STOP-CA (Statins TO Prevent the Cardiotoxicity From Anthracyclines)
Phase: PHASE2
Conditions: Heart Failure
Sponsor: Massachusetts General Hospital

 
 
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NCI Protocol #: N/A  
 
DF/HCC Protocol #: 16-440 
 
TITLE:  STOP-CA (Statins TO Prevent the Cardiotoxicity from Anthracyclines) 
 
Coordinating Center: MGH  
 
 
 
*Principal Investigator (PI):  
Tomas G Neilan, MD, MPH, MGH tneilan@mgh.harvard.edu  
 
Other Investigators:  
Marielle Scherrer-Crosbie, MD, PHD, MGH, marielle@crosbie.com 
Jeremy Abramson, MD, MGH jabramson@partners.org 
Eric Jacobsen, MD, DFCI, edjacobsen@partners.org 
Omar Nadeem, MD, onadeen@partners.org 
Aarti Asnani, MD, BIDMC aasnani@bidmc.harvard.edu 
 
Statistician: 
Donna Neuberg, ScD, DFCI, neuberg@jimmy.harvard.edu 
 
Study Coordinator: NA 
 
Responsible Research Nurse: NA 
 
Responsible Data Manager: NA 
 
NCI-Supplied Agent: NA 
 
IND: NA 
 
IND Sponsor:  NA 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
Protocol Type / Version # / Version Date: 
Original/version#1/8/18/2016 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1.0 OBJECTIVES ............................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
2.0 BACKGROUND .......................................................................................................................6 
2.2. Other Agent(s) ............................................................................................................11 
2.3 Rationale ......................................................................................................................11 
3.0 PARTICIPANT SELECTION .................................................................................................11 
4. 
REGISTRATION PROCEDURES ...................................................................................12 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................12 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................13 
5. 
TREATMENT AND/OR IMAGING PLAN .....................................................................14 
5.1 
Treatment Regimen ................................................................................................14 
5.2 
Pre-Treatment Criteria ...........................................................................................14 
5.3 
Agent Administration.............................................................................................14 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................14 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................15 
5.6 
Duration of Follow Up ...........................................................................................15 
5.7 
Criteria for Taking a Participant Off Study ...........................................................15 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................16 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................16 
7.2 
For non-CTEP protocols only: Expected Toxicities ..............................................17 
7.3 
For non-CTEP protocols only: Adverse Event Characteristics .............................17 
7.4 
For non-CTEP protocols only: Expedited Adverse Event Reporting ....................17 
7.5 
Expedited Reporting to Hospital Risk Management .............................................19 
7.6 
For non-CTEP protocols only: Routine Adverse Event Reporting .......................19 
8. 
PHARMACEUTICAL and/or IMAGING AGENT INFORMATION .............................19 
8.1 
IND Agent #1: Atorvastatin ...................................................................................19 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................21 
9.1 
Biomarker Studies ..................................................................................................21 
9.2 
Laboratory Correlative Studies ..............................................................................21 
Blood will be processed within 30 minutes, frozen and stored at -80oC. ......................................22 
10. 
STUDY CALENDAR .......................................................................................................22 

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11. 
MEASUREMENT OF EFFECT........................................................................................23 
11.1 
Other Response Parameters ...................................................................................23 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................23 
12.1 
Data Reporting .......................................................................................................23 
12.2 
Data Safety Monitoring..........................................................................................24 
13. 
STATISTICAL CONSIDERATIONS...............................................................................24 
13.1 
Study Design/Endpoints.........................................................................................24 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................27 
13.3 
Interim Monitoring Plan ........................................................................................28 
13.4 
Analysis of Primary Endpoints ..............................................................................28 
13.5 
Analysis of Secondary Endpoints ..........................................................................28 
13.6 
Reporting and Exclusions ......................................................................................28 
14. 
PUBLICATION PLAN .....................................................................................................29 
 
 
 

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1.0 OBJECTIVES 
 
The purpose of this protocol is to test the effect of statin therapy, as compared to placebo, on the 
cardiac dysfunction after administration of anthracyclines among patients with lymphoma.  
 
Anthracyclines are a mainstay of cancer treatment with more than 100,000 patients treated per 
year with anthracyclines in the United States; however, their use is associated with increased 
rates of heart failure and left ventricular (LV) dysfunction. Once anthracycline-induced 
cardiotoxicity (AIC) is symptomatic, survival is dramatically decreased. There is significant 
scientific plausibility and supportive observational data that statins may protect the heart during 
the administration of anthracyclines. STOP-CA (Statins TO Prevent the Cardiotoxicity from 
Anthracyclines) is a multi-center randomized double-blind placebo controlled trial, in 270 statin-
naive patients who will be randomized 1:1 to atorvastatin 40mg/daily or placebo to determine 
whether atorvastatin started prior to anthracyclines reduces anthracycline-induced cardiotoxicity 
(AIC) among patients with newly diagnosed lymphoma. The endpoint AIC is defined based on 
expert consensus as a ≥10% reduction in LVEF to <55% within the first 12 months after 
therapy.1-3 LVEF will be measured using the gold-standard, cardiac magnetic resonance (CMR), 
performed in an established core clinical trials laboratory by expert readers. Participants will be 
recruited over 3 years from large volume academic oncology networks. Myocardial fibrosis is a 
key intermediary that occurs prior to the development of LV dysfunction. CMR is the gold-
standard imaging technique for fibrosis;4, 5 therefore, to test whether the sub-acute development 
of myocardial fibrosis can predict the late occurrence of AIC and whether statins reduce 
myocardial fibrosis, we also propose measuring the extent of fibrosis at baseline and 6 months. 
We hypothesize that statins will attenuate myocardial fibrosis and that the extent of early fibrosis 
will predict the decrease in LVEF at 12 months. Both echocardiography and serum troponin are 
more widely available than CMR; therefore, in a third aim, we will test whether strain by 
echocardiography and troponin levels measured early during chemotherapy (after 4 of 8 standard 
cycles, ≈ 3 months), can identify patients at high risk of AIC.   
 
If successful, this study will show that statins started prior to anthracyclines preserve LVEF, that 
statins prevent anthracycline-induced myocardial fibrosis and that the early measurement of 
myocardial strain or troponin during anthracyclines can identify patients at high risk of a 
subsequent LVEF decrease.  
 
