit 1 (baseline measurements) will occur from 2 weeks before the patient starts systemic breast cancer treatment 
(trastuzumab with or without anthracycline) up to 3 weeks after starting treatment. Participants will be asked to 
refrain from eating for 3 hours before the visit. The following procedures will be performed during this visit: 
1. Review medical history, medications, and laboratory test results 
2. Vital signs assessment and measurement of weight  
3. ECOG performance status 
4. Blood collection for CMRI and clinical labs: Less than 1 mL of blood will be drawn for measurement of 
hematocrit and creatinine levels used for CMRI calculations. Fasting for 3 hours prior to the CMRI is 
recommended. Five mL of blood will be drawn for laboratory blood tests for a lipid panel and creatine 
phosphokinase (CPK). If a lipid panel was done at the pre-study evaluations or if lipid panel results 
within 30 days prior to this visit are available, the lipid panel will not be done. A CMPL will not be 
required because one will be done at the pre-study evaluations. 
5. Optional blood collection (28 mL) from participants who consent to have their blood samples banked for 
future studies of blood biomarkers 
6. Urine pregnancy test for women < 60 years of age who have not had a menstrual period in the last 30 
days. Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required 
to have a pregnancy test. 


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7. Cardiac magnetic resonance imaging (CMRI) 
8. Interviewer-administered questionnaire to obtain demographic information (detailed race and ethnicity, 
education); medical history, including history of cancer and BRCA testing; reproductive history, oral 
contraceptives and hormones; alcoholic beverage consumption and tobacco smoking histories; physical 
activity; and anthropometry 
9. Self-administered QLQ-C30 and QLQ-BR23 to assess quality of life and symptoms 
10. Review inclusion and exclusion criteria 
11. Dispense the study agent and review instructions for how to take it 
12. Dispense the study diary and review instructions for completing it  
 
7.3.2  Visit 2 – Month 1 Standard of Care Visit 
 
A standard of care oncologist visit for routine monitoring will occur 1 month (± 2 weeks) after initiation of the 
statin intervention. The following procedures will be performed during this visit: 
1. Review medical history, medications, and laboratory test results 
2. Physical exam including vital signs assessment and measurement of weight  
3. Symptom assessment and ECOG performance status 
4. Clinical labs for CBDF and CMPL 
5. Review inclusion and exclusion criteria 
6. Collect study agent and assess compliance (pill count) 
7. Collect and review study diary 
8. Assess adverse events 
9. Dispense study agent and diary 
 
7.3.3  Visit 3 – Month 3 Standard of Care Visit 
 
A standard of care oncologist visit for routine monitoring will occur 3 months (± 2 weeks) after initiation of the 
statin intervention. The following procedures will be performed during this visit: 
1. Review medical history, medications, and laboratory test results 
2. Physical exam including vital signs assessment and measurement of weight  
3. Symptom assessment and ECOG performance status 
4. Clinical labs for CBDF and CMPL 
5. Follow-up 2D-echocardiogram (may be on a different day) 
6. Review inclusion and exclusion criteria 
7. Collect study agent and assess compliance (pill count) 
8. Collect and review study diary 
9. Assess adverse events 
10. Dispense study agent and diary 
 
7.3.4  Visit 4 – Month 6 Research Visit 
 
A research visit will occur 6 months (± 2 weeks) after initiation of the statin intervention. Participants will be 
asked to refrain from eating for 3 hours before the visit. The following procedures will be performed during this 
visit. Participants with metallic breast expanders in place will not be required to do the 6-month CMRI and the 
blood collection for CMRI. 
1. Review medical history, medications, and laboratory test results 
2. Vital signs assessment and measurement of weight  


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3. ECOG performance status 
4. Blood collection for CMRI and clinical labs: Less than 1 mL of blood will be drawn for measurement of 
hematocrit and creatinine levels used for CMRI calculations. Fasting for 3 hours prior to the CMRI is 
recommended. Five mL of blood will be drawn for laboratory blood tests for a CMPL and a lipid panel. If 
CMPL results within 30 days prior to this visit are available, the CMPL will not be done. 
5. Optional blood collection (28 mL) from subjects who consent to have their blood samples banked for 
future studies of blood biomarkers 
6. Urine pregnancy test for women < 60 years of age who have not had a menstrual period in the last 30 
days. Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required 
to have a pregnancy test. 
7. Cardiac magnetic resonance imaging (CMRI) 
8. Interviewer-administered follow-up questionnaire to obtain information about changes in exposures and 
behaviors between visits 
9. Self-administered QLQ-C30 and QLQ-BR23 to assess quality of life and symptoms 
10. Review inclusion and exclusion criteria 
11. Collect study agent and assess compliance (pill count) 
12. Collect and review study diary 
13. Assess adverse events 
14. Dispense study agent and diary 
 
7.3.5  Visit 5 – Month 9 Standard of Care Visit 
 
A standard of care oncologist visit for routine monitoring will occur 9 months (± 2 weeks) after initiation of the 
statin intervention. The following procedures will be performed during this visit: 
1. Review medical history, medications, and laboratory test results 
2. Physical exam including vital signs assessment and measurement of weight  
3. Symptom assessment and ECOG performance status 
4. Clinical labs for CBDF and CMPL 
5. Follow-up 2D-echocardiogram (may be on a different day) 
6. Review inclusion and exclusion criteria 
7. Collect study agent and assess compliance (pill count) 
8. Collect and review study diary 
9. Assess adverse events 
10. Dispense study agent and diary 
 
7.3.6 
Telephone Calls and Email/Text Messages 
 
Study participants will be followed during the intervention via telephone calls every four weeks (± 7 days) by the 
clinical research staff to assess compliance and adverse events. Participants who report having taken < 85% of the 
study drug doses between phone calls, or whose pill count at a study visit reveals < 85% compliance, will be 
called every two weeks (± 3 days) to monitor compliance until compliance resolves to at least 85%. In addition, 
participants will receive a phone call the day before each scheduled research visit to remind them to refrain from 
eating for 3 hours prior to the visit. Participants will also be reminded to bring any leftover study drugs and the 
study diary with them to every visit. Study participants will also be called during the week before their final visit 
(Visit 6) to remind them to take the study drug every day until the visit appointment. 
 
Participants who opt to receive reminders for study medication intake via email or text messages will be contacted 
by the study staff during the first week of the study and further as needed. The study staff will send emails or text 
messages on cellular phone; participants will be encouraged to respond to these messages indicating if the study 


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drug has been taken. These responses will be used to assess compliance and will be reviewed during phone 
contacts. For participants who miss more than one dose of the study drug in a week, the email/text reminders will 
continue further into dosing period. Since agent compliance is very important during the final week of the 
intervention, text/email messages will be sent to all study participants who opt to receive these reminders.  
 
The following information with be collected during the telephone calls: 
• 
Medication compliance review. Participants will be asked if they missed any doses of medication, and the 
dates of all missed doses will be recorded. 
• 
Concomitant medication review 
• 
Adverse events. Participants will be asked if they have experienced any of the following symptoms to 
assess adverse events:  
o Joint pain 
o Mild muscle aches 
o Diarrhea 
o Upper respiratory infection 
o Nausea 
o Urinary tract infection (painful or difficult urination) 
o Pain in extremity (feet, ankles, hands, wrists) 
• 
Additional symptoms experienced by participants will be recorded to assess adverse events  
 
7.4 
Evaluation at Completion of the Study Intervention 
 
7.4.1  Visit 6 – Month 12 Research Visit 
 
The final research visit will occur 12 months (± 2 weeks) after initiation of the statin intervention. Participants 
will be asked to refrain from eating for 3 hours before the visit. The following procedures will be performed 
during this visit. Participants with metallic breast expanders in place may be scheduled for the 12-month CMRI 
and blood collection for CMRI up to 3 months later (15 months) to allow for the final CMRI to be done.  
1. Review medical history, medications, and laboratory test results 
2. Vital signs assessment and measurement of weight  
3. ECOG performance status 
4. Blood collection for CMRI and clinical labs: Less than 1 mL of blood will be drawn for measurement of 
hematocrit and creatinine levels used for CMRI calculations. Fasting for 3 hours prior to the CMRI is 
recommended. Five mL of blood will be drawn for laboratory blood tests for a CMPL and a lipid panel. If 
CMPL results within 30 days prior to this visit are available, the CMPL will not be done.  
5. Optional blood collection (28 mL) from subjects who consent to have their blood samples banked for 
future studies of blood biomarkers 
6. Urine pregnancy test for women < 60 years of age who have not had a menstrual period in the last 30 
days. Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required 
to have a pregnancy test. 
7. Cardiac magnetic resonance imaging (CMRI) 
8. Interviewer-administered follow-up questionnaire to obtain information about changes in exposures and 
behaviors between visits 
9. Self-administered QLQ-C30 and QLQ-BR23 to assess quality of life and symptoms 
10. Collect study agent and assess compliance (pill count) 
11. Collect and review study diary 
12. Assess adverse events 
 
7.5 
Post-intervention Follow-up Procedures 


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Clinical research staff will make follow-up telephone calls to study participants on days 30 ± 7, 60 ± 7, and 90 ± 7 
after completion of the statin intervention to assess symptoms and adverse events.  
 
7.6 
Removal of Subjects from Study 
 
Patients can be taken off the study intervention and/or study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) for 
discontinuation will be documented and may include: 
 
7.6.1 
Patient voluntarily withdraws (follow-up permitted);  
 
7.6.2 
Patient withdraws consent (termination of intervention and follow-up); 
 
7.6.3 
Patient is unable to comply with protocol requirements; 
 
7.6.4 
Patient becomes ineligible for the trial; 
 
7.6.5 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
 
7.6.6 
Treating physician judges continuation on the study would not be in the patient’s best interest; 
 
7.6.7 
Patient becomes pregnant (pregnancy to be reported along same timelines as a serious adverse event); 
 
7.6.8 
Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma of the 
skin) that requires treatment, which would interfere with this study; 
 
7.6.9 
Lost to follow-up. If a research subject cannot be located to document survival after a period of 2 years, 
the subject may be considered “lost to follow-up.” All attempts to contact the subject during the two years 
must be documented and approved by the Data Monitoring Committee.  
 
7.7 
Methods for Clinical Procedures 
 
Cardiac magnetic resonance imaging (CMRI). CMRI will be performed at each visit using the 3 Tesla system 
devoted to research. The protocols prepared and tested by Dr. Li’s team will be used for imaging [82-84]. 
Comprehensive CMRI examination will include: (1) tomographic views in cine mode using electrocardiogram 
(ECG) gated steady-state-free-precession (SSFP), (2) grid tag (tissue tagging) imaging, (3) scout imaging, (4) 
single shot late gadolinium contrast enhancement, (5) T2 mapping, and (6) T1 mapping [Figure 6].  
Figure 6. Cardiac Magnetic Resonance Imaging (CMRI) Protocol 
Pre-scan preparation 
IV placement 
Blood draw for hematocrit and creatinine 
Saline flush and connect tubing for contrast administration 
▼ 
Scout imaging performed with breath holds - 5 minutes 
Standard multiplanar scout • Check/optimize position 
Scout for ventricular short axis (SA) • Select 3 SA slices-basal, mid and apical 
Check for artifact and optimize image planes 
▼ 
T2 mapping - 3 minutes 
3 short axes - basal, mid and apical 


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▼ 
T1 mapping - 2 minutes 
Baseline imaging prior to contrast 
▼ 
Cardiac systolic and diastolic function evaluation 
Tagged imaging (systolic) and (diastolic) - three slice short axis 
▼ 
Gadolinium administration < 1 minute 
Start timer 
Give 0.20 mmol/kg Gad at 3 mL/second then 15 mL saline at 3 mL/second 
▼ 
Cardiac function evaluation 
SA cine series - 4-chamber and 2-chamber views for calculation of LVEF, LVOT and RVEF 
▼ 
Single shot late gadolinium enhancement - 5 minutes  
HLA, VLA, SA 
▼ 
T1 mapping at 12 minutes post gadolinium 
Repeat of baseline pre-contrast imaging  
Must be performed at 12 minutes post-contrast 
Prior to the CMRI an IV will be inserted and a small blood sample (< 1 mL) will be drawn from participants. An 
i-STAT blood analyzer at the CSMC Research Imaging Core will be used to measure hematocrit and creatinine. 
The hematocrit value is used to calculate myocardial extracellular volume (ECV) with the T1 mapping. The 
creatinine value is used to calculate the glomerular filtration rate (GFR). If the GFR is < 60, the CMRI will be 
performed without gadolinium. Women < 60 years of age who have not had a menstrual period in the last 30 days 
will be required to have a urine pregnancy test before the CMRI. Women who have had a hysterectomy, both 
ovaries removed, or a tubal ligation will not be required to have a pregnancy test. The Research Imaging Core will 
do an onsite urine pregnancy test. Women who are pregnant will not undergo the CMRI. 
 
After the pregnancy test, hematocrit, and GFR have been evaluated, scout images will be obtained for ventricular 
short axis and whole heart imaging, followed by T2 mapping. Baseline pre-contrast short axis imaging will be 
performed for T1 mapping. This will be repeated at 12 minutes post-contrast. Cine imaging for calculation of left 
and right ventricular ejection fraction and characterization of regional wall motion will occur after administration 
of gadolinium contrast. This will be followed by single shot late gadolinium enhancement, and then T1 mapping 
at 12 minutes post-contrast. In brief, with the patient in the supine position, high resolution, perpendicular images 
through the chest will be collected to locate the heart. Images will be acquired with a breath-hold at the end of 
expiration. The time required for the entire MRI protocol will be approximately 75 minutes. Images will be 
evaluated by consensus of skilled interpreters trained in CMRI imaging. A cardiac imaging physician blinded to 
clinical information of the subjects will read the CMRIs and evaluate them for any incidental findings. 
Myocardial blood flow quantitation at rest and calculation of T1 relaxation time for the myocardium will be 
performed using in-house dedicated analysis software as previously published [85]. We will analyze T1 mapping 
using quantitative parametric images of myocardial extracellular blood volume using MOLLI recovery images to 
generate a ∆R1 map [69]. Information on LV filling, peak filling rate (PFR), and time to peak filling rate (tPFR), 
will be obtained by cine imaging. Quantitative analyses will use tissue tagging grid imaging for calculation of 
indices of strain and relaxation from systolic and diastolic optimized tagged cine images to obtain global 
circumferential strain (GCS), its time derivative in systole (CSs rate) and diastole (CSd rate), and the peak rate of 
basal to apical untwisting (UTR). 
 
Gadolinium Contrast (Gadavist). Intravenous contrast agents such as Gadavist are an extracellular gadolinium-
based chelate. All of the clinically approved intravenous contrasts that might be used in this study have excellent 


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safety profiles and are commonly used in CMRI studies. Unlike iodinated contrast agents used in CT, gadolinium-
based CMRI contrast agents do not cause nephrotoxicity. Allergic reactions are extremely rare, but may be more 
common in persons with a history of allergic reactions to iodinated contrast. Studies support a rate of serious 
allergy reactions of 1 in 20,000.  
 
Blood specimen. A blood specimen will be collected from each participant at Visits 1, 4, and 6. Participants will 
receive a phone call reminder the day before the visit to refrain from eating for 3 hours prior to the visit. Five mL 
of blood will be collected for laboratory blood tests into one 5 mL gold top SST tube. The time and date of the 
blood draw and of the participant’s last meal will be recorded. Blood tests will be done for a lipid panel at Visits 
1, 4, and 6. The lipid panel will not be done at Visit 1 if a lipid panel was done at the pre-study evaluations or if 
lipid panel results within 30 days prior to the visit are available. A CMPL will be done at Visits 4 and 6. A CMPL 
will not be required at Visit 1 because one will be done at the pre-study evaluations. If CMPL results within 30 
days prior to Visit 4 or Visit 6 are available, the CMPL will not be done at that visit. Lab values within the past 30 
days are sufficient for monitoring, and we wish to prevent patients having to undergo unnecessary repeat tests. A 
blood test for creatine phosphokinase (CPK) will be done at Visit 1 only. Depending on where the participant visit 
occurs, the blood testing will be done at the CSMC Clinical Laboratory or at the Tower Hematology Oncology 
Medical Group laboratory. 
 
Prior to the CMRI, less than 1 mL of blood will be drawn at the CSMC Research Imaging Core for measurement 
of hematocrit and creatinine levels used for CMRI calculations. An i-STAT blood analyzer at the Imaging Core 
will be used to measure the hematocrit and creatinine. Fasting for 3 hours prior to the CMRI is recommended for 
optimal contrast enhancement. 
 
An additional (optional) 28 mL blood sample will be collected before the CMRI from subjects who consent to 
have their blood samples banked for future studies of blood biomarkers. Fasting for 10 hours before the optional 
blood collection is recommended but is not required. The blood will be drawn at the CSMC Research Imaging 
Core into four vacutainers, including one 10 mL green top heparinized tube, one 10 mL red top serum tube, and 
two 4 mL lavender top EDTA tubes. The vacutainers will be placed on ice in a cooler and transported to the 
CSMC Clinical Research Office (CRO) Research Laboratory for processing within 2 hours of collection. The four 
vacutainers will be centrifuged as specified in the blood processing SOP. After centrifugation, cryovials will be 
prepared from the blood specimens including plasma, serum, red blood cells, and buffy coat for DNA extraction. 
Processed specimens will be stored at -80oC for future studies of cardiac blood biomarkers. If the participant 
fasted for 10 hours prior to the visit for the optional blood collection, she may have a snack after the blood draw 
and before the CMRI if desired. 
 
8.0  
MEASUREMENT OF EFFECT AND CRITERIA FOR EVALUATION 
 
8.1 
Prevention of Cardiotoxicity Due to Breast Cancer Treatment 
 
This randomized clinical trial aims to evaluate the impact of statin on preventing cardiotoxicity due to 
trastuzumab treatment (with or without anthracycline) in breast cancer patients. Cardiac function will be primarily 
measured by global circumferential strain (GCS), a sensitive measure of cardiac function, which is predictive of 
future cardiac events. Secondary outcomes will include additional global measures of cardiac function (e.g. left 
ventricular ejection fraction), cardiac morphology (mass, wall thickness, internal dimensions), diastolic function, 
and tissue viability (fibrosis, edema, inflammation). We anticipate that trastuzumab treatment will impair GCS, 
and increase markers of fibrosis, edema, and/or inflammation. We hypothesize that there will be less change in 
GCS and secondary outcomes measures with atorvastatin intervention compared to placebo. 
 
8.2 
Methods for Evaluation of Cardiac Function 
 
Cardiac MRI will be performed at baseline, 6 months and 12 months after randomization as outlined in Section 
7.7. Imaging will include: (1) conventional cinematic imaging, to assess myocardial morphology and global 
function; (2) magnetic resonance tissue tagging, to assess GCS, along with other secondary endpoint measures 
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such as strain rate and untwisting rate; (3) T1 mapping (before and after the administration of gadolinium), to 
assess myocardial fibrosis and tissue viability; (4) T2 mapping, to assess myocardial edema and inflammation; 
and (5) late gadolinium enhancement, to assess focal scar. 
Table 3. Summary of Endpoints Measured by Cardiac Magnetic Resonance Imaging (CMRI) 
CMRI procedure 
Measurement 
Cine-imaging + tissue tagging 
 
Systolic function 
GCS (primary endpoint), GLS, peak LV twist and torsion 
Diastolic function 
Untwisting rate 
Cardiac function and morphology 
Left ventricular ejection fraction (LVEF), LV end diastolic 
volume (LV EDV), LV end systolic volume (LV ESV), 
cardiac output (CO), LV mass, LV concentricity 
T1 mapping + Gadolinium enhancement 
Myocardial fibrosis and tissue viability, extracellular volume 
T2 mapping 
Edema and inflammation 
 
8.3 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event, inadequate agent supply, noncompliance, concomitant 
medications, or medical contraindication. Participants will continue to be followed, if possible, for safety reasons 
and in order to collect endpoint data according to the schedule of events. As described in section 7.5, clinical 
research staff will follow participants by telephone on days 30 ± 7, 60 ± 7, and 90 ± 7 after the participant 
discontinues the study agent to assess symptoms and adverse events. Standard of care data (medical history, 
laboratory test results, concomitant medications, echocardiogram data) will continue to be collected via review of 
the participant’s electronic medical record at the time points specified in the Schedule of Time and Events. If 
feasible, we will conduct a research visit to collect final measurements for participants who permanently 
discontinue the study agent early. An end-of-study research visit will be conducted 12 months after initiation of 
the statin intervention (Visit 6). All CMRI procedures will be done at this visit. The blood collections for clinical 
labs and future research, and the follow-up risk and quality of life questionnaires, will not be done. The following 
procedures will be performed during the end-of-study visit: 
1. Review medical history, medications, and laboratory test results 
2. Vital signs assessment and measurement of weight  
3. ECOG performance status 
4. Blood collection for CMRI: Less than 1 mL of blood will be drawn for measurement of hematocrit and 
creatinine levels used for CMRI calculations.  
5. Urine pregnancy test for women < 60 years of age who have not had a menstrual period in the last 30 
days. Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required 
to have a pregnancy test. 
6. Cardiac magnetic resonance imaging (CMRI)  
 
8.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons:  
• 
Adverse Event 
• 
Death  
• 
Lost to follow-up/Participant Withdrawal 
• 
Participant Refused Follow-up 
• 
Physician Decision 
• 
Protocol Defined Follow-up Completed 
• 
Protocol Violation   
• 
Study Complete  
• 
Ineligible 


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• 
Other  
 
Participants will continue to be followed, if possible, for safety reasons and in order to collect endpoint data 
according to the schedule of events. Participants will be removed from study agent if investigators feel it is in the 
interest of subject to do so. As described in section 7.5, clinical research staff will follow up by telephone on days 
30 ± 7, 60 ± 7, and 90 ± 7 after the participant goes off-study to assess symptoms and adverse events. Standard of 
care data (medical history, laboratory test results, concomitant medications, echocardiogram data) will continue to 
be collected via review of the participant’s electronic medical record at the time points specified in the Schedule 
of Time and Events. If feasible, we will conduct a research visit to collect final measurements for participants who 
go off-study early. An end-of-study research visit will be conducted 12 months after initiation of the statin 
intervention (Visit 6). All CMRI procedures will be done at this visit. The blood collections for clinical labs and 
future research, and the follow-up risk and quality of life questionnaires, will not be done. The following 
procedures will be performed during the end-of-study visit: 
1. Review medical history, medications, and laboratory test results 
2. Vital signs assessment and measurement of weight  
3. ECOG performance status 
4. Blood collection for CMRI: Less than 1 mL of blood will be drawn for measurement of hematocrit and 
creatinine levels used for CMRI calculations.  
5. Urine pregnancy test for women < 60 years of age who have not had a menstrual period in the last 30 
days. Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required 
to have a pregnancy test. 
6. Cardiac magnetic resonance imaging (CMRI)    
 
9.0 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Rationale for Methodology Selection 
 
Cardiac magnetic resonance imaging (CMRI) is considered the gold standard imaging technique for accurate 
quantification of systolic and diastolic function, and the addition of tissue tagging helps determine specific 
myocardial structural changes related to twist and torsion of the left ventricle during systole and diastole. CMRI 
can also detect fibrosis with late gadolinium enhancement and T1 mapping. Reliance on 2-dimensional 
echocardiography (2-D echo) for the identification of cardiac damage is limited as it lacks the requisite sensitivity 
to detect subtle changes in left ventricular (LV) function. Newer sophisticated echocardiographic imaging 
techniques, including myocardial strain and speckle tracking can identify early pre-clinical LV systolic 
dysfunction pre- and post-treatment, but the quality is sonographer-dependent and is limited by patient body 
habitus. Moreover, early myocardial injury, edema, and fibrosis are missed on echocardiography. 
 
9.2 
Laboratory Correlates and Biomarkers 
 
A blood specimen will be collected from participants at each research visit. Less than 1 mL of blood will be drawn 
for measurement of hematocrit and creatinine levels used for CMRI calculations. Five mL of blood will be collected 
for clinical blood tests. An additional (optional) 28 mL blood sample will be collected from subjects who consent 
to have their blood samples banked for future studies of blood biomarkers. 
 
Clinical blood tests (5 mL). Blood tests will be done at all research visits for statin monitoring. A lipid panel will 
be done at Visits 1, 4, and 6. The lipid panel will not be done at Visit 1 if a lipid panel was done at the pre-study 
evaluations or if lipid panel results within 30 days prior to the visit are available. A CMPL will be done at Visits 4 
and 6. A CMPL will not be required at Visit 1 because one will be done at the pre-study evaluations. If CMPL 
results within 30 days prior to Visit 4 or Visit 6 are available, the CMPL will not be done at that visit. Creatine 
phosphokinase (CPK) will be measured at Visit 1 to establish a patient-specific reference for this indicator of 
muscle toxicity. During the trial, if the patient reports unexplained muscle pain or weakness, CPK will be tested 
again to check for elevation. 
 


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Optional banked samples for future studies (28 mL). Processed blood will be stored at -80°C for future studies 
of blood biomarkers. Future studies may include: (a) investigation of high-sensitivity troponin (hs-TnT), a 
biomarker of myocardial injury; (b) studies of two novel biomarkers of cardiac fibrosis, galectin-3 (GAL3) and 
apoptosis / inflammation, growth differentiation factor 15 (GDF15), which play regulatory roles in extracellular 
matrix remodeling and are associated with impaired cardiac function and chronic heart failure; (c) investigation of 
brain naturetic peptide (BNP), a biomarker of myocardial stretch; and (d) examination of pro-inflammatory 
markers IL-6 and hs-CRP. 
 
9.3 
Specimen Banking 
 
Patients participating in this trial will be invited to participate in an optional repository study, MetaBank 
(Pro35861). Subjects who consent for MetaBank will provide an additional 28 mL of blood at each research visit, 
and the blood, as well as their leftover specimens collected during this trial, will be stored and maintained in the 
MetaBank for use in future research. Specimens will be retained in MetaBank freezers, equipped with temperature 
activated alarms, located in the Shuman Basement of the Davis Research Building at CSMC. Specimens will be 
stored indefinitely or until they are used up. If future use is denied or withdrawn by the patient, best efforts will be 
made to stop any additional studies and to destroy the specimens. 
 