1.1 Study Design 
This is randomized double blind placebo controlled clinical trial.  
They will be treated with atorvastatin or placebo for 12 months.  
The endpoint will be left ventricular ejection fraction (LVEF) by cardiac MRI measured at 12 
months 
 
1.2 Primary Objectives 
To determine whether atorvastatin results in a significant reduction in the incidence of AIC 
among patients with lymphoma over 12 months; AIC is defined as a reduction of ≥10 percentage 
points in LVEF to <55%.  
 
1.3  Secondary Objectives 

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Number 1: To compare the effect of statins, vs. placebo, on the development of myocardial 
fibrosis after anthracyclines. In a sub-study of 80 patients from Aim 1 (n=40 in each arm), we 
will measure myocardial fibrosis by calculation of the myocardial extracellular volume (ECV) 
using CMR, as previously described,6-8 at baseline and 6 months to determine: 
a. 
Whether statins prevent the anthracycline-induced increase in myocardial fibrosis at 6 
months.  
b. 
Whether a change in fibrosis or LVEF at 6 months predicts the occurrence of AIC at 12 
months.  
 
Number 2: We will determine whether an early decrease in myocardial strain or an increase in 
high-sensitivity troponin during anthracyclines (after 4 of 8 standard cycles (≈ 3 months)) can 
predict subsequent development of AIC at 12 months. We will test:  
a. 
Whether statins, as compared to placebo, prevent the reduction in strain or the increase in 
troponin throughout the study period (12 months).  
b. 
Whether a change in troponin, strain, or both at 3 months predicts AIC at 12 months. 
c. 
Whether a change in troponin, strain or both at 3 months predicts fibrosis detected by ECV 
at 6 months.  
 
2.0 BACKGROUND 
 
2.1 Study Disease 
 
There are 13.7 million cancer survivors in the United States, and it is estimated that over 2 
million are at risk for cancer treatment-induced cardiotoxicity (National Cancer Institute NIOH 
et al., n.d.). The number of patients at risk may further increase with the lengthening of survival, 
aging of patients, and multiplication of novel additional treatments. Of these patients, a large 
proportion is at risk of developing anthracycline-induced cardiotoxicity (AIC).  
 
The primary aim of STOP-CA (Statins TO Prevent the Cardiotoxicity from Anthracyclines) is to 
test in a multi-center randomized double-blind placebo controlled trial whether statins attenuate 
the anthracycline-induced reduction in left ventricular ejection fraction (LVEF) in patients with 
lymphoma. If successful, this study will show that statins started prior to anthracyclines preserve 
LVEF, that statins prevent anthracycline-induced myocardial fibrosis and that the early 
measurement of myocardial strain or high-sensitivity troponin during anthracyclines can identify 
patients at high risk of a subsequent LVEF decrease.  
 

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A.1. Anthracycline-induced cardiotoxicity is a 
major adverse factor in the long-term outcomes 
of cancer survivors: Survival after a cancer 
diagnosis has dramatically improved.9 
Anthracyclines are a key component of standard 
chemotherapy regimens among patients with 
breast cancer, leukemia, lymphoma and 
sarcoma. Congestive heart failure (CHF), driven 
primarily by the use of anthracyclines, is now a 
leading cause of death and disability among 
cancer survivors 10, 11 and the National Cancer 
Institute’s estimates that over 2 million cancer 
survivors are at risk of CHF from anthracyclines.9, 12 The rates of cardiotoxicity and CHF 
described among patients treated with anthracyclines vary depending on the definition used, 
length of follow-up and the population at risk. However, data suggest that between 15% and 45% 
of patients will have a significant decline in LVEF of ≥10% 13-15 and that at 5 years up to 20% 
develop symptomatic heart failure (Figure 1).16 Once established, anthracycline-induced 
symptomatic heart failure has a predicted two-year survival of 40%.17 Therefore, survival is 
improving among cancer patients; however, CHF after anthracyclines is a major cause of 
long-term morbidity and mortality among cancer survivors.   
 
A.2. Why Lymphoma? We propose to study patients with lymphoma for the following reasons: 
1. Lymphoma is a frequent malignancy with over 80,000 patients diagnosed each year in the 
USA.9    
2. Survival is improving among patients with lymphoma and the overall survival of patients is 
high (over 70% at 5 years),9 emphasizing the importance of preventing co-morbidities associated 
with cancer treatment.  
3. The use of anthracyclines among patients with breast cancer has declined over the last decade 
from 80% to 30%;18 In contrast, anthracyclines remain a standard therapy in >80% of lymphoma 
patients.9  
4. Studies have consistently shown that over 20% of patients with lymphoma treated with 
anthracyclines will have a significant decrease in LVEF of ≥10% to less than 55% within 12 
months.13-15 
5. In preliminary data (see preliminary data section), the rate of heart failure and death among 
1644 patients with lymphoma treated with anthracyclines was almost 6 times that of breast 
cancer patients and 2 times that of patients with other cancers similarly treated with 
anthracyclines. 
 
Anthracycline-based chemotherapy is the standard treatment for lymphoma, the most 
frequent hematological malignancy in the United States. Patients with lymphoma are at 
higher risk of heart failure as compared to other patients treated with anthracyclines.  
 

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A.3. Potential approaches to prevent anthracycline-induced cardiotoxicity: Current approaches 
to preventing the progression from 
AIC to symptomatic heart failure 
include instituting a cardioprotective 
regimen once a decrease in LVEF is 
detected. However, Cardinale et al. 
demonstrated that such an approach is 
ineffective as almost 40% of patients 
did not recover their LVEF despite 
immediate intervention.19 An 
alternative approach is to start 
medications prior to administration of anthracyclines to prevent or limit the occurrence of AIC; 
this has been the focus of several clinical studies that have reported either a small or no effect on 
LVEF and low tolerated treatment doses (Table 1).14, 19-22 Dexrazoxane, an iron chelator, has also 
been shown in studies to reduce cardiotoxicity.23 However, small studies reported an increase in 
the incidence of second primary malignancies in dexrazoxane-treated patients; therefore the FDA 
has advised that its use be limited.24-26 Thus, current therapies that have been tested to 
prevent progression of AIC or to prevent or reduce AIC, using medications such as ACE 
inhibitors, beta-blockers, or dexrazoxane have either a small or no effect or have toxicity 
concerns.  
 