The Principal Investigator will be responsible for reviewing and approving requests for clinical specimen from 
potential research collaborators outside of Cedars-Sinai Medical Center. Collaborators will be required to 
complete the MetaBank Data and Specimen Usage Agreement specifying the planned use of the specimens, and a 
Material Transfer Agreement that states specimens will only be released for use in disclosed research. Any data 
obtained from the use of clinical specimen will be the property of Cedars-Sinai Medical Center for publication 
and any licensing agreement will be strictly adhered to.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial value. The Informed 
Consent form contains this information and informs the subject that there is the potential for financial gain by 
Cedars-Sinai Medical Center, the investigator or a collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided to research collaborators 
when specimens are made available:  
• 
Diagnosis 
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Study Design/Description 
 
This phase II randomized, double-blinded, placebo-controlled trial evaluates the effect of statin use versus placebo 
on global circumferential strain (GCS), a measure of LV dysfunction, in women newly diagnosed with breast 
cancer using state-of-the-art imaging (CMRI). Secondary outcomes will include additional global measures of 
cardiac function (e.g. left ventricular ejection fraction), diastolic function, cardiac morphology (mass, wall 
thickness, internal dimensions), and tissue viability (fibrosis, edema, inflammation). Assuming a 20% drop-out 
rate, 60 women diagnosed with stage 1-3 breast cancer recommended to undergo trastuzumab treatment, with or 
without anthracycline, will be randomized to 12 months of atorvastatin intervention or placebo resulting in a final 
sample of 48 women completing both follow-up visits. Measurements will be taken at three time points: Baseline, 
from 2 weeks before the patient starts systemic breast cancer treatment (trastuzumab with or without 
anthracycline) up to 3 weeks after starting treatment; Follow-up, 6 months and 12 months post-initiation of the 
statin intervention. At each of the three time points, information regarding the participant’s medical history, 
medication use, risk factors, physical functioning, and quality of life will be obtained as adjustment variables. 
 


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10.2 
Sample Size and Accrual 
 
Sample size: Intervention = 60 (30 statin:30 placebo) randomized sample; Analytic sample after 20% drop out = 
48 (24:24).  
 
The planned duration of accrual is 24 months with an expected accrual rate of 2-3 subjects per month. We 
anticipate that all evaluable participants will have completed all study procedures within three years. Power and 
precision arguments are provided below.  
 
10.3 
Randomization and Intervention 
 
Randomization will be carried out by the SOCCI Research Pharmacy among consented subjects who meet all 
eligibility criteria after the eligibility evaluations and CRO confirmation of eligibility, and who are registered for 
the trial. A secure web-based system maintained by the Biostatistics and Bioinformatics Core at CSMC will 
randomly assign women to either statin or placebo based on sequences that minimize imbalances between the 
arms on diagnosis. Study personnel will be blinded to actual assignment. The randomization algorithm computes 
real-time marginal totals according to the method of Pocock and Simon [86], which ensures near equal allocation 
to the two treatment strategies. Intention-to-treat analysis is initiated at the time of randomization. Based on the 
literature cited above, a lipophilic statin, atorvastatin calcium, was selected for the intervention. Independent 
pharmacists will dispense either active or placebo atorvastatin according to the computer-generated assignment. 
The placebo is designed to be identical in color, consistency, and appearance to atorvastatin. Dosing and 
administration of atorvastatin will be consistent with the recommended regimen: 20 mg once a day. 
 
10.4 
Endpoints/Statistical Considerations 
 
Our primary outcome, global circumferential strain obtained by CMRI, is a composite measure of myocardial 
deformation as the heart contracts and relaxes. The non-parametric Wilcoxon-Mann-Whitney test will be used to 
test the equality of statin treatment (atorvastatin) to placebo in reducing or preventing LV dysfunction through 
comparison of change in GCS values (∆ length / original length, expressed as % / seconds) measured from 2 
weeks prior to start of systemic breast cancer treatment to 1 year post-initiation of the statin intervention. Power 
calculations use a two group t-test based on previously published data [87], which indicate a standard deviation of 
4.3 for baseline GCS and 3.1 for GCS 1 year post 
treatment initiation. A conservative estimate of the 
standard deviation of the difference of these two 
random variables will assume no correlation between 
pre- and post-treatment GCS, which gives an estimated 
standard deviation of 5.3 =√(4.32 + 3.12). With 20% 
dropout rate, we plan to enroll a total of 60 patients 
with each group having 30 patients, leaving 24 per 
group after loss to follow up. Based on the asymptotic 
efficiency of a Mann-Whitney test under non-normal 
distributions in the groups, the minimum detectable 
differences in the power calculations have been done 
using an adjusted sample size that is 15% smaller than 
that anticipated, or 20 per group. Assuming the same standard deviation for both groups, a two-sided two sample 
t-test would allow us to detect a minimum detectable difference in means between treatment and placebo groups 
for the change in GCS ranging from 4.8 to 2.4 units depending on the actual post- versus pre-GCS correlation (0 
to 0.8), assuming 80% power and a 5% significance level. Other minimum detectable differences that assume 
higher correlation between pre- and post-treatment GCS are shown in Table 4. 
 
10.5 
Statistical Analysis Plan 
 
Primary analyses will be conducted on an intention-to-treat basis on all patients who complete the 12-month 
CMRI. The distribution of the covariates, including age, race, dose of trastuzumab treatment (and anthracycline if 
Table 4. Minimum detectable differences for repeated 
measures design. A two-group t-test assumes 80% power, 
5% significance, and 20 patients per group. It is also 
assumed that the standard deviation is 4.32 at baseline and 
3.12 at 1 year post-treatment, and that the paired differences 
standard deviation is the same for treatment and placebo 
groups. Selected values of correlation between a pair of 
observations made on the same subjects are presented. 
Correlation of  
post vs. pre-GCS 
Standard Deviation 
of post vs. pre-GCS 
Minimum Detectable 
Difference 
0 
5.3 
4.8 
0.2 
4.8 
4.3 
0.4 
4.2 
3.8 
0.6 
3.5 
3.2 
0.8 
2.6 
2.4 


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applicable), laterality, radiation dose, smoking status, BMI, baseline measures of fibrosis, hormone use, and 
comorbid conditions, will be summarized and compared between the intervention and control groups to assess the 
adequacy of the randomization. Chance differences between groups will be adjusted for using multiple regression 
modeling. The assumptions of the t-test and regression will be examined for the distribution of the difference in 1 
year post-treatment initiation GCS minus pre-treatment GCS. Non-normal distribution or unequal variance 
between groups will be corrected using a transformation (e.g. log, arcsin, Box-Cox). If a transformation is 
inadequate for the t-test a Wilcoxon-Mann-Whitney test will be used instead. Patients may not receive a uniform 
dose of trastuzumab treatment, given that some patients may be enrolled for up to 3 weeks after starting systemic 
breast cancer treatment and patients undergoing an AC-TH regimen will receive anthracycline first, followed by 
trastuzumab. While our primary analysis will be with all patients assumed to have received homogeneous 
trastuzumab treatment, we plan to conduct sub-analyses in participants randomized to atorvastatin to evaluate 
whether patients who initiate statin after receiving one or more doses of trastuzumab treatment experience a 
different level of cardioprotection than patients who initiate statin before receiving any trastuzumab treatment. 
Secondary analyses. Secondary analyses will compare the statin and placebo groups regarding differences from 
baseline to 12 months follow-up in the following outcomes using a similar approach to the main outcome: (1) 
myocardial structural changes through CMRI and pre- and post-gadolinium myocardial T1 values for fibrosis; and 
(2) myocardial functional changes, through cine CMRI and tissue tagging. As described above, we will take note 
of any chance difference in covariates and adjust for factors in a multiple regression analysis. Assumptions of the 
regression models for GCS and two secondary outcome measures will be examined primarily through analysis of 
residuals after adjustment for potential covariates. If necessary, transformations to the outcomes will be made as 
described for the main analysis. Missing data. Care will be taken to minimize missing data to the extent possible. 
Assuming ≤ 10% missing data, multiple imputation on covariates (not primary or secondary outcomes) will be 
considered for statistical analysis. In the unlikely event of > 10% missing values, we will consider a missing data 
mechanism [88]. After diagnosing the possible missing data mechanism, we will evaluate the potential influence 
of missing data by conducting sensitivity analyses under several assumptions of missingness [89]. 
 
10.6 
Contamination (Cross-Over) and Drop-Outs 
 
We anticipate some contamination from the statin intervention to placebo due to non-compliance and this will be 
monitored and managed through blood tests. We do not expect cross-over from the placebo to statin group as 
women will be aware that they might be on statins already and would not want to jeopardize their safety and care. 
However, current clinical guidelines for prescription of statins may also influence drop-outs among women who 
wish to reduce the risk of cardiovascular disease [10]. These guidelines recommend targeting women with 
cardiovascular disease, LDL cholesterol ≥ 190 mg/dL, and women ages 40-75 years with diabetes or a 10-year 
cardiovascular disease risk ≥ 7.5%. Most of these women would not meet the eligibility criteria for study 
participation. The drop-out rate is conservatively expected to be 20% from baseline to 1 year follow-up. 
 
10.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of atorvastatin. 
 
10.8 
Evaluation of Response 
 
Changes in global circumferential strain obtained by CMRI will be evaluated for all randomized participants. 
 
10.9 
Interim Analysis 
 
There will be no planned interim analyses.  
 
11.0 
ADVERSE EVENTS  
 
11.1 
Experimental Therapy 
 
The study intervention, atorvastatin calcium, is a standard drug and dose commercially available for primary and 


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secondary prevention of cardiovascular disease. Atorvastatin has a widely accepted tolerability profile with few 
serious side effects [6]. A list of adverse events (AEs) that have occurred or might occur (Reported Adverse 
Events and Potential Risks) can be found in Section 6.2, Pharmaceutical Information, as well as the Investigator 
Brochure or package insert. 
 
11.2 
Adverse Event Monitoring 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure 
the safety of Subjects enrolled in the studies as well as those who will enroll in future studies using similar agents. 
Adverse events are reported in a routine manner at scheduled times during a trial. Additionally, certain adverse 
events must be reported in an expedited manner to allow for optimal monitoring of patient safety and care.  
 
AEs will be collected throughout the study period and at follow-up time points. Grade 1 and 2 laboratory 
abnormalities/AEs will not be collected, with the exception of AST or ALT > 3x the upper limit of normal, which 
are known AEs related to statin use and indicate that a participant must be evaluated for possible discontinuation 
of the study agent. Only lab abnormalities graded 3 or above and that are considered at least possibly related to the 
study agent will be collected and reported. All serious adverse events (SAEs) will continue to be collected, 
regardless of attribution. 
 
All patients experiencing an adverse event, considered at least possibly related to the study drug with the 
exception of grade 1 and 2 laboratory abnormalities, will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse event return to baseline;  
➢ any abnormal laboratory values have returned to baseline;  
➢ there is a satisfactory explanation other than the study drug for the changes observed; or 
➢ death. 
 
11.3 
Definitions 
 
11.3.1 Definition of Adverse Event 
 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment and which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
 
11.3.2 Severity of Adverse Events 
 
All non-hematologic adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. The CTCAE provides descriptive terminology and a grading scale for each 
adverse event listed. The CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html. 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly 
affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
 


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11.3.3 Serious Adverse Events 
 
A “serious” adverse event is defined in regulatory terminology as any untoward medical occurrence that: 
 
11.3.3.1 Results in death. If death results from (progression of) the disease, the disease should be reported as a 
serious adverse event (SAE) itself. 
 
11.3.3.2 Is life-threatening (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). 
 
11.3.3.3 Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. 
 
11.3.3.4 Results in persistent or significant disability or incapacity. 
 
11.3.3.5 Is a congenital anomaly/birth defect. 
 
11.3.3.6 Is an important medical event. Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for reporting as a serious adverse event. 
The event may require medical or surgical intervention to prevent one of the outcomes listed in the 
definition of “Serious Adverse Event.” For example: allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
 
11.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. Any event that 
occurs more than 30 days after the last dose of treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported accordingly. 
 
Step 4:  Determine the prior experience of the adverse event. Expected events are those that have been previously 
identified as resulting from administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
 
11.5 
Reporting Requirements for Adverse Events 
 


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11.5.1 Expedited Reporting 
 
• 
The Principal Investigator must be notified within 24 hours of learning of any serious adverse events, 
regardless of attribution, occurring during the study or within 30 days of the last administration of the 
study drug.  
 
• 
The CSMC IRB must be notified no later than 10 business days after the investigator becomes aware 
of the event or receives an external report of “any unanticipated problems involving risk to subjects or 
others” (UPR/UPIRSO). The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths, or other problems), which in the opinion of the 
Principal Investigator was unanticipated, involved risk to subjects or others, and was possibly 
related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that alters the level 
of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor safety report), 
interim result, or other finding that indicates an unexpected change to the risk/benefit ratio for the 
research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by the 
Principal Investigator. 
 
11.5.2 Routine Reporting 
 
All other adverse events – such as those that are expected, or are unlikely or definitely not related to the study 
participation – are to be reported annually as part of regular data submission. 
 
11.6 
Stopping Rules 
 
There are no formal stopping rules. The study agent, atorvastatin calcium, is a commonly prescribed drug 
indicated for long-term use. The study agent will be stopped in the event of an AE ≥ grade 3 considered possibly, 
probably, or definitely related to the study agent. The study agent will be restarted after resolution unless the 
subject experiences grade 3 or greater myopathy (unexplained muscle symptoms and CPK > 5 times ULN) or 
persistent hepatotoxicity (ALT or AST > 3 times ULN) that is considered possibly, probably, or definitely related 
to the study agent, in which case the study agent will be permanently discontinued. 
 
12.0 
STUDY MANAGEMENT 
 
12.1 
Conflict of Interest 
 
All investigators will follow the Cedars Sinai Medical Center conflict of interest policy. There are no conflicts of 
interest to report.  
 