A.4. There is significant plausibility supporting the potential role of statins, specifically 
atorvastatin 40 mg, to prevent or reduce anthracycline-induced cardiotoxicity: The only 
available prospective data stem from a randomized trial of 40 patients testing whether statins 
prevent the anthracycline-induced reduction in LVEF;27 the authors randomized 20 patients  to 
pre-treatment with atorvastatin 40 mg and 20 patients to placebo and found a significant 
difference of 9% in LVEF between experimental groups over 6 months. Larger populations have 
been studied retrospectively, with the results suggesting that statins reduce heart failure 
admissions and the rate of clinical heart failure (6 vs. 18%) among patients treated with 
anthracyclines.28, 29 Furthermore, experimental data support a protective role for statins for 
prevention of AIC and preservation of LVEF.30-32 In mice treated with anthracyclines, statins 
reduced oxidative stress, myocardial cell death and preserved cardiac function.30-32 A key 
advantage of statin therapy is an acceptable risk-to-benefit ratio, their use is not limited by the 
adverse hemodynamic changes associated with ACE inhibition or beta-blockade and there is no 
concern for an increased risk of secondary malignancies.33 There is significant biological 
plausibility and supportive preliminary clinical data to hypothesize a positive effect of 
statins on the anthracycline-induced reduction in LVEF. The only randomized study on the 
effects of statins on the cardiac function of patients treated with anthracyclines included 11 
patients with lymphoma. Therefore, additional work is required to provide support for a 
large multi-center RCT powered to clinical end-points.  
 
A.5. LVEF is a robust surrogate for adverse cardiac events and the primary end-point chosen for 
STOP-CA, an reduction in LVEF of ≥10% to <55%, occurs frequently among lymphoma patients 
and predicts the subsequent development of clinical heart failure in patients receiving 
anthracyclines: Left ventricular ejection fraction is a robust surrogate for adverse cardiovascular 
outcomes including heart failure and cardiovascular death among broad groups of patients.34-36 

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The American College of Cardiology/American Heart Association heart failure guidelines 
identify 4 stages of heart failure. Stage B CHF is defined as an asymptomatic reduction of 
cardiac function below the normal range (e.g., LVEF <55% by CMR) and is associated with an 
increased risk of progression to heart failure.37, 38 We will use the definition for a significant 
change in LVEF after anthracyclines as recommended by both Oncology and Cardiology 
statements, a reduction in LVEF of ≥10% to <55%.1-3 Among patients treated with 
anthracyclines, consistent data have shown that at least 20% of patients with lymphoma will 
develop a ≥10% reduction in LVEF to <55% at 1 year.13-15 Additionally, data have shown that a 
reduction in LVEF of ≥10% to <55% has marked clinical prognostic significance. Specifically, 
in a study of 1487 subjects who received anthracyclines, there was a 16% rate for the subsequent 
development of clinical heart failure among those who had a ≥10% fall in LVEF as compared to 
a 0% rate among those who did not.39 Therefore, LVEF is a robust surrogate for the risk for 
clinical heart failure and cardiovascular death and a decrease in LVEF of ≥10% to <55% is 
frequent, is a recognized definition of anthracycline-induced cardiotoxicity and predicts the 
development of heart failure.   
 
A.6. LVEF by CMR is the gold-standard: Measurement of the LVEF using cardiac magnetic 
resonance (CMR) is the gold standard technique to reliably and reproducibly quantify the LVEF 
with less than a 3% temporal variability.40, 41 The variability of LVEF, a combination of the 
biological and technical variability, is a major factor in the ability of a technique to perform 
serial monitoring during chemotherapy or to act as a robust end-point in clinical trials. 
Therefore, we will measure LVEF using CMR as the primary modality as it is the gold-
standard method.    
 
A.7. Anthracyclines induce myocardial fibrosis that is detectable using novel CMR sequences 
and statins may prevent AIC by a reduction in 
myocardial fibrosis: Pathological studies in 
animal and humans have consistently shown 
that anthracyclines induce myocardial fibrosis 
42-44 and myocardial fibrosis is a key 
intermediate step between injury and the 
development of heart failure.45 Magnetic 
resonance imaging is the gold-standard non-
invasive technique for the detection of 
myocardial fibrosis.5 However, we found that 
late gadolinium enhancement (LGE), the 
current clinical standard CMR sequence for 
detection of fibrosis, was present in only 6% of patients treated with anthracyclines (Figure 2);46 
LGE-based methods need a normal reference myocardium to identify abnormal; with 
anthracyclines, the fibrosis is diffuse and thus, is underestimated.8 Therefore, we, and others, 
have developed a CMR technique using the relative distribution of gadolinium to obtain a 
quantitative measure of the extracellular volume (ECV).6-8, 47, 48 The ECV has been validated as a 
robust measure of myocardial fibrosis in both mice and humans.7, 49 In a retrospective clinical 
study, we found that the ECV was markedly elevated in patients with prior anthracycline 
treatment (Figure 2) and found that the greater the increase in the ECV, the more extensive the 
degree of cardiac dysfunction.8 Additionally, in preliminary findings in mice, we show using 

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CMR that anthracyclines induce myocardial fibrosis and that the extent of myocardial fibrosis is 
associated with survival (see preliminary data). Therefore, we propose in a sub-study to test 
whether anthracyclines induce myocardial fibrosis in humans and whether myocardial fibrosis 
predicts later AIC. In mice, statins prevent the anthracycline-induced cardiac dysfunction 
possibly via prevention of myocardial fibrosis.31 Therefore, we hypothesize that statins may 
reduce myocardial fibrosis in humans. Therefore, we will test whether ECV by CMR 
identifies patients at high risk of AIC and whether statins reduce myocardial fibrosis in 
humans.   
 