12.2 
Institutional Review Board (IRB) Approval and Consent 
 
It is expected that the IRB will have the proper representation and function in accordance with federally mandated 
regulations. The IRB should approve the consent form and protocol. 
 


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In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory 
requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles that have their origin 
in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study and 
will be given the opportunity to review the consent form. Each consent form must include all the relevant 
elements currently required by the FDA Regulations and local or state regulations. Once this essential information 
has been provided to the patient and the investigator is assured that the patient understands the implications of 
participating in the study, the patient will be asked to give consent to participate in the study by signing an IRB 
approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and personally 
dated by the patient and by the person who conducted the informed consent discussion. 
 
12.3 
Registration Procedures 
 
All subjects that sign informed consent will be assigned a subject number sequentially by their date of consent. 
Those subjects that do not pass the screening phase will be listed as screen failures on the master list of consented 
subjects. Eligible subjects, as determined by screening procedures and verified by a treating investigator, will be 
registered on study at Cedars Sinai Medical Center by the Study Coordinator. 
 
Issues that would cause treatment delays after registration should be discussed with the Principal Investigator (PI). 
If a patient does not receive protocol therapy following registration, the patient’s registration on the study may be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible. 
 
The study team will track all subjects who sign consent on a subject screening/enrollment log using a unique 
screening ID (S01, S02, etc.). Subjects found to be ineligible will be recorded as screen failures. Subjects found to 
be eligible will be registered. 
 
12.3.1 Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by the SOCCI Clinical Research Office 
(CRO). The following documents will be completed and provided for review: 
 
• 
Registration form (or equivalent) 
• 
Copy of required laboratory tests 
• 
Copy of required imaging reports 
• 
Eligibility checklist (signed by investigator) 
• 
Signed patient consent form and Subject’s Bill of Rights 
• 
HIPAA authorization form 
 
12.3.2 Registration 
 
After eligibility is verified, registration is completed as follows: 
 
• 
Assign a patient study number 
• 
Assign the patient a dose as determined through communication with Biostatistics and the principal 
investigator 
• 
Enter the patient in OnCore 
• 
Notify the investigational pharmacy and treating physicians that a subject has gone on study and 
anticipated treatment start date 
 
Oversight by the principal investigator is required throughout the entire registration process. 


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12.4 
Record Keeping and Data Management 
 
Data storage and tracking systems will be developed using the Research Electronic Data Capture (REDCap) 
application, stored and maintained on a secure CSMC Enterprise Information Systems (EIS) server. REDCap is a 
web-based application that is HIPAA compliant (secure location, automatic encryption, authentication, 
authorization, and audit trail) and is only accessed via password. Appropriate administrative, physical, and 
technical safeguards are in place to ensure the confidentiality, integrity, and security of electronic protected health 
information (EPHI). Security measures for the databases include password management, transmission security, 
and data encryption to guard against unauthorized access to EPHI while it is being transmitted over the network. 
Only certified research personnel who are listed on the approved IRB application will be given access to the data. 
Questionnaire data will be entered into the REDCap database. The data will be checked for missing data and 
reviewed for accuracy by clinical research staff. Programs will be developed to prevent data entry errors and to 
perform extensive data edits, including checks for inconsistences and permissible variable values. A data 
dictionary will document all database activities, and contain detailed information about each database variable. A 
secure OnCore database will be developed to track the storage locations and status of study biospecimens.  
 
12.5 
Data and Safety Monitoring Board (DSMB) 
 
A Data Safety Monitoring Board (DSMB) will be convened and will meet every six months to review data 
relating to safety and efficacy, to conduct and review interim analyses, and to ensure the continued scientific 
validity and merit of the study, according to the SOCCI DSMB Charter. There will be interim reviews conducted 
by the DSMB for the purpose of monitoring study conduct and assessing subject safety. The interim reviews will 
include review of all monitoring and audit reports; serious adverse events (SAEs) that occur; and protocol 
deviations and exceptions. The DSMB findings and any concerns and recommendations will be reported in 
writing to the Principal Investigator. A summary report will be forwarded by the Principal Investigator or his/her 
designee to the Cedars-Sinai Medical Center IRB. 
 
12.6 
Executive Committee and Internal Advisory Board (IAB) 
 
The project investigators with the assistance of the study coordinator will have day-to-day responsibility for the 
trial. They will ensure that recruitment and scientific goals are met according to the milestone schedule. The 
Executive Committee, including Drs. Goodman, Wei, Mita, and Bairey Merz; and Ms. Travis-Teague, will have 
monthly teleconferences and quarterly in-person meetings. Meeting agendas will include the following content 
areas: 
a) Present and review data obtained and evaluate progress toward achieving recruitment and follow-up goals; 
b) Identify and resolve all impediments to the successful implementation and completion of the project; 
c) Review and discuss interim data to assist in planning the remaining work; 
d) Discuss, coordinate, and delegate presentations to community and advocacy groups regarding the growing 
importance of cardioprotection among women with breast cancer; 
e) Promote enthusiasm and maintain the momentum of the project. 
 
An IAB will review the study and assist the investigators in protocol development, problem solving, evaluating 
scientific progress, identifying research opportunities, and guiding future research planning. The IAB will meet 
annually with the Executive Committee, although each IAB member will be available for consultation and advice 
on an ad hoc basis. The composition of the IAB includes Dr. Armando Giuliano, Co-director of the Brandman 
Breast Center, a breast surgeon who promulgated the practice of the sentinel node biopsy and a recent recipient of 
the Susan Komen Brinker Award for Scientific Distinction in Clinical Research, their highest award for clinical 
research;  Dr. Beth Karlan, an oncologist and Director of the Women's Cancer Program who sits on the National 
Cancer Advisory Board; Dr. Debiao Li, Director of the Biomedical Imaging Research Institute and President of 
the International Society for Magnetic Resonance in Medicine; and Dr. Steven Piantadosi, immediate past 
Director of the Samuel Oschin Comprehensive Cancer Institute and one of the world's leading experts in the 
design and analysis of clinical trials for cancer research. Following the end of the meeting, the IAB will prepare a 
written report to the Executive Committee. 


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12.7 
Adherence to the Protocol 
 
Adherence to the protocol, Good Clinical Practice (GCP) and institutional policy will be monitored by the PI 
during the course of the study through routine Disease Research Group (DRG) meetings (or equivalent). In 
addition, the SOCCI CRO Quality Management Core (QMC) will conduct the following: 
1)   Audit preparations (AP) prior to audit conducted by any external auditing agency (i.e., NCI or FDA). The 
purpose of an AP is to ensure adequate source documentation to support protocol compliance and data 
integrity are present and organized, and to identify and correct any major findings prior to the external 
audit, if possible. 
2)   A thorough review of selected subject cases, regulatory files, and Investigational Product (IP) 
accountability records (if applicable) within 2-3 months after the first subject is enrolled and annually 
thereafter while subjects are receiving investigational intervention. Reviews will include a representation 
of cases, pharmacy, and regulatory files from external sites. 
3)   Central eligibility verification for all subjects enrolled as described in protocol section 12.3.1 Eligibility 
Verification.  
4)   Central review of all eligibility waivers and exception requests by a SOCCI Medical reviewer to assess 
appropriateness and risk to ensure quality data and ensure subject safety protections for investigator 
initiated research. 
5) For multi-site studies, a central review of subject registration and eligibility verification. 
 
For any protocol, the QMC has the authority to request more frequent reviews or closer safety monitoring if it is 
deemed appropriate for any reason. Additionally, to monitor data quality and protocol compliance once all 
subjects have discontinued intervention, decreased monitoring may be implemented. 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the study 
patient requires alternative treatment, the study shall be conducted exactly as described in the approved protocol.  
 
For any such emergency modification implemented, an IRB modification form must be completed within five (5) 
business days of making the change.  
 
12.8 
Amendments to the Protocol 
 
Should amendments to the protocol be required, the amendments will be originated and documented by the 
Principal Investigator. It should also be noted that when an amendment to the protocol substantially alters the 
study design or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRB for approval prior to 
implementation.  
 
12.9 
Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). Source documents include all 
recordings of observations or notations of clinical activities and all reports and records necessary for the 
evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking regulatory 
approval and marketing, these documents shall be retained for at least two years after the last approval of 
marketing application in an International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study report of this 
investigational study. 


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12.10 Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 21 
of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator is responsible 
for personally overseeing the treatment of all study patients. The Principal Investigator must assure that all study 
site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the required data will 
be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be conducted and the 
Principal Investigator will provide access to his/her original records to permit verification of proper entry of data. 
At the completion of the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 


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REFERENCES 
 
1. 
American Cancer Society. What are the key statistics about breast cancer? [Last revised: 01/05/2017]. 
http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics. 
2. 
Yu AF, Steingart RM, Fuster V. Cardiomyopathy associated with cancer therapy. J Card Fail 
2014;20(11):841-52. 
3. 
Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with 
chemotherapy: a systematic review and meta-analysis. Eur J Cancer 2013;49(13):2900-9. 
4. 
Vejpongsa P, Yeh ET. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J 
Am Coll Cardiol 2014;64(9):938-45. 
5. 
Eschenhagen T, Force T, Ewer MS, de Keulenaer GW, Suter TM et al. Cardiovascular side effects of 
cancer therapies: a position statement from the Heart Failure Association of the European Society of 
Cardiology. Eur J Heart Fail 2011;13(1):1-10. 
6. 
Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug 
interactions. Circulation 2004;109(23 Suppl 1):III50-7. 
7. 
Atorvastatin [package insert, revised March 2015]. Greenstone LLC (USA), Peapack, NJ. Accessed April 
12, 2017. http://labeling.greenstonellc.com/ShowLabeling.aspx?id=983. 
8. 
Rogers SL, Magliano DJ, Levison DB, Webb K, Clarke PJ et al. A dose-specific meta-analysis of lipid 
changes in randomized controlled trials of atorvastatin and simvastatin. Clin Ther 2007;29(2):242-52. 
9. 
Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M et al. Abstract S5-04: Ten year follow-up of 
BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with 
doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, 
carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. 2015 San Antonio Breast Cancer 
Symposium. Cancer Research 2016;76(4 Supplement):S5-04. 
10. 
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB et al. 2013 ACC/AHA guideline on 
the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am 
Coll Cardiol 2014;63(25 Pt B):2889-934. 
11. 
Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as 
antiinflammatory agents? Circulation 2004;109(21 Suppl 1):II18-26. 
12. 
Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, 
diagnosis, and management. J Am Coll Cardiol 2009;53(24):2231-47. 
13. 
Seidman A, Hudis C, Pierri MK, Shak S, Paton V et al. Cardiac dysfunction in the trastuzumab clinical 
trials experience. J Clin Oncol 2002;20(5):1215-21. 
14. 
Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN et al. Risk of heart failure in breast 
cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer 
Inst 2012;104(17):1293-305. 
15. 
Yu AF, Yadav NU, Lung BY, Eaton AA, Thaler HT et al. Trastuzumab interruption and treatment-
induced cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat 2015;149(2):489-
95. 
16. 
de Korte MA, de Vries EG, Lub-de Hooge MN, Jager PL, Gietema JA et al. 111Indium-trastuzumab 
visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline 
treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related 
cardiotoxicity. Eur J Cancer 2007;43(14):2046-51. 
17. 
Rosa GM, Gigli L, Tagliasacchi MI, Di Iorio C, Carbone F et al. Update on cardiotoxicity of anti-cancer 
treatments. Eur J Clin Invest 2016;46(3):264-84. 
18. 
Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S et al. ErbB2 is essential in the prevention of dilated 
cardiomyopathy. Nat Med 2002;8(5):459-65. 
19. 
Mohan N, Shen Y, Endo Y, ElZarrad MK, Wu WJ. Trastuzumab, but Not Pertuzumab, Dysregulates 
HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production 
in Human Cardiomyocytes. Mol Cancer Ther 2016;15(6):1321-31. 
20. 
De Keulenaer GW, Doggen K, Lemmens K. The vulnerability of the heart as a pluricellular paracrine 
organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res 
2010;106(1):35-46. 


IIT2015-12-Goodman-STOP 
Protocol Version 3.1, November 29, 2017 
–46– 
21. 
Escalante CP, Chang YC, Liao K, Rouleau T, Halm J et al. Meta-analysis of cardiovascular toxicity risks 
in cancer patients on selected targeted agents. Support Care Cancer 2016;24(9):4057-74. 
22. 
Fallah-Rad N, Walker JR, Wassef A, Lytwyn M, Bohonis S et al. The utility of cardiac biomarkers, tissue 
velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular 
dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with 
adjuvant trastuzumab therapy. J Am Coll Cardiol 2011;57(22):2263-70. 
23. 
de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O et al. Trastuzumab-
associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J 
Clin Oncol 2014;32(20):2159-65. 
24. 
Chavez-MacGregor M, Zhang N, Buchholz TA, Zhang Y, Niu J et al. Trastuzumab-related cardiotoxicity 
among older patients with breast cancer. J Clin Oncol 2013;31(33):4222-8. 
25. 
Wang SY, Long JB, Hurria A, Owusu C, Steingart RM et al. Cardiovascular events, early discontinuation 
of trastuzumab, and their impact on survival. Breast Cancer Res Treat 2014;146(2):411-9. 
26. 
Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new 
entity. J Clin Oncol 2005;23(13):2900-2. 
27. 
Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH. Use of myocardial strain 
imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer 
chemotherapy: a systematic review. J Am Coll Cardiol 2014;63(25 Pt A):2751-68. 
28. 
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M et al. Adjuvant trastuzumab in HER2-
positive breast cancer. N Engl J Med 2011;365(14):1273-83. 
29. 
Tsai HT, Isaacs C, Fu AZ, Warren JL, Freedman AN et al. Risk of cardiovascular adverse events from 
trastuzumab (Herceptin((R))) in elderly persons with breast cancer: a population-based study. Breast 
Cancer Res Treat 2014;144(1):163-70. 
30. 
Rupert CE, Coulombe KL. The roles of neuregulin-1 in cardiac development, homeostasis, and disease. 
Biomark Insights 2015;10(Suppl 1):1-9. 
31. 
Perry MC, Dufour CR, Eichner LJ, Tsang DW, Deblois G et al. ERBB2 deficiency alters an E2F-1-
dependent adaptive stress response and leads to cardiac dysfunction. Mol Cell Biol 2014;34(23):4232-43. 
32. 
Varga ZV, Ferdinandy P, Liaudet L, Pacher P. Drug-induced mitochondrial dysfunction and 
cardiotoxicity. Am J Physiol Heart Circ Physiol 2015;309(9):ajpheart 00554 2015. 
33. 
Zeglinski M, Ludke A, Jassal DS, Singal PK. Trastuzumab-induced cardiac dysfunction: A 'dual-hit'. Exp 
Clin Cardiol 2011;16(3):70-4. 
34. 
Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: 
from bench to bedside. J Clin Oncol 2008;26(22):3777-84. 
35. 
Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL et al. Identification of the molecular basis of 
doxorubicin-induced cardiotoxicity. Nat Med 2012;18(11):1639-42. 
36. 
Ma J, Wang Y, Zheng D, Wei M, Xu H, Peng T. Rac1 signalling mediates doxorubicin-induced 
cardiotoxicity through both reactive oxygen species-dependent and -independent pathways. Cardiovasc 
Res 2013;97(1):77-87. 
37. 
Lenihan DJ, Oliva S, Chow EJ, Cardinale D. Cardiac toxicity in cancer survivors. Cancer 2013;119 Suppl 
11:2131-42. 
38. 
Little MP, Tawn EJ, Tzoulaki I, Wakeford R, Hildebrandt G et al. Review and meta-analysis of 
epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease 
risks, and their possible mechanisms. Radiat Environ Biophys 2010;49(2):139-53. 
39. 
Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older 
women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 
2007;25(25):3808-15. 
40. 
Cox JA, Swanson TA. Current modalities of accelerated partial breast irradiation. Nat Rev Clin Oncol 
2013;10(6):344-56. 
41. 
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U et al. Risk of ischemic heart disease in 
women after radiotherapy for breast cancer. N Engl J Med 2013;368(11):987-98. 
42. 
Marek-Trzonkowska N, Kwieczynska A, Reiwer-Gostomska M, Kolinski T, Molisz A, Siebert J. Arterial 
Hypertension Is Characterized by Imbalance of Pro-Angiogenic versus Anti-Angiogenic Factors. PLoS 
One 2015;10(5):e0126190. 
43. 
Takahashi Y, Satoh M, Tabuchi T, Nakamura M. Prospective, randomized, single-blind comparison of 


IIT2015-12-Goodman-STOP 
Protocol Version 3.1, November 29, 2017 
–47– 
effects of 6 months' treatment with atorvastatin versus pravastatin on leptin and angiogenic factors in 
patients with coronary artery disease. Heart Vessels 2012;27(4):337-43. 
44. 
Bauer AJ, Banek CT, Needham K, Gillham H, Capoccia S et al. Pravastatin attenuates hypertension, 
oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension. 
Hypertension 2013;61(5):1103-10. 
45. 
Groemping Y, Rittinger K. Activation and assembly of the NADPH oxidase: a structural perspective. 
Biochem J 2005;386(Pt 3):401-16. 
46. 
Sarfstein R, Gorzalczany Y, Mizrahi A, Berdichevsky Y, Molshanski-Mor S et al. Dual role of Rac in the 
assembly of NADPH oxidase, tethering to the membrane and activation of p67phox: a study based on 
mutagenesis of p67phox-Rac1 chimeras. J Biol Chem 2004;279(16):16007-16. 
47. 
Nakagami H, Jensen KS, Liao JK. A novel pleiotropic effect of statins: prevention of cardiac hypertrophy 
by cholesterol-independent mechanisms. Ann Med 2003;35(6):398-403. 
48. 
Hernandez G, Thornton C, Stotland A, Lui D, Sin J et al. MitoTimer: a novel tool for monitoring 
mitochondrial turnover. Autophagy 2013;9(11):1852-61. 
49. 
Andres AM, Hernandez G, Lee P, Huang C, Ratliff EP et al. Mitophagy is required for acute 
cardioprotection by simvastatin. Antioxid Redox Signal 2014;21(14):1960-73. 
50. 
Lange T, Nentwich MF, Luth M, Yekebas E, Schumacher U. Trastuzumab has anti-metastatic and anti-
angiogenic activity in a spontaneous metastasis xenograft model of esophageal adenocarcinoma. Cancer 
Lett 2011;308(1):54-61. 
51. 
Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects 
of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 1998;19(1):26-37. 
52. 
Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP et al. Statin prescriptions and breast cancer 
recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 2011;103(19):1461-8. 
53. 
Cheng WP, Lo HM, Wang BW, Chua SK, Lu MJ, Shyu KG. Atorvastatin alleviates cardiomyocyte 
apoptosis by suppressing TRB3 induced by acute myocardial infarction and hypoxia. J Formos Med 
Assoc 2016. 
54. 
Sun G, Li Y, Ji Z. Atorvastatin attenuates inflammation and oxidative stress induced by 
ischemia/reperfusion in rat heart via the Nrf2 transcription factor. Int J Clin Exp Med 2015;8(9):14837-
45. 
55. 
Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B et al. Assessment of echocardiography and biomarkers 
for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and 
trastuzumab. Circ Cardiovasc Imaging 2012;5(5):596-603. 
56. 
Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and incremental value 
of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr 
2013;26(5):493-8. 
57. 
Ho E, Brown A, Barrett P, Morgan RB, King G et al. Subclinical anthracycline- and trastuzumab-induced 
cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking 
echocardiographic study. Heart 2010;96(9):701-7. 
58. 
Cho GY, Marwick TH, Kim HS, Kim MK, Hong KS, Oh DJ. Global 2-dimensional strain as a new 
prognosticator in patients with heart failure. J Am Coll Cardiol 2009;54(7):618-24. 
59. 
Sawaya H, Plana JC, Scherrer-Crosbie M. Newest echocardiographic techniques for the detection of 
cardiotoxicity and heart failure during chemotherapy. Heart Fail Clin 2011;7(3):313-21. 
60. 
Rosen BD, Edvardsen T, Lai S, Castillo E, Pan L et al. Left ventricular concentric remodeling is 
associated with decreased global and regional systolic function: the Multi-Ethnic Study of 
Atherosclerosis. Circulation 2005;112(7):984-91. 
61. 
Choi EY, Rosen BD, Fernandes VR, Yan RT, Yoneyama K et al. Prognostic value of myocardial 
circumferential strain for incident heart failure and cardiovascular events in asymptomatic individuals: the 
Multi-Ethnic Study of Atherosclerosis. Eur Heart J 2013;34(30):2354-61. 
62. 
Hor KN, Wansapura J, Markham LW, Mazur W, Cripe LH et al. Circumferential strain analysis identifies 
strata of cardiomyopathy in Duchenne muscular dystrophy: a cardiac magnetic resonance tagging study. J 
Am Coll Cardiol 2009;53(14):1204-10. 
63. 
Mordi I, Bezerra H, Carrick D, Tzemos N. The Combined Incremental Prognostic Value of LVEF, Late 
Gadolinium Enhancement, and Global Circumferential Strain Assessed by CMR. JACC Cardiovasc 
Imaging 2015;8(5):540-9. 


IIT2015-12-Goodman-STOP 
Protocol Version 3.1, November 29, 2017 
–48– 
64. 
Saito M, Negishi K, Eskandari M, Huynh Q, Hawson J et al. Association of left ventricular strain with 
30-day mortality and readmission in patients with heart failure. J Am Soc Echocardiogr 2015;28(6):652-
66. 
65. 
Agarwal M, Shufelt C, Mehta PK, Gill E, Berman DS et al. Cardiac risk factors and myocardial perfusion 
reserve in women with microvascular coronary dysfunction. Cardiovasc Diagn Ther 2013;3(3):146-52. 
66. 
Shufelt CL, Thomson LE, Goykhman P, Agarwal M, Mehta PK et al. Cardiac magnetic resonance 
imaging myocardial perfusion reserve index assessment in women with microvascular coronary 
dysfunction and reference controls. Cardiovasc Diagn Ther 2013;3(3):153-60. 
67. 
Goykhman P, Mehta PK, Minissian M, Thomson LE, Berman DS et al. Subendocardial ischemia and 
myocarditis in systemic lupus erythematosus detected by cardiac magnetic resonance imaging. J 
Rheumatol 2012;39(2):448-50. 
68. 
Nelson MD, Szczepaniak LS, Wei J, Haftabaradaren A, Bharadwaj M et al. Diastolic dysfunction in 
women with signs and symptoms of ischemia in the absence of obstructive coronary artery disease: a 
hypothesis-generating study. Circ Cardiovasc Imaging 2014;7(3):510-6. 
69. 
Dall'Armellina E, Piechnik SK, Ferreira VM, Si QL, Robson MD et al. Cardiovascular magnetic 
resonance by non contrast T1-mapping allows assessment of severity of injury in acute myocardial 
infarction. J Cardiovasc Magn Reson 2012;14:15. 
70. 
de Meester de Ravenstein C, Bouzin C, Lazam S, Boulif J, Amzulescu M et al. Histological Validation of 
measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from 
Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T. J Cardiovasc Magn Reson 2015;17:48. 
71. 
Sharif B, Dharmakumar R, LaBounty T, Arsanjani R, Shufelt C et al. Towards elimination of the dark-
rim artifact in first-pass myocardial perfusion MRI: removing Gibbs ringing effects using optimized 
radial imaging. Magn Reson Med 2014;72(1):124-36. 
72. 
Broussard JL, Nelson MD, Kolka CM, Bediako IA, Paszkiewicz RL et al. Rapid development of cardiac 
dysfunction in a canine model of insulin resistance and moderate obesity. Diabetologia 2016;59(1):197-
207. 
73. 
Nelson MD, Szczepaniak LS, LaBounty TM, Szczepaniak E, Li D et al. Cardiac steatosis and left 
ventricular dysfunction in HIV-infected patients treated with highly active antiretroviral therapy. JACC 
Cardiovasc Imaging 2014;7(11):1175-7. 
74. 
Nelson MD, Haykowsky MJ, Petersen SR, DeLorey DS, Stickland MK et al. Aerobic fitness does not 
influence the biventricular response to whole body passive heat stress. J Appl Physiol (1985) 
2010;109(5):1545-51. 
75. 
Nelson MD, Haykowsky MJ, Petersen SR, DeLorey DS, Cheng-Baron J, Thompson RB. Increased left 
ventricular twist, untwisting rates, and suction maintain global diastolic function during passive heat 
stress in humans. Am J Physiol Heart Circ Physiol 2010;298(3):H930-7. 
76. 
Nelson MD, Altamirano-Diaz LA, Petersen SR, DeLorey DS, Stickland MK et al. Left ventricular 
systolic and diastolic function during tilt-table positioning and passive heat stress in humans. Am J 
Physiol Heart Circ Physiol 2011;301(2):H599-608. 
77. 
Schmitz KH, Prosnitz RG, Schwartz AL, Carver JR. Prospective surveillance and management of cardiac 
toxicity and health in breast cancer survivors. Cancer 2012;118(8 Suppl):2270-6. 
78. 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A et al. The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst 1993;85(5):365-76. 
79. 
Sprangers MA, Groenvold M, Arraras JI, Franklin J, te Velde A et al. The European Organization for 
Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first 
results from a three-country field study. J Clin Oncol 1996;14(10):2756-68. 
80. 
Letellier ME, Dawes D, Mayo N. Content verification of the EORTC QLQ-C30/EORTC QLQ-BR23 
with the International Classification of Functioning, Disability and Health. Qual Life Res 2015;24(3):757-
68. 
81. 
Maji D, Shaikh S, Solanki D, Gaurav K. Safety of statins. Indian J Endocrinol Metab 2013;17(4):636-46. 
82. 
Coelho-Filho OR, Rickers C, Kwong RY, Jerosch-Herold M. MR myocardial perfusion imaging. 
Radiology 2013;266(3):701-15. 
83. 
Messroghli DR, Nordmeyer S, Dietrich T, Dirsch O, Kaschina E et al. Assessment of diffuse myocardial 
fibrosis in rats using small-animal Look-Locker inversion recovery T1 mapping. Circ Cardiovasc Imaging 


IIT2015-12-Goodman-STOP 
Protocol Version 3.1, November 29, 2017 
–49– 
2011;4(6):636-40. 
84. 
Schelbert EB, Testa SM, Meier CG, Ceyrolles WJ, Levenson JE et al. Myocardial extravascular 
extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans: 
slow infusion versus bolus. J Cardiovasc Magn Reson 2011;13:16. 
85. 
Ugander M, Oki AJ, Hsu LY, Kellman P, Greiser A et al. Extracellular volume imaging by magnetic 
resonance imaging provides insights into overt and sub-clinical myocardial pathology. Eur Heart J 
2012;33(10):1268-78. 
86. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
controlled clinical trial. Biometrics 1975;31(1):103-15. 
87. 
Mavinkurve-Groothuis AM, Marcus KA, Pourier M, Loonen J, Feuth T et al. Myocardial 2D strain 
echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for 
acute lymphoblastic leukaemia (ALL): a prospective study. Eur Heart J Cardiovasc Imaging 
2013;14(6):562-9. 
88. 
Rubin DB. Inference and missing data. Biometrika 1976;63(3):581-592. 
89. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data. Second Edition. John Wiley & Sons: New 
York, 2002. 
 