A.8. Improving on current clinical and widely applicable methods for detection of AIC: The 
serial measurement of LVEF is the current gold-standard technique for detection of AIC. 
However, even in expert hands, data show that LVEF 
may underestimate the presence and extent of 
cardiomyocyte damage.50 Furthermore, intervention 
once the LVEF is decreased fails to reverse the LV 
dysfunction in over 40% of patients.19 Therefore, 
research has focused on more sensitive and earlier 
detection of AIC.51, 52 Troponin is a marker of 
myocardial injury that is increased after 
anthracyclines.23, 51, 53 Similarly, among patients 
receiving anthracyclines, peak myocardial systolic 
strain, a sensitive echocardiographic marker of systolic function (Figure 3) decreases prior to a 
change in LVEF and predicts the late reduction in LVEF. In prior work we found that, in patients 
with breast cancer treated with anthracyclines, taxanes, and trastuzumab, an increase in high-
sensitivity troponin to >99th percentile upper normal reference limit and a ≥10% reduction in 
myocardial strain, both measured after the cessation of anthracyclines, were predictive of a 
subsequent decrease in LVEF.53, 54 Indeed the combination of troponin and strain after the 
cessation of anthracyclines had a sensitivity of 87% and a negative predictive value of 91% for 
the detection of subsequent AIC.53 However, no such serial data exists among patients with 
lymphoma and there are no data testing the predictive value of strain and troponin measured 
during anthracyclines. The standardization and widespread application of strain are major goals 
of the American Society of Echocardiography (ASE) and have led to the development of novel 
algorithms and measurements methods that we will test.55, 56 These new techniques are easy to 
implement and common to all echocardiography machines and softwares.56 Therefore, strain 
and high-sensitivity troponin detect AIC early. Both measures are available and widely 
scalable. We found that a reduction in myocardial strain and an increase in troponin after 
cessation of anthracyclines predicted the late reduction in LVEF. Therefore, we propose to 
test whether measurement of troponin and strain earlier during anthracyclines can predict 
AIC.  
 
b. Previous studies supporting the proposed research 
 
Evidence to support the primary hypothesis that statins will prevent the anthracycline-induced 
reduction in LVEF: We prospectively recruited 72 patients with breast cancer undergoing 
anthracycline-based chemotherapy and measured LVEF prior to and after 12 months.53 In total, 8 
patients (11%) were treated with statins prior to the initiation of chemotherapy. There was no 

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difference in the baseline LVEF between patients who were or were not on statins prior to 
chemotherapy (64±5% in both groups). After anthracyclines, there was no decrease in LVEF in 
the statin group (64±9%); in comparison there was a decrease of 5% in the LVEF in the placebo 
groups (59±6%, p=0.06). This trend persisted even after adjustment for traditional cardiovascular 
risk factors and for treatment by ACE inhibitors and beta-blockers (p=0.08). Similarly, in a 
retrospective study, , Chotenimitkhun et al. tested the effect of incidental statin therapy on the 
reduction in LVEF after anthracyclines among 52 patients.29 They found that the LVEF after 
anthracyclines was unchanged in the statin group but the LVEF was 7% lower in the placebo-
treated group.29 In the only randomized clinical trial testing the effect of statins on LVEF, Acar 
et al. found that the LVEF was unchanged among the 20 patients in the statin-treated group and 
was decreased by 9% among the 20 patients on placebo.27 Therefore, preliminary data 
support the hypothesis that there is no decrease in LVEF after anthracyclines among 
patients on statins.     
 
The rate of death or heart failure admission after treatment with anthracyclines is higher among 
patients with lymphoma than in other patients treated with anthracyclines: Overall, 1644 
consecutive MGH patients with lymphoma treated with anthracyclines were followed for a 
median of 3 years. In that period, 67 (4%) developed symptomatic heart failure or cardiac death. 
In comparison, the other major population that is treated with anthacyclines are patients with 
breast cancer. In a similar follow-up period of 3 years, 5 (0.7%) of 711 patients with breast 
cancer developed symptomatic heart failure or cardiac death (P<0.0001 vs. lymphomas).  
 
Therefore, patients with lymphomas have a higher rate of cardiac death or heart failure 
from anthracyclines than other similarly-treated cancer populations.  
 
Summary of the preliminary results: The preliminary data suggests the following;  
1. In two retrospective series and one small randomized study, statins prevented any 
anthracycline-associated reduction in LVEF.    
2. Patients with lymphoma treated with anthracyclines develop more major cardiac events 
than similarly-treated patients with other cancers. 
 
2.2. Other Agent(s) 
 
The overall rate of statin-related side effects is anticipated to be low. In statin clinical trials, the 
reported rate of myopathy and hepatotoxicity is ≈ 0.5%. Statin therapy has not been shown to 
adversely affect cancer-related outcomes, and indeed in large epidemiological studies statins 
have been reported to decrease recurrence rates of cancers. 
 
2.3 Rationale 
 
The background has been provided in 2.1 
 
3.0 PARTICIPANT SELECTION 
 
3.1 Inclusion Criteria: 
• ≥18 years of age 

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• All patients with newly diagnosed lymphoma 
• Scheduled to receive anthracycline-based chemotherapy therapy  
 
3.2 Exclusion Criteria: 
• Statin use or Statin use is indicated based on guidelines 
• Pregnancy or breastfeeding 
• Unable to provide informed consent 
• Unexplained persistent elevation of transaminases (>3 times upper limits of normal) 
• Concomitant use of oral cyclosporine 
• Contraindication to a CMR (metallic object, severe claustrophobia, pacemaker, vascular 
clip 
 
3.3 Inclusion of Women and Minorities 
 
Approximately 45% of new cases of lymphoma are women. Therefore, we anticipate that the 
final study population will be relatively evenly divided between men and women. Women with 
child-bearing potential may potentially also be recruited, however, it is unlikely that a pregnant 
woman will be undergoing anthracycline-based chemotherapy but for completeness a urine 
pregnancy test will be administered and in the unlikely case of a pregnancy, the patient will be 
excluded. Gadolinium chelates, while widely used and generally safe as intravenous cardiac 
magnetic resonance contrast agents, may dissociate in amniotic fluid and are considered “Class 
3” drugs; they should only be used when the anticipated benefit outweighs the potential risk and 
are generally avoided in pregnancy. Statins are Category D drugs which includes those" which 
have caused, are suspected to have caused or may be expected to cause, an increased incidence 
of human fetal malformations or irreversible damage" and may also have adverse 
pharmacological effects. We will therefore exclude pregnant women. 
 
Subjects will be recruited without regard for racial, social, economic, or other status. There is no 
evidence that race or ethnicity influences the prevalence of anthracycline-induced cardiac 
dysfunction. The population of the greater Boston area is 80% Caucasian, 6% Black, 8% 
Hispanic, 4% Asian and 2% other. In general, subject recruitment should occur in proportion to 
the ethnic balance of the referral community. However, because we recognize that minorities are 
relatively under-represented in clinical studies, we will make an active effort to include 
minorities. We will support this effort by making all IRB-approved advertisements and study 
materials available in Spanish, Portuguese, French/Creole and Mandarin.  
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Office of Data Quality (ODQ) 
central registration system. Registrations must occur prior to the initiation of protocol therapy. 
Any participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied. 

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An investigator will confirm eligibility criteria and a member of the study team will complete the 
ODQ protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Notify the ODQ Registrar of registration cancellations as soon as 
possible.  
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The ODQ registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. The registration procedures are as follows: 
 
• Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments.  
• Complete the ODQ protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical record and/or research chart. To be eligible for 
registration to the protocol, the participant must meet all inclusion and exclusion 
criterion as described in the protocol and reflected on the eligibility checklist. 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies.  
• Fax the eligibility checklist(s) and all pages of the consent form(s) to the ODQ at 617-
632-2295. For Phase I protocols, attach participant dose level assignment confirmation 
from the sponsor. 
• The ODQ Registrar will (a) review the eligibility checklist, (b) register the participant on 
the protocol, and (c) randomize the participant when applicable. 
• An email confirmation of the registration and/or randomization will be sent to the site’s 
oncology clinical trials pharmacy. 
 
4.3 
External Site Registration process 
 
• The external site obtains informed consent and screens the participant for 
eligibility.  
• An appropriately delegated and qualified individual at the external site 
signs off as screening staff on the eligibility checklist.  
• The external site sends the completed eligibility checklist and signed 
informed consent document to the DF/HCC coordinating center.  
• When required per REGIST-104, an enrollment monitor at the coordinating 
center must verify participant eligibility and sign the eligibility checklist.  

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• The DF/HCC coordinating center is responsible for registering the subject 
in OnCore (de-centralized), or sending the registration packet to ODQ 
(centralized).  
• The DF/HCC coordinating center will forward registration confirmation to 
the external site.  
• The external site must notify the coordinating center of subject status 
changes (off treatment, off study).  
• The DF/HCC coordinating center is responsible for updating the subject 
status in OnCore (de-centralized), or notifying ODQ (centralized). 
 
 
 
5. TREATMENT AND/OR IMAGING PLAN 
 
5.1 
Treatment Regimen 
 
Atorvastatin (or placebo) will be at a dose of 40 mg once a day. If the participant develops 
muscle pain, myalgia, then the study drug dose can be reduced to 20 mg once a day or placebo. 
 
Atorvastatin (or placebo) will be taken nightly. Treatment will be administered on an outpatient 
basis. Reported adverse events and potential risks are described in Section 7.   
 
5.2 
Pre-Treatment Criteria 
 
If required (no recent measurement of < 1 month), measurement of CBC, potassium, renal 
function and liver function will be obtained.  Lab values will be used from oncology providers if 
needed. 
 
5.3 
Lab Values 
 
Lab values for follow up visits will be taken from subjects oncology team throughout study 
calendar until patient is off study. 
 
5.4 
Agent Administration 
 
The drug is taken by mouth, once a day (evening) for the entire study. The study medication 
should be swallowed. The drugs can be taken with food and with any other medications. Any 
unused study drug will be brought back for the next study visit. The medications can be stored at 
room temperature for the duration of the study. If the medication is vomited, it can be taken 
again within the same day.  
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Atorvastatin is widely used in clinical care and is not an investigational agent.  

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Patients will be followed throughout the study by a nurse practitioner under the supervision of a 
cardiologist.  
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will be of 12 months. In the absence of treatment delays due to adverse 
event(s), treatment may continue for 12 months or until one of the following criteria applies: 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
A ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff. 
 
Emergency unblinding will occur in case of unacceptable adverse event that may be caused by 
atorvastatin, i.e. severe allergic reaction or rhabdomyolyis.  
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Tomas G Neilan at 617 7269292 (page) or 617 6864322 (cell phone).  
 
5.7 
Duration of Follow Up 
 
This study lasts for 12 months after start of the treatment. Participants removed from protocol 
therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the 
adverse event. 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 

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A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Treatment will be temporarily suspended if the liver function tests elevate by more than 3 times 
normal. If it is determined that the elevation in liver function tests are due to another cause, the 
treatment will be reinstated provided the liver function tests return to normal. The patients with 
side effects will not be excluded from the protocol. If the participant develops muscle pain, 
myalgia, then the study drug dose can be reduced to 20 mg once a day or placebo. If the 
symptoms do not respond to this within 1 week then the study drug is stopped. This is what 
happens in clinical practice.    
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1.1 Adverse Event List(s) for Commercial Agent(s) 
 
Atorvastatin: Subjects will be randomized to either placebo or atorvastatin as part of the 
proposed protocol.  
 
Risk of statin therapy: Subjects will be randomized to either placebo or atorvastatin as part of the 
proposed protocol. The reported risks of atorvastatin therapy include statin myopathy, 
rhabdomyolyis, renal failure as a result of rhabdomyolysis, and hepatotoxicity. 
Muscle toxicity: In statin clinical trials, the reported incidence of myopathy is low (0.1%) and 
data from a large meta-analysis (with 246,955 patients) of patients taking statins has been 
reported the incidence of myopathy to be similar to control. In another compilation of 
randomized controlled statin trials revealed that among 83,858 patients randomly assigned to 
receive either statin treatment or placebo, there were 49 cases of myositis and 7 cases of 
rhabdomyolyis in the statin groups, compared with 44 cases of myositis and 5 cases of 
rhabdomyolyis in the placebo groups. The risk of skeletal muscle effects such as myopathy and 
rhabdomyolyis increase in a dose-dependent manner with advanced age (≥65) and renal 
impairment. However, patients with renal failure will be excluded due to the administration of 
CMR contrast. 
 
Hepatotoxicity: Based on guidelines, a modest elevation in transaminases to less than 3 times the 
upper limits of normal will not be considered a contra-indication to inclusion in the study. The 
incidence of elevated liver biochemical tests is increased to 1% of patients on statins. The 
majority of liver abnormalities occur within the first 3 months of therapy. Fulminant hepatic 
failure from statin therapy, without the presence of rhabdomyolyis and renal failure, is rare. 
 

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7.2 
For non-CTEP protocols only: Expected Toxicities 
 
7.2.1 Adverse Events List(s)  
 
Reported in 7.1.1 
 
7.3 
For non-CTEP protocols only: Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
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. 
 
7.4 
For non-CTEP protocols only: Expedited Adverse Event Reporting  
 
7.4.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
7.4.2 The following text is required for DF/HCC-led multi-institutional studies only and must 
be deleted for studies performed solely at DF/HCC and/or DF/PCC institutions.  
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, unexpected 
grade 4 toxicities, and grade 5 (death) regardless of study phase or attribution. 
 