 
 


IIT2015-12-Goodman-STOP 
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–50– 
APPENDIX A 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry on 
all pre-disease performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary 
nature (e.g., light housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care, but unable to carry out 
any work activities. Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time. Capable of only 
limited self-care, confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. Cannot 
carry on any self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 
 
 
 


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APPENDIX B 
STUDY DIARY 
Please bring your completed diary and your study drug supply, including empty bottles, to every study visit. 
This will help us keep track of your study drug and how well you are tolerating it. 
 
Participant Study ID:  
 
Participant Name:  
 
 
Date Study Drug Dispensed:  
 
Participant Signature:  
 
 
Study Drug Dispensed for: 
 Visit 1 (Baseline) – Visit 2 (Month 1) 
 Visit 2 (Month 1) – Visit 3 (Month 3) 
 Visit 3 (Month 3) – Visit 4 (Month 6) 
 Visit 4 (Month 6) – Visit 5 (Month 9) 
 Visit 5 (Month 9) – Visit 6 (Month 12) 
 
 
Instructions 
Complete one line in the table for each day you take the study drug.  
Please contact the study research staff at «staff phone number» if you have any questions. 
• Take your study drug once per day at bedtime or with an evening meal. Please swallow the capsule whole 
and do not chew, crush, or open it. Take the capsule at the same time every day.  
• Record the date and time of day you took the study drug.  
• If you miss a dose of the study drug, take it as soon as you remember. Do not take the drug if it has been 
more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do 
not take two doses of the study drug at the same time.  
• If you notice any side effects such as joint pain, mild muscle aches, diarrhea, nausea, respiratory infection, 
painful or difficult urination, pain in feet, ankles, hands, or wrists, or if you have any other symptoms, 
please write them in the Comments column and report them to the study staff when they call you. 
Day 
Date 
Time Study Drug Taken 
Check if Dose Missed 
Comments 
1 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
2 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
3 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
4 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
5 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
6 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
7 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
8 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
9 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
10 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
11 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
12 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
13 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
14 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
15 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
16 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 


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Day 
Date 
Time Study Drug Taken 
Check if Dose Missed 
Comments 
17 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
18 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
19 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
20 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
21 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
22 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
23 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
24 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
25 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
26 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
27 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
28 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
29 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
30 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
31 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
32 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
33 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
34 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
35 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
36 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
37 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
38 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
39 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
40 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
41 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
42 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
43 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
44 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
45 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
46 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
47 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
48 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
49 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
50 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 


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Day 
Date 
Time Study Drug Taken 
Check if Dose Missed 
Comments 
51 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
52 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
53 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
54 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
55 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
56 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
57 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
58 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
59 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
60 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
61 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
62 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
63 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
64 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
65 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
66 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
67 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
68 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
69 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
70 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
71 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
72 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
73 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
74 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
75 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
76 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
77 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
78 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
79 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
80 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
81 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
82 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 


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Day 
Date 
Time Study Drug Taken 
Check if Dose Missed 
Comments 
83 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
84 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
85 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
86 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
87 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
88 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
89 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
90 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
91 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
92 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
93 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
94 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
95 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
96 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
97 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
98 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
99 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
100 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
101 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
102 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
103 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
104 
 
____:____  
 a.m. / 
 p.m. 
 Dose not taken today 
 
 
 
FOR STUDY TEAM USE ONLY  
Staff Initials: 
Date study drug dispensed:  
Date study drug returned:  
Number of pills/capsules dispensed:  
Number of pills/capsules returned:  
Number of pills/capsules that should have been taken:  
Discrepancy/notes 
 

ICF_001.pdf: 
IRB No:  Pro00043120/ CR00013299 
Approval Date:  2/1/2018  
 
IIT2015-12-Goodman-STOP Protocol v3.1, Version Date: 11/29/2017 
Main ICF, Version Date: 12/04/2017 
Page 1 of 19 
 
CONSENT FORM FOR RESEARCH 
 
TITLE:  
Statin Therapy Operates to Prevent Heart Disease in Breast Cancer 
Survivors Trial (STOP Heart Disease in Breast Cancer Survivors Trial)  
 
SPONSOR:  
California Breast Cancer Research Program (CBCRP) 
 
PARTICIPATING RESEARCHERS: 
Marc T. Goodman, PhD, MPH  
Principal Investigator 
310-423-6188 
Janet Wei, MD 
Co-Investigator 
310-423-9680 
C. Noel Bairey Merz, MD 
Co-Investigator 
310-423-9680 
Philomena F. McAndrew, MD 
Co-Investigator 
310-285-7216 
Monica M. Mita, MD, MSc 
Co-Investigator 
310-248-6729 
Michael B. Van Scoy-Mosher, MD  
Co-Investigator 
310-659-9397 
Mary El-Masry, MD 
Co-Investigator 
310-888-8680 
Heather McArthur, MD, MPH 
Co-Investigator 
310-967-2700 
Reva K. Basho, MD 
Co-Investigator 
310-423-8255 
Christine Pacheco Claudio, MD 
Co-Investigator 
310-423-9680 
Panteha Rezaeian, MD 
Co-Investigator 
310-423-9680 
 
STUDY CONTACT PHONE NUMBER AT CSMC: Marc T. Goodman, PhD, MPH 
310-423-6188 
 
AFTER HOURS CONTACT (24 HOURS):   
Your study doctor at the phone number listed above  
 
This research study is sponsored by the California Breast Cancer Research Program (CBCRP).  
The CBCRP only reimburses Cedars-Sinai Medical Center for the costs associated with running 
the study; CBCRP is not providing additional compensation to Cedars Sinai Medical Center or the 
Principal Investigator for their participation in the study. 
 
1. 
WHAT IS THE PURPOSE OF THIS RESEARCH STUDY? 
 
Breast cancer and heart disease are major health concerns for women in the United States.  While 
aggressive screening and advanced treatment for breast cancer have significantly improved how 
long women live following diagnosis, women who are treated for breast cancer are at risk for heart 
problems because treatment that is aimed to kill breast cancer cells can cause damage to the heart.   
 
Statins are widely used drugs that lower cholesterol levels and seem to rapidly reduce 
inflammation that may be harmful to heart tissue.  Some studies suggest that statins may decrease 
the risk of heart disease in breast cancer patients, but this possibility has not been studied 
thoroughly in a clinical trial.  We are doing this study to examine the effects of atorvastatin, a type 
of statin, on changes to the heart among women undergoing breast cancer treatment.  We think 
that atorvastatin may reduce or eliminate the harmful effects of treatment to the heart tissue of 
breast cancer patients. 


IRB No:  Pro00043120/ CR00013299 
Approval Date:  2/1/2018  
 
IIT2015-12-Goodman-STOP Protocol v3.1, Version Date: 11/29/2017 
Main ICF, Version Date: 12/04/2017 
Page 2 of 19 
 
Atorvastatin is approved by the U.S. Food and Drug Administration (FDA) to reduce the risk for 
heart attack, stroke, and chest pain in patients who have heart disease or risk factors for heart 
disease such as smoking, high blood pressure, low HDL cholesterol, or family history of early 
heart disease.  It is also approved to lower the risk for heart attack or stroke in patients with type 2 
diabetes and risk factors such as diabetic eye or kidney problems, smoking, or high blood 
pressure.  However, atorvastatin is not approved by the FDA to decrease the risk of heart disease 
in women receiving breast cancer treatment so the use of this drug in this study is considered 
investigational. 
 
You are being asked to take part in this research study because you are a woman who has been 
newly diagnosed with stage 1-3 breast cancer and you will receive trastuzumab (Herceptin), with 
or without anthracycline chemotherapy (such as doxorubicin (Adriamycin) or epirubicin (Ellence)) 
for treatment of your breast cancer. 
 
The study will enroll up to 60 people in total. 
 
2. 
WHAT WILL HAPPEN DURING THE STUDY? 
 
This section provides a general overview of what will happen during your participation in this 
study.  Information included below should be considered along with the flowchart of procedures 
attached as Appendix A.   
 
The flowchart shows a timeline for research-related or standard of care procedures that are 
involved in your participation in this study.  Research-related procedures are those performed 
solely for the research.  They would not be performed if you did not take part in the study.  
Standard of care (routine) procedures would be performed both as part of this study and if you 
do not participate in this study.    
 
A table describing common medical procedures done solely for the purposes of monitoring and 
assessing your condition during this study is attached as Appendix B to the end of this consent 
form.  Standard of care procedures that will be repeated or done at greater frequency are listed in 
the flow chart, attached Appendix A.  
 
Overview of study: 
This is a randomized, double-blind research study.  
• “Randomized” means that you will be assigned to a study group by chance, like flipping a 
coin.  You will be randomized into one of two study groups, and will have an equal chance 
of being placed in one of the groups described below.  
• “Double-blind” means neither you nor the researchers will know what group you are 
assigned to. 
This is a placebo-controlled study.  It will compare the effects of atorvastatin against the effects of 
a placebo (an inactive substance, such as, a sugar pill) on changes to the heart before and during 
breast cancer treatment. 
Research participants in this study will get either atorvastatin or a placebo.  You will not get both.  
This study has two study groups: 




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(cramping, bloating, flatulence, diarrhea, nausea) are possible, but very rare with this small 
amount of lactose. 
 
Risks of atorvastatin 
The study drug atorvastatin may affect how different parts of your body work, such as your liver 
and kidneys.  Atorvastatin is not safe for people with active liver disease.  You will have blood 
tests before and during the study to monitor your liver and kidney function.  Women who are 
pregnant or may become pregnant should not use atorvastatin.  When taken during pregnancy, 
atorvastatin may cause harm to a developing baby.  If you are able to become pregnant, you will 
have a pregnancy test before the study and at each research study visit.  Let your study doctor 
know immediately if you have chronic liver disease or if you believe you might be pregnant. 
 
Other possible side effects of atorvastatin are summarized in the table below.  You will be asked to 
keep a diary during the study to record any side effects and symptoms you may be experiencing. 
Occasional,  
some may be serious  
(occurs in 4-20% of people) 
Possible,  
some may be serious  
(occurs in 1-3% of people) 
Rare,  
and serious  
(occurs in less than 1% of people) 
• Joint pain 
• Mild muscle aches 
• Diarrhea 
• Upper respiratory infections 
(symptoms: stuffy or runny 
nose) 
• Nausea 
• Urinary tract infection 
(symptoms: painful or 
difficult urination) 
• Pain in extremity (feet, 
ankles, hands, wrists) 
• Insomnia (trouble sleeping) 
• Indigestion (symptoms: 
bloating (full feeling), 
belching, gas, stomach 
pain) 
• Confusion, forgetfulness, or 
memory problems  
• Allergic reaction including 
swelling of the face, lips, 
tongue, and/or throat that may 
cause difficulty in breathing or 
swallowing 
• Liver failure (symptoms: 
weakness, fatigue, weight loss, 
yellowing of the skin or eyes) 
• Rhabdomyolysis (a breakdown 
of muscle tissue), a rare 
condition that may cause 
kidney damage (symptoms: 
muscle pain, tenderness, or 
weakness; dark colored urine) 
 
Food and Medication Interactions 
Grapefruit and grapefruit juice may interact with atorvastatin and lead to potentially dangerous 
effects.  Do not consume grapefruit products (grapefruit, grapefruit juice, grapefruit seed extract, 
or dietary supplements containing grapefruit) during this study.  Atorvastatin also interacts with 
some medications in a way that increases the risk of muscle injury called myopathy (symptoms: 
unexplained muscle weakness or pain).  Atorvastatin should not be taken by people who are also 
taking some medications, such as the antibiotics erythromycin or clarithromycin; the 
immunosuppressant cyclosporine; the antifungal drug itraconazole; colchicine, a drug used to treat 
gout; the hepatitis C drug telaprevir; the cardiovascular drug gemfibrozil; HIV protease inhibitors 
including tipranavir, lopinavir, ritonavir, saquinavir, darunavir, and fosamprenavir; or red yeast 
rice, a natural substance that has cholesterol-lowering properties.  Tell your study doctor 


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immediately if you use any of these medications, or if any new medications are prescribed for you 
during the study.  
 
Unknown Risks 
There also may be other side effects or risks that we cannot predict.  Many side effects may go 
away shortly after the study medication or procedure is stopped.  However, in some cases they 
may be serious, long-lasting, permanent, and/or fatal.  Tell your study doctor if you notice or feel 
anything different so they can check if you may be having a side effect. 
 
Reproductive and Lactation Risks  
Taking part in this research study can affect an unborn baby.  Therefore, you should not become 
pregnant while on this study.  If you or your partner is capable of becoming pregnant you will 
need to use birth control.  Check with the researcher about approved birth control methods to use 
while participating in this study.    
 