7.4.3 DF/HCC Expedited Reporting Guidelines 
 

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Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
The following text and table apply to DF/HCC-led multi-institutional studies only and 
must be deleted for studies performed solely at DF/HCC and/or DF/PCC institutions. 
 
Other investigative sites will report SAEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.   
 
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 
AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar 
days 
 
5 calendar 
days# 
 
5 calendar 
days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 24 business hours of learning 
of the event. 
 
 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 
CTCAE 
SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.5 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.6 
For non-CTEP protocols only: Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8. PHARMACEUTICAL AND/OR IMAGING AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1 
IND Agent #1: Atorvastatin 
 
8.1.1 Description 
 
Atorvastatin is a member of the drug class known as statins, which are used primarily as a lipid-
lowering agent and for prevention of events associated with cardiovascular disease. Like all 
statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue 
that plays a key role in production of cholesterol in the body. 
 
Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to 
maximum plasma concentration (Tmax) of 1–2 h. The absolute bioavailability of the drug is 
about 14%, but the systemic availability for HMG-CoA reductase activity is approximately 30%. 
Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main 
cause for the low systemic availability. Administration of atorvastatin with food produces a 25% 
reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption), 
although food does not affect the plasma LDL-C-lowering efficacy of atorvastatin. Evening dose 
administration is known to reduce the Cmax and AUC by 30% each. However, time of 
administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin. 
 
It is highly protein bound (≥98%), and studies have shown it is likely secreted into human breast 
milk. 
 
Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to form 
active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. As 
a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of 
CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction 
was tested in vitro with concurrent administration of erythromycin, a known CYP3A4 isozyme 

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inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor 
of cytochrome 3A4. 
 
Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovered in 
the urine. Bile elimination follows hepatic and/or extrahepatic metabolism. There does not 
appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-
life of 14 h. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life 
of 20–30 h, which is thought to be due to the active metabolites. Atorvastatin is also a substrate 
of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal 
lumen during drug absorption. 
 
Specific populations: 
 
Geriatric: Plasma concentrations of atorvastatin in healthy elderly subjects are higher than those 
in young adults, and clinical data suggests a greater degree of LDL-lowering at any dose for 
patients in the population as compared to young adults. 
 
Gender: Plasma concentrations are generally higher in women than in men, but there is no dose 
adjustment suggested.  
 
Renal impairment: Renal disease has no influence on plasma concentrations of atorvastatin and 
dosing need not be adjusted in these patients. 
 
Hemodialysis: Hemodialysis will not significantly alter drug levels or change clinical effect of 
atorvastatin. 
 
Hepatic impairment: In patients with chronic alcoholic liver disease, levels of atorvastatin may 
be significantly increased depending upon the extent of liver disease. 
 
8.1.2 Form 
 
Atorvastatin will be given as 40 mg capsules (or 20 mg capsules if myalgias) supplied by 
the MGH and BWH pharmacy or the external sites pharmacy. 
 
8.1.3 Storage and Stability 
 
The capsules can be kept at room temperature throughout the study. 
 
8.1.4 Availability 
 
Study staff will provide pharmacy with a fund number to purchase and blind study drug. 
The compounding pharmacy will blind active drug and provide a matching placebo and 
the clinical trials pharmacy will dispense the blinded study drug to subjects free of 
charge. 
8.1.5 Preparation 
 

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The dose will be a capsules prepared by the pharmacy.  
 
8.1.6 Administration 
 
Atorvastatin will be taken each evening. The capsules can be swallowed. If a dose is 
missed (not taken by midnight of the scheduled day) then the participant will not take an 
extra dose the following day but will just take the regular dose.  
 
8.1.7 Ordering 
 
The agent is commercially available and will be ordered through the MGH and BWH 
pharmacy or the external sites pharmacy.  
 
8.1.8 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.9 Destruction and Return 
 
Unused supplies of atorvastatin will be returned by the patients at each visit and 
destroyed immediately. Expired capsules can be destroyed per DFCI/HCC SOP since 
expiration dates will not be extended. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
We will draw blood before chemotherapy, at 3 cycles and at the end of the study (12 months 
treatment). We will measure biomarkers of cardiac injury, in particular troponin, which we have 
shown to be a predictor of later cardiac dysfunction in women with breast cancer treated with 
anthracyclines, taxanes and trastuzumab and correlate them with measures of cardiac function. 
We have already measured these biomarkers in another population.  
 
9.2 
Laboratory Correlative Studies 
 
Include the following collection/processing details when developing this section: (a) amount and 
type of specimen collected; (b) number, size, and type of tubes or cryovials used for collection; 
and (c) processing instructions. 
 
9.2.1 Troponin – Laboratory Correlative Study #1 
 

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9.2.1.1 
Collection of Specimen(s) 
30 ml of blood will be sampled. 
 
9.2.1.2 
Handling of Specimens(s) 
Blood will be processed within 30 minutes, frozen and stored at -80oC. 
 
9.2.1.3 
Shipping of Specimen(s) 
At regular intervals, the specimens will be shipped to the MGH where they will be stored.  
 
9.2.1.4 
Site(s) Performing Correlative Study 
MGH/DFCI 
 
10. STUDY CALENDAR 
 
After consent is obtained, patients will undergo a baseline visit including a questionnaire, vital 
sign measurements, an MRI, echocardiogram and blood sampling. A pregnancy test (urine beta-
HCG) will be performed as appropriate. A second visit similar to the first one will be scheduled 
after 3 cycles of chemotherapy (approx 3 months). The final study visit will be at 12 months 
where subjects will undergo an echo, MRI and blood sampling.  
 
An additional visit for the sub-group in the MRI mechanistic sub-study will occur at 6 months 
where this sub-group will undergo an additional cardiac MRI. 
 
We will do a balanced randomization with blocks of 2 patients for each cancer site.  
 
Baseline evaluations are to be conducted within 1 week prior to start of anthracyclines therapy.  
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 7 days of the protocol-specified date, unless 
otherwise noted. 
 
 
Pre-
Stud
y 
Stud
y 
Drug 
1 
mont
h 
2 
month
s 
3 
month
s 
6 
month
s 
12 
month
s 
24 
month
s 
Atorvastatin/placeb
o 
 
x-----------------------------------------------------------x  
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Perceived Stress 
Scale 
X 
 
 
 
x 
x 
x 
 
Physical exam 
X 
 
 
 
x 
 
x 
 
Vital signs  
X 
 
x 
 
x 
 
x 
 

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Protocol Version Date: 
 
23 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
x 
x 
 
Phone call: Adverse 
and clinical events 
X 
 
x 
x 
x 
x 
x 
x 
LFTS 
X 
 
x 
 
x 
 
 
 
Lipids/Blood 
biomarkers 
X 
 
 
 
X 
 
X 
 
B-HCG 
X 
 
 
 
 
x 
x 
 
Echocardiogram 
X 
 
 
 
x 
 
x 
 
MRI 
X 
 
 
 
 
x 
x 
 
Pill count 
(Monthly) 
 
 
 
 
 
 
 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Other Response Parameters 
 
The primary outcome measure is LVEF compared between groups. Specifically, we will measure 
the LVEF between baseline and the endpoint of the study (12 months after randomization).  
 
The secondary outcome measures include adverse cardiac events (heart failure requiring 
diuretics, admission for heart failure, or death), strain and biomarkers.  
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The research staff will collect, manage, and perform quality checks on the data for this 
study via REDCAP.  Outside site research staff will be given access to REDCAP after 
approval from OncPro and will have privileges to ensure data capture.   
 
12.1.2 Responsibility for Data Submission 
 
The responsibility will lie on the site staff from DF/HCC, DF/PCC, and external sites to 
submit data and/or data forms as needed into REDCAP 

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12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Randomization process: Within the DF/HCC, randomized comparative studies are conducted in 
a manner such that for a blinded randomization, the individual assigning study treatment is not a 
member of the study team but from the office for the Office of Data Quality (ODQ). Central 
randomization is performed according to an algorithm provided by the statistician. This will be a 
permuted blocks algorithm, with block size of 4. Randomized treatment assignment will be 
delivered to research pharmacy at the site in an unblinded fashion, and pharmacy will dispense 
blinded study drug. ODQ has extensive experience working with both local and distant research 
pharmacies on blinded randomized placebo-controlled studies, and the system is already in place. 
 
Primary End-Point 
 
Our primary endpoint will be the proportion of patients in each group that have a decrease 
of 10% or more in LVEF to <55% from baseline to 12 months after initiation of 
anthracyclines. 
 
Assumptions: We anticipate that 20% of the patients in the placebo group will reach the primary 
end-point. This assumption is based on significant prior literature; specifically, Limat et al. 
performed a prospective study where they enrolled patients similar to those proposed in this 
study (lymphoma receiving anthracycline-based chemotherapy) and performed a baseline 
measurement of LVEF and a measurement at 1 year. Their primary end-point was a more 
stringent cut-off than recommended by guidelines or being used in this study, a decrease of 
>15% in LVEF. They found that 20% of their population had a reduction of >15% in LVEF. 
Using CMR, two studies have tested the percentage of patients with a significant reduction in 
LVEF after anthracyclines. In a prospective observational study, Drafts and colleagues found 

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that 26% of patients decreased their LVEF to <50% and in a prospective randomized study, 
Bosch and colleagues found that up to 33% of patients decreased their LVEF to <55%. In the 
single small randomized study which also used 40 mg of atorvastatin with 20 subjects in each 
arm, there was no decrease in LVEF after anthracyclines among patients on statins. Our base 
case assumptions are as follows: 20% of the placebo group and 5% of the statin treatment group 
will meet the primary endpoint and we will be able to enroll 300 patients meeting all inclusion 
and exclusion criteria. From these, we anticipate a drop-out rate of approximately 10% due to a 
one year mortality of ≈5% and atorvastatin related side-effects in 4% of patients. The remaining 
270 patients will provide us with a 98% power to detect a 15% difference in the proportions of 
those achieving the primary end-point at a one-sided significance level of 0.05. Moreover, we 
will have a 70% power if the difference in the percentage reaching the primary end-point 
between groups falls as low as 10%. 
 
Analysis Plan: The study is designed as a prospective double-blind randomized study. All 
statistical analyses will be performed based on intent-to-treat and repeat imaging will be 
performed at 1 year in all patients. In particular, we will include subjects who could not complete 
the study protocol due to statin toxicity and patients who started anthracyclines but did not 
complete the entire scheduled protocol. Chi-square analysis will be used to determine whether 
statins decrease the primary end-point. 
 
Secondary End-Points Aim 1: 
Aim 1a.We will test whether cardiac risks factors (blood pressure, age, sex, glucose or 
cholesterol levels, prior history of cardiac disease, LVEF at baseline) or cancer specific risk 
factors (anthracycline dose, radiotherapy) are predictive of the effect of statins on LVEF. 
 
Analysis Plan: In patients treated with statins, we will use a logistic regression model to evaluate 
whether cardiac risks factors or cancer specific risk factors are predictive of the effect of statins 
on LVEF. Patients on statins and eligible for statins will be excluded. Therefore, cholesterol 
levels will be relatively homogenous and we will not pre-stratify our cohort based on cholesterol. 
Radiotherapy is not routinely used in the cohort and is used in <5% of cases, there we will also 
not pre-stratify based on the use of radiotherapy. However, we will use cholesterol values (as a 
continuous variable) and the use of radiotherapy (as a binary variable) to perform a post-hoc 
analysis. Additionally, all patients are intended to have the same dose of anthracyclines and dose 
adjustments are made during therapy in response primarily to toxicities. Therefore, we will 
additionally test the interaction between the dose of anthracyclines and the effect of statins as a 
post-hoc analysis. 
 
Aim 1b. We will test whether statins reduce cardiac events. 
 
Adjudication plan: The occurrence of clinical adverse cardiac events will be adjudicated based 
on consensus opinion of a clinical adjudication committee containing three board-certified 
cardiologists blinded to experimental group (Drs. Francis, Scherrer-Crosbie and Neilan). 
 
Analysis Plan: All statistical analyses will be performed based on intent-to-treat. Fisher exact 
tests will be used to determine whether statins decrease the combined end-point of death or heart 
failure. 

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26 
 
Aim 1c. We will test whether statins are safe. 
 
Analysis Plan: Chi-square will be used to test for differences between the two treatment groups 
for categorical secondary endpoints. 
 
Specific Aim 2:  
Determine the effect of statins on myocardial fibrosis. In a sub-study of 80 patients from Aim 
1 (n=40 in each arm), we will measure myocardial fibrosis by calculation of the myocardial 
extracellular volume (ECV) using CMR, as previously described, at baseline and 6 months to 
determine:  
c. Whether statins prevent the anthracycline-induced increase in myocardial fibrosis at 6 months 
as compared to placebo. 
d. Whether a change in fibrosis or LVEF at 6 months predicts the occurrence of AIC at 12 
months. 
 