Women should not breastfeed a baby while on this study.   
 
Unknown Risks to the Developing Embryo or Fetus (an unborn baby) 
If you are pregnant, or become pregnant during participation in this research, the study drug or 
procedures might involve risks to an embryo or fetus, which are currently unknown.  It is 
important that you contact your study doctor immediately if you believe you might be pregnant. 
 
Risks of Cardiac Magnetic Resonance Imaging (CMRI), Infusion Procedure, and Contrast 
There are no known side effects from exposure to a magnetic field. However, it is not safe to have 
a CMRI if you have metal implanted in your body.  CMRI cannot be performed on patients with 
pacemakers, defibrillators, implanted electronic devices, or some metallic implants, including 
breast expanders.  Before having a CMRI you will be asked to complete a short questionnaire, 
which will help determine if MRI is safe for you.  Please tell your study doctor if you plan to have 
additional breast surgery or breast reconstruction that includes breast expanders during the time 
you are in the study. Women who have breast reconstruction surgery after enrollment/completion 
of the baseline visit that includes metallic breast expanders prohibiting MRI will not be required to 
do the CMRI while the breast expanders are in place. 
Infusion is the administration of drugs directly into your bloodstream using intravenous (IV) lines. 
The risks associated with IV lines are described separately in Appendix B. During the CMRI 
procedure, you will have an intravenous line (IV) placed and you will be given an infusion of a 
gadolinium-based contrast (Gadavist). This is a non-iodine contrast agent taken up by the tissues 
of your body, highlighting areas and allowing them to be seen and studied by the radiologist. The 
gadolinium-based contrast is rapidly cleared from the body by your kidneys through urine. 
Gadolinium is generally very safe. Side effects or reactions are uncommon but may occur. The 
most common side effects are mild headache, nausea (feeling sick), and dizziness for a brief time 
following the gadolinium injection. You may have a warm, flushed sensation during the injection 
of the contrast materials and a metallic taste in your mouth that lasts for a few minutes. Rarely 
(occurs in less than 1 in 100 people) gadolinium can cause low blood pressure and 
lightheadedness. This can be treated immediately with IV fluids. Very rarely (occurs in less than 1 
in 1,000) people may have an allergy to the gadolinium. The use of gadolinium-based contrast 
agents in patients who already have serious kidney problems or who have a liver transplant may 


IRB No:  Pro00043120/ CR00013299 
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lead to a possibly fatal disease called nephrogenic systemic fibrosis (NSF) involving the skin, 
muscle, and internal organs. 
 
Participation in Double-Blinded Studies 
Participation in a double-blind study means that you may not be able to participate in other, 
similar trials since unblinding would generally only occur for emergent, life-threatening situations. 
We might not be able to tell you if you received the study drug or placebo in a situation where you 
would like to qualify for another research study.  Because you may not know the study group to 
which you were assigned, in the future should you wish to participate in a different study that 
requires knowing what drug you received in this study, you may not be eligible to participate in 
the different study. 
 
Follow-up Visit for Discontinuing Participants 
While you are free to discontinue your participation at any time, we encourage you to complete a 
final research study visit.  During this visit, we will conduct tests to collect safety data, and discuss 
any information that may be important to share with your treating physician. 
 
Incidental Findings and Duplicate Tests 
The procedures in this study are for research purposes and no clinical care or information will be 
provided to you as part of this study. 
 
It is possible that the study procedures could detect a medical problem that was not the focus of 
the research and about which you may not already be aware.  If we learn that the results of 
research procedures could suggest information relevant in an important way to your health, we 
will notify you.  We will not provide any specific diagnosis about the information seen during 
research scans performed at the Research Imaging Core facility, although we may suggest your 
physician order a particular test or procedure to further investigate the finding.  Your primary care 
physician will determine if it is in your best interest to obtain this test for you.  There may be 
added risks of having further diagnostic tests, and we suggest that you discuss this with your 
primary care physician. 
 
You will not be provided with information from the screening blood test to check your kidney 
function other than noting whether your screen met our standards.  If not, you will be told and 
encouraged to discuss this with your primary physician.  We will not provide the blood test results 
to your primary physician. 
 
4. 
ARE THERE BENEFITS IN TAKING PART IN THE STUDY? 
 
If you agree to take part in this research study, there may or may not be direct medical benefit to 
you.  If you are randomized to receive atorvastatin, the possible benefit of taking part in the 
research study is that the study drug may reduce treatment-related damage to the heart. However, 
no benefit is guaranteed. If you are randomized to receive placebo, you should not expect to 
benefit from taking part in this research study. In either case, it possible that your condition may 
remain unchanged or even get worse. 
 
We hope the information learned from this research study will benefit other women with breast 
cancer in the future by helping us to learn about the impact of treatment on the heart and whether 
statins will reduce the harmful effects of treatment to the heart tissue.  


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5. 
WHY WOULD MY PARTICIPATION BE STOPPED? 
 
Your participation in this study may be stopped at any time by the researchers or the sponsor 
without your consent for any reason, including: 
•    The study is stopped or suspended; 
•  Funding for the study is reduced, stopped, or withdrawn; 
• 
If it is in your best interest; 
• 
You do not consent to continue in the study after being told of changes in the 
research that may affect you; 
•  You do not follow the study procedures. 
 
You may choose (or you may be required) to withdraw from certain parts of the study, but invited 
to continue with other parts.  For example, you might stop taking a study drug, but continue with 
follow-up visits or allow us to continue to collect data from your medical records.  Separate 
written consent will be requested if your continued participation will involve procedures not 
described in this consent form. 
 
6. 
ARE THERE ANY OTHER OPTIONS? 
 
Your participation is voluntary so you have the right to decline to participate or to withdraw from 
this research study at any time without any penalty or loss of benefits to which you would be 
entitled outside of the study.  Choosing not to participate will not affect the care you receive at 
Cedars-Sinai Health System. 
 
If you decide not to take part in this study, you have other choices. For example: 
• 
you may choose to be treated following the usual clinical approach: receiving trastuzumab 
treatment (with or without anthracycline) without receiving statins  
• 
you may choose to take part in a different study at CSMC or elsewhere, if one is available 
• 
you could decide not to be treated. 
 
The researcher will discuss these options and their risks and benefits with you. 
 
7. 
WILL MY INFORMATION BE KEPT CONFIDENTIAL? 
 
We will do our best to make sure that the personal information collected as part of this study is 
kept private.  However, we cannot guarantee total privacy.  A copy of your research consent and 
authorization forms may be filed in your electronic medical record at CSMC.  Your personal 
information may be given out if required by law.  If information from this study is published or 
presented at scientific meetings, your name and other identifiable personal information will not be 
used.  Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: accrediting agencies, government and regulatory groups 
(such as Food and Drug Administration (FDA), Office for Human Research Protections (OHRP), 
etc.), safety monitors, companies that sponsor the study, and authorized representatives of the 
sponsor.  
 
The study team will facilitate any required access to your records by authorized representatives of 
the Sponsor to verify the information collected for the study.   


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You will be asked to sign a separate “Authorization Form” that outlines with whom your 
information may be shared for the purposes of this research and under what circumstances.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Website will not include information that can identify you.  At most, the 
Website will include a summary of the results.  You can search this Website at any time. 
 
As part of this research, it is necessary to restrict your right to access copies of health information 
created during your participation in your research while the research study is in progress.  This 
restriction is necessary to maintain the blinding, in other words, it is important to the study 
outcomes that you not know into which treatment group you were assigned.  Your right to access 
this information will be restored upon completion of the entire study. 
 
8. 
WHAT IF I BECOME ILL OR INJURED BECAUSE OF TAKING PART IN THIS 
STUDY? 
 
Contact your researcher at once if you feel that you are ill or have been injured because of taking 
part in this study.  If it is a medical emergency, call 911 or go to an emergency room.  Promptly 
notify your researcher of your situation at the phone number listed on page 1 of this consent form. 
 
Who pays for my research related illness or injury? 
Cedars-Sinai has no plans to pay for costs associated with treatment of research related injury or 
illness.  We will make every effort to seek reimbursement from your health plan.  However, you 
will be responsible for any deductibles and co-payments required under your health plan and for 
any claims ultimately denied by your health plan.  Financial assistance may be available under 
Cedars-Sinai’s Charity Care Policy and Procedure.  If you feel that you have had a research-
related injury and need financial assistance, please contact the IRB Office at 310-423-3783. 
 
9. 
FINANCIAL CONSIDERATIONS 
 
Costs of Participation 
Please review the attached Appendix A flowchart for a listing of items, drugs, and services that 
will be billed to you and/or your insurance and those that will be covered by the study sponsor. 
 
The study drug (atorvastatin or placebo) will be supplied at no cost to you during your 
participation in this study.  Only items, drugs, and services that are reasonable and necessary for 
your medical care throughout the study will be billed to your insurance.  You remain responsible 
for all deductibles, co-pays, and balances under your health benefit plan.  If your insurance 
company does not pay, you will be billed for those charges.  You should check with your health 
benefit plan if you have questions or concerns about your insurance coverage. 
 
Compensation for Participating 
You will receive $100 for each research study visit you complete.  The total amount you will 
receive if you complete the whole study, all three research visits, is $300.  If you do not complete 
the entire research study, you will only be paid for those visits you do complete.   
 


IRB No:  Pro00043120/ CR00013299 
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You may be required to complete a W-9 Form in order to receive payment.  The W-9 Form will be 
maintained by our accounting department at Cedars-Sinai.  Although any amount of payment may 
be reportable (check with a tax professional if you have questions about your obligations), if total 
payment by Cedars-Sinai is $600 or more in a calendar year, a 1099 Form will be filed with the 
IRS in accordance with federal tax law.   
 
If you are a Cedars-Sinai employee, you should provide your employee identification number to 
the research team so that your payment can be appropriately processed through Payroll.  For your 
own protection and to comply with tax laws, your payment for participation will be reported to the 
IRS together with other compensation you receive from Cedars-Sinai.  
 
Compensation will be managed by Greenphire, Inc., a private company contracted to issues a 
ClinCard - a specially designed debit card onto which your compensation for research 
participation will be loaded.  When a visit is completed, funds will be approved and loaded onto 
your card.  The funds will be available within 1 business day and often times immediately after 
being loaded and can be used at your discretion.  You will be issued one card for the duration of 
your participation.  If your card is lost or stolen, please ask a study team member for a replacement 
ClinCard.  In some instances, your compensation may be in the form of a gift card, check, or other 
form of payment issued by Cedars-Sinai. 
 
In order to be able to issue you a ClinCard, we will need to share your name, address, social 
security number, and date of birth with Greenphire, Inc.  All information is stored in a secure 
fashion and is deleted from the ClinCard system once the study has been completed and the funds 
on the card have been exhausted.  Your information will not be shared with any third parties and 
will be kept completely confidential. 
 
You will have the option to receive updates related to appointment reminders and payment 
reminders and updates via text message and email message (Standard text messaging rates will 
apply).  You will have the opportunity to opt-in to receive these messages, however, you are not 
required to provide your cell phone or email address to be enrolled in the study or use a 
ClinCard.  If you choose to receive messages and decide at a later date that you want to stop these 
messages, you will have the ability to opt-out.  All information is stored in a secure fashion and is 
deleted from the ClinCard system once the study has been completed and the funds on the card 
have been exhausted.  Your information will not be shared with any third parties and will be kept 
completely confidential. 
 
Financial Interest in the Research 
The Principal Investigator and institution have no potential financial conflict of interest with 
respect to this study. 
 
10. 
WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
 
Please contact one of the investigators listed on the first page of this form for questions or 
concerns about the research.   
 
If you have questions, problems, or concerns that you want to discuss with someone who is not 
associated with this study, or want to offer suggestions or feedback, please contact: 
 


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Cedars-Sinai Human Research Protection Program (HRPP) Phone: (310) 423-3783 
Email: ResearchConcerns@cshs.org 
 
The Cedars-Sinai HRPP has been established to protect the rights and welfare of research 
participants.  You may also contact the Cedars-Sinai HRPP if you want to offer input or obtain 
information regarding the study. 
 
 


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11. 
CONSENT PROVISIONS  
 
If you sign this form below, it means that:   
 
(1) You have taken the time to carefully read and understand the information presented in this 
informed consent form; you should discuss it with others, and if appropriate seek a second 
opinion to make an informed decision; 
(2) The information concerning the research study and its involved procedures has been fully 
explained to you and your questions have been answered to your satisfaction;  
(3) You have received and understand all of the information you desire regarding your 
participation in the research study;  
(4) You have considered the potential risks, any anticipated benefits and alternatives (and their 
relative risks and benefits) of participation; 
(5) You are voluntarily agreeing to participate in this research study; 
(6) You understand that by consenting to participate in the research, you are not giving up any of 
your legal rights (other than the postponement of your access to certain health information as 
described in this informed consent form);  
(7) You understand that you have the right to be informed of significant new findings related to 
this research study which may affect your willingness to continue participating in this study; and 
(8) You have been provided with a copy of the “Experimental Subject’s Bill of Rights” and have 
been provided with an opportunity to ask questions regarding the Bill of Rights. 
 
We will give you a copy of this signed and dated consent form and a signed copy of the 
Experimental Subject’s Bill of Rights. 
 
 
SIGNATURE BY THE PARTICIPANT: 
 
 
 
 
 
 
 
 
Name of Participant (Print) 
Signature of Participant 
Date of Signature 
 
 
 
SIGNATURE BY THE INVESTIGATOR: 
I have personally explained the research to the participant in non-technical terms, answered all 
questions, and attest that he/she freely consents to participate.  The participant has been provided 
with the Experimental Subject’s Bill of Rights. 
 
 
 
 
 
 
Signature of the Investigator Who Obtained Consent 
 
Date of Signature 
 
 
 
 
 
SIGNATURE BY THE INTERPRETER/WITNESS: 


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(Signature of an interpreter is only required when a non-English speaking subject is consented 
with the assistance of an interpreter and an IRB-approved ‘short form.’  The witness may be any 
person who is conversant in both English and the language of the Non-English speaking subject, 
such as the interpreter (the certified hospital interpreter), study staff, a family member, or other 
person.  The witness signs the consent forms to confirm that the oral interpretation occurred.) 
 
 
 
 
 
 
Signature of Interpreter/Witness 
 
Date of Signature 
 
 
 


IRB No:  Pro00043120/ CR00013299 
Approval Date:  2/1/2018  
 
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EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
In accordance with California Health and Safety Code 24172, any person who is required to 
consent to participate as a subject in a research study involving a medical experiment or who is 
requested to consent on behalf of another has the right to: 
 
1. 
Be informed of the nature and purpose of the experiment. 
 
2. 
Be given an explanation of the procedures to be followed in the medical experiment, and 
any drug or device to be utilized. 
 
3. 
Be given a description of any attendant discomforts and risks to the subject reasonably to 
be expected from the experiment. 
 
4. 
Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable. 
 
5. 
Be given a disclosure of any appropriate alternative procedures, drugs or devices that 
might be advantageous to the subject, and their relative risks and benefits. 
 
6. 
Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise. 
 
7. 
Be given an opportunity to ask any questions concerning the experiment or the procedure 
involved. 
 
8. 
Be instructed that consent to participate in the medical experiment may be withdrawn at 
any time and the subject may discontinue participation in the medical experiment without 
prejudice. 
 
9. 
Be given a copy of any signed and dated written consent form used in relation to the 
experiment. 
 
10. Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue 
influence on the subject’s decision. 
 
 
 
 
 
 
 
Signature of Experimental Subject 
Date 
 


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Distribution instruction for researchers: 
 
The signed (i) Consent form, (ii) Authorization for Use and Disclosure of Identifiable Health 
Information and (iii) "Experimental Subject’s Bill of Rights" (the latter required if the research 
study involves medical interventions)* should be distributed to: 
 
1) Medical Chart 
2) Research Participant 
3) Pharmacy (if a drug study) 
4) Principal Investigator’s research records (original) 
 


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APPENDIX A:  FLOWCHART OF PROCEDURES – Medicare Coverage Analysis (MCA) Review 
Procedures 
Pre-
Study* 
Visit 1^1 
 (start the 
study drug) 
Visit 2* 
(1 month  
after starting 
study drug) 
Visit 3* 
(3 months  
after starting 
study drug) 
Visit 4^ 
 (6 months  
after starting  
study drug) 
Visit 5* 
(9 months  
after starting 
study drug) 
Visit 6^ 
 (12 months  
after starting  
study drug) 
Follow-Up Calls 
(for 3 months 
after last dose 
of study drug) 
Standard of Care Procedures: Items, drugs and services that are part of regular care and would be done even if you did not take part in this 
research study. These will be billed to you and/or your insurance company. 
Review Medical and Surgical History, 
Laboratory Results, and Medications 
X 
X 
X 
X 
X 
X 
X 
 
Demographics 
X 
X 
 
 
 
 
 
 
Physical Exam and Symptom 
Assessment 
X 
 
X 
X 
 
X 
 
 
Vital signs, measure weight 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
Hematology: CBC with Differential 
(CBDF) 
X 
 
X 
X 
 
X 
 
 
Chemistry: Comprehensive Metabolic 
Panel (CMPL)2  
X 
 
X 
X 
X 
X 
X 
 
2D Echocardiogram 
X 
 
 
X 
 
X 
 
 
Trastuzumab treatment, with or without 
anthracycline 
X 
Research Related Procedures: Items, drugs and services done for research purposes only. These will be covered by the sponsor of the study 
and will NOT be billed to your insurance company. 
Informed Consent and HIPAA form 
X 
 
 
 
 
 
 
 
Assess eligibility/review 
inclusion/exclusion criteria 
X 
X 
X 
X 
X 
X 
 
 
Registration and randomization to 
atorvastatin or placebo 
X 
 
 
 
 
 
 
 
Urine Pregnancy Test for women <60 
years old who have not had a period in 
the last 30 days3 
X 
X 
 
 
X 
 
X 
 
Blood Tests: Lipid Panel4 
X 
X 
 
 
X 
 
X 
 
Blood Test: Creatine phosphokinase 
(CPK)5 
 
X 
 
 
 
 
 
 


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Procedures 
Pre-
Study* 
Visit 1^1 
 (start the 
study drug) 
Visit 2* 
(1 month  
after starting 
study drug) 
Visit 3* 
(3 months  
after starting 
study drug) 
Visit 4^ 
 (6 months  
after starting  
study drug) 
Visit 5* 
(9 months  
after starting 
study drug) 
Visit 6^ 
 (12 months  
after starting  
study drug) 
Follow-Up Calls 
(for 3 months 
after last dose 
of study drug) 
Blood Collection for Research 
(optional) for future studies of blood 
biomarkers 
 
X 
 
 
X 
 
X 
 
Cardiac Magnetic Resonance Imaging 
(CMRI) to measure your heart function6 
 
X 
 
 
X 
 
X 
 
Blood Tests: hematocrit and creatinine7 
 
X 
 
 
X 
 
X 
 
Questionnaires: risk factors, quality of 
life 
 
X 
 
 
X 
 
X 
 
Dispense study drug and diary 
 
X 
X 
X 
X 
X 
 
 
Collect study drug and diary 
 
 
X 
X 
X 
X 
X 
 
Assess Adverse Events and 
Compliance: ask about side effects of 
the study drug and any missed doses 
 
 
X 
X 
X 
X 
X 
 
Telephone Calls8  
X 
Every 4 weeks (± 7 days) ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ Days 30, 60, 90 
(± 7 days) 
Take the study drug and complete a 
diary to record when you take the drug 
 
Daily ––⎯⎯–⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ 
 
 
* Pre-Study Evaluations and Visits 2, 3, and 5 are Standard of Care visits. All visits will have a window of ± 2 weeks.  
^ Visits 1, 4, and 6 are research visits to collect endpoint data and will coincide with Standard of Care visits whenever possible. All visits will have a 
window of ± 2 weeks. 
1 Visit 1 (baseline measurements) will occur from 2 weeks before the patient starts systemic breast cancer treatment (trastuzumab with or without 
anthracycline), up to 3 weeks after starting treatment. 
2 A Comprehensive Metabolic Panel (CMPL) will not be required at Visit 1 because one will be done at the Pre-Study Evaluations. If CMPL results 
within 30 days prior to Visit 4 or Visit 6 are available, the CMPL will not be done at that visit because lab values within the past 30 days are sufficient 
for monitoring. If lab results are not available, the CMPL will be repeated and will be billed to research/covered by the study. 
3 Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required to have a pregnancy test. CSMC Research 
Imaging Core policy requires a pregnancy test to be done on the day of the MRI, just prior to the scan. The Imaging Core will require a pregnancy test 
to be repeated at Visit 1 even though one was done at the Pre-Study Evaluations. The patient will not be billed for the pregnancy tests; they will be 
billed to research/covered by the study. 


IRB No:  Pro00043120/ CR00013299 
Approval Date:  2/1/2018  
 
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4 If Lipid Panel results within the past 12 months are not available, a Lipid Panel will be done to confirm eligibility prior to registration. The Lipid 
Panel will not be done at Visit 1 if a Lipid Panel is done at the Pre-Study Evaluations, or if Lipid Panel results within 30 days prior to the visit are 
available. 
5 If the participant reports unexplained muscle pain or weakness during the trial, CPK will be tested again to check for elevation. The CPK test will be 
billed to research/covered by the study. 
6 Women who have breast reconstruction surgery after enrollment/completion of the baseline visit that includes metallic breast expanders prohibiting 
MRI will not be required to do the CMRI while the breast expanders are in place. Participants with metallic breast expanders in place will not be 
required to do the Visit 4 (6-month) CMRI and the blood collection for CMRI, and may be scheduled for the Visit 6 (12-month) CMRI and blood 
collection for CMRI up to 3 months later (15 months) to allow for the final CMRI to be done. 
7 Less than 1 ml of blood will be drawn for measurement of hematocrit and creatinine levels used for CMRI calculations. 
8 Telephone contact with patients during the screening period to assess interest and answer questions. Telephone contact with patients every four weeks 
(± 7 days) during the intervention to assess compliance and adverse events. Participants who report having taken < 85% of the study drug doses 
between phone calls, or whose pill count at a study visit reveals < 85% compliance, will be called every two weeks (± 3 days) to monitor compliance 
until compliance resolves to at least 85%. Follow-up telephone contact on days 30 ± 7, 60 ± 7, and 90 ± 7 after completion of the statin intervention to 
assess adverse events. 
 
 
 


IRB No:  Pro00043120/ CR00013299 
Approval Date:  2/1/2018  
 
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Main ICF, Version Date: 12/04/2017 
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APPENDIX B:  Detailed Description of Common Medical Procedures Performed for Research Purposes and Associated Risks 
The procedures listed below are often performed as part of routine care for a person with your condition.  They are being repeated, or performed 
more frequently as part of this research.  However, the risks associated with each procedure should be comparable to what you would experience 
even if you were undergoing the procedure outside this research study. 
Study Procedure 
Related Risks 
Blood Draw: You will have your blood drawn at each research study 
visit. You will be asked to refrain from eating for 3 hours before each 
blood draw. A needle will be placed in the vein in your arm to draw 
blood. About 6 mL (1¼ teaspoons) of your blood will be collected 
during each visit. 
Blood drawing may cause some pain and has a small risk of bleeding, 
bruising, or infection at the puncture site. There is also a small risk of 
fainting. The blood will be drawn by a person trained to collect blood 
using sterile (clean) equipment, minimizing the risk of infection or injury. 
A very small needle will be used for drawing your blood to minimize 
discomfort. 
Urine Pregnancy Test: Women younger than 60 years of age who are 
able to become pregnant and have not had a menstrual period in the last 
30 days will be required to have a urine pregnancy test before the CMRI. 
If your pregnancy test is positive, you will be told and you should discuss 
available options with your primary physician. You will not be eligible for 
this research study. 
Cardiac Magnetic Resonance Imaging (CMRI): A MRI is a test that 
uses a magnetic field and pulses of radio wave energy to make pictures 
of organs and structures inside the body. A CMRI is a MRI that takes 
pictures of your heart. This is a non-invasive, non- radiation test of the 
blood flow to the heart muscle. During the procedure, you will lie down 
in a large donut-like looking magnet and we will ask you to lie still on a 
table for the duration of the procedure (about 75 minutes). You will be 
able to communicate with researchers all the time and you will have a 
panic button to use if you want to stop the procedure at any time. Fasting 
for 3 hours prior to the CMRI is recommended for optimal contrast 
enhancement. 
Before having a MRI, you should tell the radiology nurse or imaging 
technologist of any allergies you may have, and if you have any tattoos or 
wear permanent makeup. You should also tell them if you have an allergy 
to animal dander, as there is a risk of allergic reaction because the MRI 
scanner is also used with animals. You may experience some discomfort 
as you will be asked to remain relatively motionless for a long period of 
time. You may feel anxious inside the scanner due to confinement in a 
small enclosed space (claustrophobia). Also, at times, you may hear very 
loud noises as the CMRI machine is taking pictures of your body. You 
may be given headphones and may request ear plugs if you feel the noise 
is too loud.  At any time, you may ask the technician to stop the exam if 
you are unable to complete the exam.   
Intravenous (IV) lines: During the CMRI, you will receive a 
gadolinium-based contrast agent through an intravenous (IV) line. An IV 
line is a small tube that is attached to a catheter and inserted by needle 
into a vein usually in your hand or arm. Qualified medical professionals 
will place IV lines for use in this study. 
IV lines are usually safe and well tolerated and complications are rare, but 
can include phlebitis (swelling of the vein) and infection. The IV may 
come out accidentally or blood may leak around the line. If the IV is not in 
the vein, medication or fluid can enter the surrounding soft tissues, and 
can be associated with swelling, discomfort, bruising, and irritation.  
Rarely, a clot can develop in the IV line itself. If this happens, the staff 
may remove the old IV line and start a new IV line. There is also a small 
risk of feeling lightheaded and fainting. 


IRB No:  Pro00043120/ CR00013299 
Approval Date:  2/1/2018  
 
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Main ICF, Version Date: 12/04/2017 
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Study Procedure 
Related Risks 
Questionnaire: An interviewer will ask you questions to evaluate what 
factors may contribute to an individual’s risk of disease. We think it will 
take about 30 minutes to finish the questionnaire at the first visit. The 
questionnaire for the other two visits is shorter, and should take about 15 
minutes to complete. You will be asked to respond to questions about 
your reproductive history including pregnancies, disease risk factors, 
alcohol use, tobacco smoking, physical activity, other health and lifestyle 
habits, sexual activity, and quality of life. 
If you feel uncomfortable or embarrassed answering any question, you 
may choose not to answer it. The questionnaire will be labeled with a 
unique study number that will link your identity so that only the research 
team can recognize you.