Statistical Analysis 
Aim 2a. Assumptions: In our retrospective clinical study the ECV in healthy age-matched 
volunteers was 0.28 and was 0.04 lower than in patients treated previously with anthracyclines 
(0.32, mean difference and SD: 0.04±0.05). Based on these data, with 80 patients (40 from each 
treatment group) we will have 94% power to detect a treatment difference with a two-sided 0.05 
significance level. If the actual difference in the ECV between groups is only 0.03 with a SD of 
0.05, then we will still have a 75% power to detect a difference between the groups. We are 
assuming a 10% drop-out for participants in Aim 1. If we assume the same dropout rate for Aim 
2, then our final sample size will be 36 per group. A final sample size of 72 will have a 92% 
power to detect a treatment difference between the means. Analysis Plan: The ECV is a unit-less 
continuous variable. The change in ECV levels from baseline to 6 months will be compared 
between the statin- and placebo treated groups using a Student t test. 
 
Aim 2b. Analysis plan: The predictive value of the change in ECV between 0 and 6 months for 
the occurrence of the primary end-point of Aim 1 (a reduction in LVEF of ≥10% to less than 
55% at 12 months) will be determined using a logistic regression model. 
 
Specific Aim 3:  
Early clinical identification of patients at high risk of AIC. We will determine whether an 
early decrease in myocardial strain or an increase in high-sensitivity troponin during 
anthracyclines (after 4 of 8 standard cycles (≈ 3 months)) can predict subsequent development of 
AIC at 12 months. We will test:  
d. Whether statins, as compared to placebo, prevent the reduction in strain or the increase in 
troponin throughout the study period (12 months). 
e. Whether a change in troponin, strain, or both at 3 months predicts AIC at 12 months. 
f. Whether a change in troponin, strain, or both at 3 months predicts fibrosis detected by 
ECV at 6 months. 
 
Statistical Analysis: 

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Aim 3a. Assumptions: Based on existing literature and our prior data, our assumption is that the 
decrease in strain after 4 cycles of chemotherapy (≈200mg/m2 dose) in the placebo group will be 
9±10%. 
Sample Size and Power: with a type I error of 0.05, a sample of 270 patients will have a power 
of 0.99 to detect a statin effect if there is no change in strain in the statin group and a power of 
0.96 if the decrease in strain in the statin group is 50% less than that of the placebo group (9% in 
the placebo group and 4.5% in the statin group). Analysis Plan: We will first characterize the 
distribution and time course of strain and troponin in patients who do or do not reach the primary 
outcome (significant change in LVEF at 12 months on CMR as defined in Aim 1) using 
descriptive statistics. As troponin levels at baseline, 4 cycles and their changes do not follow 
normal distributions, they will be log transformed. To study the effect of statins on the time rends 
of strain and troponin, we will use a mixed-design ANOVA model to test for differences 
between the groups while incorporating repeated strain and troponin measurements at 0, 4 cycles 
and 12 months. 
 
Aim 3b. Analysis Plan: The predictive value of the change in strain and/or troponin after 4 
cycles for a significant change in LVEF on CMR at 12 months (primary endpoint of Aim 1) will 
be explored using a mixed design ANOVA model. A multivariable logistic regression model will 
then be applied, entering strain and troponin as variables. The model may be adjusted for 
additional key variables such as clinical univariate predictors and change in echocardiographic 
LVEF. 
 
Aim 3c. Analysis Plan: The predictive value of the change in strain and/or troponin after 4 
cycles for the change of fibrosis (assessed by ECV) at 6 months will be explored using a mixed-
design ANOVA model. The model may be adjusted for additional key variables such as clinical 
univariate predictors and change in LVEF. 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
Feasibility: In 2012, there were 412 patients with lymphoma treated with anthracyclines at 
MGH, DFCI and BWH (110 at MGH and 312 at DFCI and BWH). In the large cohort of 
lymphoma patients that we reported in our preliminary data, only 8% of patients (n=33) were on 
statins at the time of chemotherapy and would be excluded. Even using the new more expansive 
cholesterol guidelines 57 and assuming that all the patients who were eligible to receive statins 
were treated with statins, more than 80% of patients (n=330) would be eligible for enrollment 
annually. In aggregate, less than 30 of the remaining 330 patients would be excluded based on 
these criteria and this would leave a final total of 300 patients with lymphoma per year that 
would meet entry criteria and not meet exclusion criteria. Based on prior trials recruited by this 
group,51, 53, 54, 58, 59 we anticipate enrollment of  33% of eligible patients (≈100 per year, 8 per 
month); 5-6 patients per month will be enrolled from DFCI/BWH and 2-3 patients per month 
from the MGH. We expect a total of about 3 years to complete enrollment.   
 
In total 300 patients need to be enrolled.   
 
Accrual Targets 

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Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
25 
+ 26 
= 51 
Not Hispanic or Latino 
125 
+ 124 
= 249 
Ethnic Category: Total of all 
subjects 
150 
(A1) + 150 
= 300 
Racial Category 
 
American Indian or Alaskan 
Native 
0 
+ 0 
= 0 
Asian 
16 
+ 15 
= 31 
Black or African American 
14 
+ 13 
= 27 
Native Hawaiian or other Pacific 
Islander 
0 
+ 0 
= 0 
White 
115 
+ 117 
= 232 
Racial Category: Total of all 
subjects 
150(A2) 
+ 150 
(B2) = 300 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
13.3 
Interim Monitoring Plan 
 
See section 6 
 
13.4 
Analysis of Primary Endpoints 
 
See section 13.1  
 
13.5 
Analysis of Secondary Endpoints 
 
See section 13.1  
 
13.6 
Reporting and Exclusions 
 
Participants who never start protocol therapy will be excluded (“inevaluable”) from the analysis.  
 
13.6.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.6.2 Evaluation of the Primary Efficacy Endpoint 
 
Analyses are intent-to-treat. Specifically, all eligible participants included in the study 
must be assessed for response/outcome to therapy, even if there are major protocol 

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therapy deviations.   
 
Sub-analyses may then be performed on the basis of a subset of participants, excluding 
those for whom major protocol deviations have been identified (e.g., early death due to 
other reasons, early discontinuation of treatment, major protocol violations, etc.).  
However, these sub-analyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding participants from the 
analysis should be clearly reported.  
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
 

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